Search (insulin receptor OR insr OR cd220 antigen) AND (cancer OR tumors OR neoplasm* OR metasta*) AND signal* Limits: Publication Date from 1994/01/01 to 2003/12/31 (Only first 100 judged.) Entrez pubmed Results Items 1 - 304 of 304 1: Dontenwill M et al. IRAS is an anti-apoptotic pro...[PMID: 15028619] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 15028619 OWN - NLM STAT- MEDLINE DA - 20040318 DCOM- 20040426 LR - 20041117 PUBM- Print IS - 0077-8923 VI - 1009 DP - 2003 Dec TI - IRAS is an anti-apoptotic protein. PG - 400-12 AB - Active cell death, also known as apoptosis, has been implicated in the pathophysiology of diseases such as cancer, heart failure and neurodegenerative disorders. We report the anti-apoptotic function of IRAS, which was previously shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS) is unrelated to known proteins, except for rat IRAS and a mouse homologue named nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor. When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167 kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed normal serum growth responses. However, hIRAS expression led to prolonged cell survival against known apoptotic stimuli: serum starvation or thapsigargin or staurosporine treatments. The apoptotic population of hIRAS-expressing cells was significantly reduced, and this protection was achieved by a decrease in caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar protective effect was obtained in COS7 cells transiently transfected with hIRAS. A partial activation of the PI3 kinase pathway is possibly implicated in the anti-apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown anti-apoptotic protein involved in the regulation of cell survival. AD - Pharmacologie et Physicochimie des Interactions Cellulaires et Moleculaires, UMR CNRS 7034, Faculte de Pharmacie, Universite Louis Pasteur de Strasbourg, Illkirch, France. mdontenwill@aspirine.u-strasbg.fr FAU - Dontenwill, Monique AU - Dontenwill M FAU - Piletz, John E AU - Piletz JE FAU - Chen, Michael AU - Chen M FAU - Baldwin, James AU - Baldwin J FAU - Pascal, Geraldine AU - Pascal G FAU - Ronde, Philippe AU - Ronde P FAU - Dupuy, Laurence AU - Dupuy L FAU - Greney, Hugues AU - Greney H FAU - Takeda, Ken AU - Takeda K FAU - Bousquetd, Pascal AU - Bousquetd P LA - eng GR - MH49248/MH/NIMH PT - Journal Article PL - United States TA - Ann N Y Acad Sci JID - 7506858 RN - 0 (Carrier Proteins) RN - 0 (Chromones) RN - 0 (Culture Media, Serum-Free) RN - 0 (Enzyme Inhibitors) RN - 0 (Integrin alpha5beta1) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Morpholines) RN - 0 (NISCH protein, human) RN - 0 (Receptors, Drug) RN - 0 (imidazoline receptors) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 62996-74-1 (Staurosporine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.4.22.- (Caspases) RN - EC 3.4.22.- (caspase-3) SB - IM MH - Animals MH - Apoptosis/*physiology MH - COS Cells MH - Carrier Proteins/genetics/metabolism/*physiology MH - Caspases/metabolism MH - Cell Division/physiology MH - Cell Nucleus/metabolism MH - Chromones/metabolism MH - Culture Media, Serum-Free MH - Enzyme Inhibitors/metabolism MH - Humans MH - Integrin alpha5beta1/metabolism MH - *Intracellular Signaling Peptides and Proteins MH - Mice MH - Morpholines/metabolism MH - PC12 Cells MH - Rats MH - Receptor, Insulin/metabolism MH - Receptors, Drug/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/physiology MH - Staurosporine/metabolism EDAT- 2004/03/19 05:00 MHDA- 2004/04/27 05:00 PST - ppublish SO - Ann N Y Acad Sci 2003 Dec;1009:400-12. NR -------------------------------------------------------------------------------- 2: Oh YS et al. Conjugated linoleic acid inhi...[PMID: 14981924] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14981924 OWN - NLM STAT- MEDLINE DA - 20040225 DCOM- 20040401 LR - 20041117 PUBM- Print IS - 0250-7005 VI - 23 IP - 6C DP - 2003 Nov-Dec TI - Conjugated linoleic acid inhibits DNA synthesis and induces apoptosis in TSU-Pr1 human bladder cancer cells. PG - 4765-72 AB - BACKGROUND: Conjugated linoleic acid (CLA) has strong chemoprotective properties in experimental animal models. The insulin-like growth factor (IGF) system has been implicated as a risk factor for the development of bladder cancer. The present study examined CLA regulation of TSU-Pr1 bladder cancer cell proliferation and apoptosis and the influence of CLA on IGF-I receptor (IGF-IR) signaling. MATERIALS AND METHODS: TSU-Pr1 cells were cultured in serum-free medium with 0, 2, 5, or 10 microM CLA and/or 10 nM IGF-I. [3H]Thymidne incorporation, DNA laddering, FACS analysis, immunoprecipitation and Western blotting were performed. RESULTS: CLA decreased DNA synthesis and induced apoptosis in TSU-Pr1 cells dose-dependently. Exogenous IGF-I alone increased viable cell numbers but did not counteract growth inhibition induced by CLA. CLA decreased IGF-IR and insulin receptor substrate (IRS)-1 protein levels. In addition, CLA decreased IGF-I-induced phosphorylation of IGF-IR and IRS-1, recruitment of the p85 subunit of phosphoinositide 3-kinase to IRS-1 and phosphorylation of Akt and extracellular signal-regulated kinase-1/2. CONCLUSION: These results suggest that CLA inhibits cell proliferation and stimulates apoptosis of TSU-Pr1 cells via its inhibition of the IGF-IR signaling pathway. AD - Division of Life Sciences, Hallym University, 1 Okchon Dong, Chunchon, 200-702, Korea. FAU - Oh, Yoon S AU - Oh YS FAU - Lee, Hyun S AU - Lee HS FAU - Cho, Han J AU - Cho HJ FAU - Lee, Sang G AU - Lee SG FAU - Jung, Kyeong C AU - Jung KC FAU - Park, Jung H AU - Park JH LA - eng PT - Journal Article PL - Greece TA - Anticancer Res JID - 8102988 RN - 0 (Culture Media, Serum-Free) RN - 0 (DNA, Neoplasm) RN - 0 (Linoleic Acids, Conjugated) RN - 0 (RNA, Messenger) RN - 50-89-5 (Thymidine) SB - IM MH - Apoptosis/*drug effects MH - Bladder Neoplasms MH - Cell Death/drug effects MH - Culture Media, Serum-Free MH - DNA Replication/drug effects/genetics MH - DNA, Neoplasm/antagonists & inhibitors/*biosynthesis MH - Humans MH - Linoleic Acids, Conjugated/*pharmacology MH - RNA, Messenger/genetics MH - Research Support, Non-U.S. Gov't MH - Thymidine/metabolism MH - Transcription, Genetic/drug effects MH - Tumor Cells, Cultured EDAT- 2004/02/26 05:00 MHDA- 2004/04/02 05:00 PST - ppublish SO - Anticancer Res 2003 Nov-Dec;23(6C):4765-72. DR -------------------------------------------------------------------------------- 3: Gray SG et al. The insulin-like growth facto...[PMID: 14710369] Related Articles, Substance via MeSH, Books, LinkOut PMID- 14710369 OWN - NLM STAT- MEDLINE DA - 20040107 DCOM- 20040816 LR - 20041117 PUBM- Print IS - 0018-5043 VI - 35 IP - 11-12 DP - 2003 Nov-Dec TI - The insulin-like growth factors and insulin-signalling systems: an appealing target for breast cancer therapy? PG - 857-71 AB - There is compelling evidence from epidemiological studies in humans, as well as in vitro and in vivo experimental observations including transgenic animal models, for a role of the IGF/insulin signalling system in cancer tumourigenesis. In this review focused on breast cancer, we review the experimental evidence, discuss the cellular and molecular mechanisms of tumourigenicity by the IGFs and insulin and various possible therapeutic strategies based on the mechanisms discussed. AD - Receptor Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark. stvg@novonordisk.com FAU - Gray, S G AU - Gray SG FAU - Stenfeldt Mathiasen, I AU - Stenfeldt Mathiasen I FAU - De Meyts, P AU - De Meyts P LA - eng PT - Journal Article PT - Review PL - Germany TA - Horm Metab Res JID - 0177722 RN - 0 (Somatomedins) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM EIN - Horm Metab Res. 2004 Jan;36(1):74 MH - Animals MH - Animals, Genetically Modified MH - Breast Neoplasms/genetics/pathology/*therapy MH - Female MH - Humans MH - Insulin/immunology/*physiology MH - Mutation MH - Oncogenes MH - Receptor, Insulin/genetics/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*physiology MH - Somatomedins/immunology/*physiology RF - 100 EDAT- 2004/01/08 05:00 MHDA- 2004/08/18 05:00 AID - 10.1055/s-2004-814142 [doi] PST - ppublish SO - Horm Metab Res 2003 Nov-Dec;35(11-12):857-71. DR -------------------------------------------------------------------------------- 4: Salisbury AJ et al. Development of molecular agen...[PMID: 14710367] Related Articles, Books, LinkOut PMID- 14710367 OWN - NLM STAT- MEDLINE DA - 20040107 DCOM- 20040816 LR - 20041117 PUBM- Print IS - 0018-5043 VI - 35 IP - 11-12 DP - 2003 Nov-Dec TI - Development of molecular agents for IGF receptor targeting. PG - 843-9 AB - The type 1 insulin-like growth factor receptor (IGF1R) is a promising anticancer treatment target, being frequently overexpressed by tumours, and mediating proliferation, motility and apoptosis protection. Design of specific kinase inhibitors is problematic because of homology between the IGF1R and insulin receptor. This obstacle can be circumvented using sequence-specific molecular agents including antisense, triplex and ribozymes. Recent studies indicate that profound sequence-specific IGF1R gene silencing can be induced by small interfering RNAs that mediate RNA interference in mammalian cells. IGF1R downregulation blocks tumour growth and metastasis, and enhances sensitivity to cytotoxic drugs and irradiation. In murine melanoma cells, radiosensitisation is associated with impaired activation of Atm, which is required for initiation of cell cycle checkpoints and DNA repair pathways after double-strand DNA breaks. Furthermore, tumour cells killed in vivo following IGF1R downregulation can provoke an immune response, protecting against tumour rechallenge. After years of studying the role of the IGF system in tumour biology, novel agents for IGF1R targeting will soon be available for clinical testing. This review summarises the development of molecular agents, and considers factors that will influence clinical activity, including the requirement of established tumours for IGF signalling, and the efficacy and toxicity of IGF1R inhibitors. AD - Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS UK. FAU - Salisbury, A J AU - Salisbury AJ FAU - Macaulay, V M AU - Macaulay VM LA - eng PT - Journal Article PT - Review PL - Germany TA - Horm Metab Res JID - 0177722 RN - 0 (Antineoplastic Agents) RN - 0 (RNA, Small Interfering) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - *Antineoplastic Agents MH - Gene Expression Regulation/drug effects/*genetics MH - Humans MH - Neoplasms/*drug therapy MH - RNA, Small Interfering MH - Receptor, IGF Type 1/*antagonists & inhibitors/genetics RF - 102 EDAT- 2004/01/08 05:00 MHDA- 2004/08/18 05:00 AID - 10.1055/s-2004-814158 [doi] PST - ppublish SO - Horm Metab Res 2003 Nov-Dec;35(11-12):843-9. DR -------------------------------------------------------------------------------- 5: Modha G et al. Inducible expression of domin...[PMID: 14709803] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14709803 OWN - NLM STAT- MEDLINE DA - 20040107 DCOM- 20040826 LR - 20041117 PUBM- Print IS - 0969-711X VI - 22 IP - 3 DP - 2003 Dec TI - Inducible expression of dominant negative insulin-like growth factor I receptor in MCF-7 breast cancer cells. PG - 293-303 AB - The insulin-like growth factor I receptor (IGF-IR) is expressed in many cell types and is critical for normal growth and development. In the healthy mammary gland, the role of IGF-IR is not fully elucidated. However, IGF-IR, which is primarily expressed in the mammary epithelial cells, is known to play an obligatory role in cellular transformation, facilitating the progression to breast cancer. We have utilized the tetracycline regulatory (tet-on) system to generate an in vitro model system to allow us to further investigate IGF-I/IGF-IR function in mammary epithelial cells. A plasmid construct containing a mutant IGF-I receptor (IGF-IR-DN) fused to the tetracycline operator (tetOPh(CMV)-IGF-IR-DN) was stably transfected into MCF-7 human breast cancer cells. The conditional regulation of the IGF-IR-DN gene expression was studied in four independent clonal lines. The translated IGF-IR-DN protein was detected only in the stably transfected doxycycline- induced cells, and its expression was up-regulated (three- to sixfold) following induction. IGF-I stimulated cell proliferation diminished (twofold) in doxycycline- induced cells compared to uninduced cells, demonstrating that the transgene construct was functional and ruling out any pleiotropic effect that may be attributed to doxycycline. Interestingly, autophosphorylation of the IGF-IR and phosphorylation of the downstream substrate, insulin receptor substrate-1 (IRS-1), was not inhibited in doxycycline/IGF-I treated cells, suggesting the possibility that activation of downstream substrates other than the IRS-1 may be critical for optimal cell proliferation. This novel in vitro model should allow us to more directly examine the role of IGF-I/IGF-IR signaling and function in mammary epithelial cells. AD - Department of Pathology, University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba, Canada. FAU - Modha, Geetanjalee AU - Modha G FAU - Blanchard, Anne AU - Blanchard A FAU - Sidorchuk, Janine AU - Sidorchuk J FAU - Venditti, Marcello AU - Venditti M FAU - Shiu, Robert AU - Shiu R FAU - Myal, Yvonne AU - Myal Y LA - eng PT - Journal Article PL - United States TA - Endocrine JID - 9434444 RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-1 protein) RN - 564-25-0 (Doxycycline) RN - 60-54-8 (Tetracycline) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Blotting, Northern MH - Breast Neoplasms/*genetics/*metabolism MH - Cell Division MH - Cell Line, Tumor MH - Doxycycline/pharmacology MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Insulin-Like Growth Factor I/metabolism MH - Mutation MH - Phosphoproteins/metabolism MH - Phosphorylation MH - RNA, Messenger/biosynthesis/genetics MH - Receptor, IGF Type 1/*biosynthesis/*genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Tetracycline/pharmacology MH - Transfection MH - Transgenes EDAT- 2004/01/08 05:00 MHDA- 2004/08/27 05:00 PHST- 2003/08/19 [received] PHST- 2003/10/07 [revised] PHST- 2003/10/23 [accepted] AID - ENDO:22:3:293 [pii] PST - ppublish SO - Endocrine 2003 Dec;22(3):293-303. DR -------------------------------------------------------------------------------- 6: Burtrum D et al. A fully human monoclonal anti...[PMID: 14695208] Related Articles, Substance via MeSH, Books, LinkOut PMID- 14695208 OWN - NLM STAT- MEDLINE DA - 20031225 DCOM- 20040311 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 63 IP - 24 DP - 2003 Dec 15 TI - A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. PG - 8912-21 AB - The insulin-like growth factor I receptor (IGF-IR) is overexpressed in many diverse tumor types and is a critical signaling molecule for tumor cell proliferation and survival. Therapeutic strategies targeting the IGF-IR may therefore be effective broad-spectrum anticancer agents. Through screening of a Fab phage display library, we have generated a fully human antibody (A12) that binds to the IGF-IR with high affinity (4.11 x 10(-11) M) and inhibits ligand binding with an IC(50) of 0.6-1 nM. Antibody-mediated blockade of ligand binding to the IGF-IR inhibited downstream signaling of the two major insulin-like growth factor (IGF) pathways, mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/Akt, in MCF7 human breast cancer cells. As a result, the mitogenic and proliferative potential of IGF-I and IGF-II were significantly reduced. A12 did not block insulin binding to the insulin receptor but could block binding to atypical IGF-IR in MCF7 cells. In addition, A12 was shown to induce IGF-IR internalization and degradation on specific binding to tumor cells, resulting in a significant reduction in cell surface receptor density. In xenograft tumor models in vivo, IGF-IR blockade by A12 was shown to occur rapidly, resulting in significant growth inhibition of breast, renal, and pancreatic tumors. Histological analysis of tumor sections demonstrated a marked increase in apoptotic tumor cells in antibody-treated animals. These results demonstrate that A12 possesses strong antitumor activity in vitro and in vivo and may therefore be an effective therapeutic candidate for the treatment of cancers that are dependent on IGF-IR signaling for growth and survival. AD - ImClone Systems Incorporated, New York, New York 10014, USA. FAU - Burtrum, Douglas AU - Burtrum D FAU - Zhu, Zhenping AU - Zhu Z FAU - Lu, Dan AU - Lu D FAU - Anderson, Donna Marie AU - Anderson DM FAU - Prewett, Marie AU - Prewett M FAU - Pereira, Daniel S AU - Pereira DS FAU - Bassi, Rajiv AU - Bassi R FAU - Abdullah, Rashed AU - Abdullah R FAU - Hooper, Andrea T AU - Hooper AT FAU - Koo, Henry AU - Koo H FAU - Jimenez, Xenia AU - Jimenez X FAU - Johnson, Danielle AU - Johnson D FAU - Apblett, Robin AU - Apblett R FAU - Kussie, Paul AU - Kussie P FAU - Bohlen, Peter AU - Bohlen P FAU - Witte, Larry AU - Witte L FAU - Hicklin, Daniel J AU - Hicklin DJ FAU - Ludwig, Dale L AU - Ludwig DL LA - eng PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Antibodies, Monoclonal) RN - 0 (Ligands) RN - 0 (Peptide Library) RN - 0 (Recombinant Proteins) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - Antibodies, Monoclonal/*pharmacology MH - Antibody Specificity MH - Breast Neoplasms/therapy MH - Cell Division/drug effects MH - Female MH - Humans MH - Insulin-Like Growth Factor I/antagonists & inhibitors/metabolism MH - Ligands MH - Mice MH - Mice, Nude MH - Peptide Library MH - Phosphorylation MH - Receptor, IGF Type 1/*antagonists & inhibitors/immunology/metabolism MH - Recombinant Proteins/pharmacology MH - Signal Transduction/drug effects MH - Xenograft Model Antitumor Assays EDAT- 2003/12/26 05:00 MHDA- 2004/03/12 05:00 PST - ppublish SO - Cancer Res 2003 Dec 15;63(24):8912-21. DR -------------------------------------------------------------------------------- 7: Finlayson CA et al. Enhanced insulin signaling vi...[PMID: 14669164] Related Articles, Substance via MeSH, Books, LinkOut PMID- 14669164 OWN - NLM STAT- MEDLINE DA - 20031211 DCOM- 20040206 LR - 20050111 PUBM- Print IS - 0026-0495 VI - 52 IP - 12 DP - 2003 Dec TI - Enhanced insulin signaling via Shc in human breast cancer. PG - 1606-11 AB - Insulin is a mild mitogen and has been shown to potentiate mitogenic influence of other growth factors. Because hyperinsulinemia and/or overexpression of insulin receptors have been linked to development, progression, and outcome of breast cancer, we attempted to evaluate the mechanism of these associations. We have compared the expression of insulin receptors and the magnitude of insulin signaling in breast tumors and adjacent normal mammary tissue samples obtained from 20 patients. We observed that insulin binding more than doubled in the tumors as compared with the normal tissue (P <.01 by paired t test). Insulin signaling to Shc, judged by the magnitude of its phosphorylation, was also significantly enhanced in the tumors. In contrast, the phosphorylation of the insulin-receptor substrate-1 (IRS-1), Akt, and mitogen-activated protein (MAP) kinase were identical in the tumorous and normal mammary tissues. Finally, tumors displayed significantly increased amounts of farnesylated p21 Ras and geranylgeranylated Rho-A (P <.01), consistent with Shc-dependent activation of farnesyl (FTase) and geranylgeranyl transferases (GGTase) in the tumor tissue. We conclude that the mechanism of the mitogenic influence of insulin in breast cancer may include increased expression of insulin receptors, preferential hyperphosphorylation of Shc, and increased amounts of prenylated p21 Ras and Rho-A in tumor tissue as compared with adjacent normal mammary tissue. AD - Department of Surgery, University of Colorado Health Sciences Center, Denver, USA. FAU - Finlayson, Christina A AU - Finlayson CA FAU - Chappell, James AU - Chappell J FAU - Leitner, J Wayne AU - Leitner JW FAU - Goalstone, Marc L AU - Goalstone ML FAU - Garrity, Maureen AU - Garrity M FAU - Nawaz, Samia AU - Nawaz S FAU - Ciaraldi, Theodore P AU - Ciaraldi TP FAU - Draznin, Boris AU - Draznin B LA - eng PT - Journal Article PL - United States TA - Metabolism JID - 0375267 RN - 0 (Phosphoproteins) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, Progesterone) RN - 0 (Retroviridae Proteins, Oncogenic) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (oncogene protein v-akt) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 3.6.1.- (Proto-Oncogene Protein p21(ras)) RN - EC 3.6.1.- (rhoA GTP-Binding Protein) SB - IM MH - Adult MH - Aged MH - Breast/metabolism/surgery MH - Breast Neoplasms/*physiopathology/surgery MH - Female MH - Humans MH - Insulin/*physiology MH - Middle Aged MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Prospective Studies MH - Proto-Oncogene Protein p21(ras)/metabolism MH - Receptor, Insulin/physiology MH - Receptors, Estrogen/metabolism MH - Receptors, Progesterone/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Retroviridae Proteins, Oncogenic/metabolism MH - Signal Transduction/*physiology MH - rhoA GTP-Binding Protein/metabolism MH - src Homology Domains/*physiology EDAT- 2003/12/12 05:00 MHDA- 2004/02/10 05:00 AID - S0026049503003111 [pii] PST - ppublish SO - Metabolism 2003 Dec;52(12):1606-11. DR -------------------------------------------------------------------------------- 8: Lannon CL et al. A highly conserved NTRK3 C-te...[PMID: 14668342] Related Articles, Gene, GENSAT, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 14668342 OWN - NLM STAT- MEDLINE DA - 20040217 DCOM- 20040430 LR - 20050610 PUBM- Print-Electronic IS - 0021-9258 VI - 279 IP - 8 DP - 2004 Feb 20 TI - A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation. PG - 6225-34 AB - Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3. The EN protein functions as a constitutively active protein-tyrosine kinase with potent transforming activity in multiple cell lineages, and EN constitutively activates both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways. EN transformation is associated with constitutive tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Further, IRS-1 functions as the adaptor protein linking EN to downstream signaling pathways. However, the exact nature of the EN-IRS-1 interaction remains unknown. We now demonstrate that EN specifically binds the phosphotyrosine binding domain of IRS-1 via an interaction at the C terminus of EN. An EN mutant lacking the C-terminal 19 amino acids does not bind IRS-1 and lacks transforming ability. Moreover, expression of an IRS-1 polypeptide containing the phosphotyrosine binding domain acts in a dominant negative manner to inhibit EN transformation, and overexpression of IRS-1 potentiates EN transforming activity. These findings indicate that EN.IRS-1 complex formation through the NTRK3 C terminus is essential for EN transformation. AD - Department of Pathology, British Columbia Research Institute for Children's and Women's Health and the University of British Columbia, Vancouver, British Columbia V5Z4H4, Canada. FAU - Lannon, Chris L AU - Lannon CL FAU - Martin, Matthew J AU - Martin MJ FAU - Tognon, Cristina E AU - Tognon CE FAU - Jin, Wook AU - Jin W FAU - Kim, Seong-Jin AU - Kim SJ FAU - Sorensen, Poul H B AU - Sorensen PH LA - eng PT - Journal Article DEP - 20031209 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (DNA, Complementary) RN - 0 (DNA-Binding Proteins) RN - 0 (ETS translocation variant 6 protein) RN - 0 (ETV6-NTRK3 fusion protein, human) RN - 0 (Genetic Vectors) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Phosphoproteins) RN - 0 (Repressor Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 9002-18-0 (Agar) RN - EC 2.7.1.112 (Receptor, trkC) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Agar/pharmacology MH - Amino Acid Sequence MH - Animals MH - Binding Sites MH - Cell Differentiation MH - Cell Line MH - Cell Line, Tumor MH - Cell Survival MH - Cell Transformation, Neoplastic MH - Conserved Sequence MH - DNA, Complementary/metabolism MH - DNA-Binding Proteins/*chemistry MH - Enzyme Activation MH - Fibroblasts/metabolism MH - Genes, Dominant MH - Genetic Vectors MH - Humans MH - Mice MH - Mice, Nude MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - NIH 3T3 Cells MH - Neurons/metabolism MH - Oncogene Proteins, Fusion/*chemistry/metabolism MH - Phosphoproteins/*chemistry/metabolism MH - Phosphotyrosine/chemistry MH - Protein Binding MH - Protein Structure, Tertiary MH - Receptor, trkC/*chemistry MH - Repressor Proteins/*chemistry MH - Research Support, Non-U.S. Gov't MH - Retroviridae/genetics MH - Sequence Homology, Amino Acid MH - Signal Transduction MH - Time Factors MH - Tyrosine/chemistry/metabolism EDAT- 2003/12/12 05:00 MHDA- 2004/05/01 05:00 PHST- 2003/12/09 [aheadofprint] AID - 10.1074/jbc.M307388200 [doi] AID - M307388200 [pii] PST - ppublish SO - J Biol Chem 2004 Feb 20;279(8):6225-34. Epub 2003 Dec 9. NR -------------------------------------------------------------------------------- 9: Weber A et al. Coexpression of insulin recep...[PMID: 14654552] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 14654552 OWN - NLM STAT- MEDLINE DA - 20031205 DCOM- 20040817 LR - 20041117 PUBM- Print IS - 1078-0432 VI - 9 IP - 15 DP - 2003 Nov 15 TI - Coexpression of insulin receptor-related receptor and insulin-like growth factor 1 receptor correlates with enhanced apoptosis and dedifferentiation in human neuroblastomas. PG - 5683-92 AB - PURPOSE: We compared the expression of the insulin receptor-related receptor (IRR) in primary human neuroblastomas with other biological and clinical parameters and the impact of its expression on prognostic outcome. EXPERIMENTAL DESIGN: We studied 49 neuroblastomas of different clinical stages and histological subtypes for (a) IRR, insulin-like growth factor 1 receptor (IGF-1R), TrkA, p75 neurotrophin receptor, and MYCN mRNA expression by reverse transcription-PCR; (b) MYCN gene amplification by Southern blot analyses; (c) cyclin A protein expression by Western blot analyses indicating proliferation rate; and (d) apoptotic index (AI) by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end-labeling assay. RESULTS: IRR mRNA expression was found in 25 (51%) neuroblastomas and correlated with stages 1, 2, 3, and 4S disease and with age 60 micro mol/L. Genistein and kaempferol potently induced G(2)/M cell cycle arrest. Genistein, quercetin, kaempferol and biochanin A, but not daidzein and rutin, counteracted the antiapoptotic effects of IGF-I. Human prostate epithelial cells grown in growth factor-supplemented medium were also sensitive to growth inhibition by polyphenols. Genistein, biochanin A, quercetin and kaempferol reduced the insulin receptor substrate-1 (IRS-1) content of AT6.3 cells and prevented the down-regulation of IGF-I receptor beta in response to IGF-I binding. IGF-I-stimulated proliferation was dependent on activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and phosphatidylinositide 3-kinase pathways. Western blotting demonstrated that ERK1/2 was constitutively phosphorylated in AT6.3 cells with no change in response to IGF-I, whereas IRS-1 and AKT were rapidly and sensitively phosphorylated after IGF-I stimulation. Several polyphenols suppressed phosphorylation of AKT and ERK1/2, and more potently inhibited IRS-1 tyrosyl phosphorylation after IGF-I exposure. In summary, polyphenols from soy and tomato products may counteract the ability of IGF-I to stimulate proliferation and prevent apoptosis via inhibition of multiple intracellular signaling pathways involving tyrosine kinase activity. AD - Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA. FAU - Wang, Shihua AU - Wang S FAU - DeGroff, Valerie L AU - DeGroff VL FAU - Clinton, Steven K AU - Clinton SK LA - eng GR - P30 CA16058/CA/NCI GR - R01CA72482-03/CA/NCI PT - Journal Article PL - United States TA - J Nutr JID - 0404243 RN - 0 (Flavonoids) RN - 0 (Phenols) RN - 0 (Phosphoproteins) RN - 0 (Polymers) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (polyphenols) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Blotting, Western MH - Cell Cycle/drug effects MH - Cell Division/*drug effects MH - *Flavonoids MH - Flow Cytometry MH - Insulin-Like Growth Factor I/*pharmacology MH - Lycopersicon esculentum/*chemistry MH - Male MH - Phenols/*pharmacology MH - Phosphoproteins/metabolism MH - Polymers/*pharmacology MH - Prostatic Neoplasms/enzymology/metabolism/*pathology MH - Protein-Tyrosine Kinase/*antagonists & inhibitors MH - Rats MH - Receptor, IGF Type 1/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*drug effects MH - Soybeans/*chemistry EDAT- 2003/07/04 05:00 MHDA- 2003/08/26 05:00 PST - ppublish SO - J Nutr 2003 Jul;133(7):2367-76. NR -------------------------------------------------------------------------------- 30: Morelli C et al. Estrogen receptor-alpha regul...[PMID: 12821935] Related Articles, Gene, HomoloGene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12821935 OWN - NLM STAT- MEDLINE DA - 20030624 DCOM- 20030718 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 22 IP - 26 DP - 2003 Jun 26 TI - Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. PG - 4007-16 AB - In breast cancer cells, 17-beta-estradiol (E2) upregulates the expression of insulin receptor substrate 1 (IRS-1), a molecule transmitting insulin-like growth factor-I (IGF-I) signals through the PI-3K/Akt survival pathways. The stimulation of IRS-1 by E2 has been documented on the transcriptional level. Here we studied whether the expression of estrogen receptor (ER)-alpha affects IRS molecules post-transcriptionally. We used ER-alpha-negative MDA-MB-231 breast cancer cells and MDA-MB-231 cells with re-expressed ER-alpha. In MDA-MB-231 cells cultured under serum-free conditions, IRS-1 and IRS-2 were degraded through the 26S proteasome and calpain pathways. Re-expression of ER-alpha in MDA-MB-231 cells correlated with enhanced stability of IRS molecules. This effect coincided with significantly reduced ubiquitination of IRS-1 and IRS-2, but did not involve increased IRS-1 and IRS-2 transcription. The interference of ER-alpha with IRS-1 and IRS-2 turnover could rely on the competition for common degradation pathways, as in MDA-MB-231/ER cells, ER-alpha processing was blocked by proteasome and calpain inhibitors. Notably, a fraction of the cytosolic ER-alpha colocalized and coprecipitated with IRS-1 and IRS-2, indicating a possible common destination for these proteins. The stabilization of IRS-1 in MDA-MB-231/ER cells was paralleled by the upregulation of the IRS-1/Akt/GSK-3 pathway and improved survival in the presence of IGF-I, whereas IRS-2 was not involved in IGF-I signaling. AD - Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Morelli, Catia AU - Morelli C FAU - Garofalo, Cecilia AU - Garofalo C FAU - Bartucci, Monica AU - Bartucci M FAU - Surmacz, Eva AU - Surmacz E LA - eng PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (Estrogen Receptor alpha) RN - 0 (Ligands) RN - 0 (Multienzyme Complexes) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Estrogen) RN - 0 (Ubiquitin) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - EC 3.4.- (Peptide Hydrolases) RN - EC 3.4.22 (Cysteine Endopeptidases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - EC 3.4.99.- (ATP dependent 26S protease) SB - IM MH - Blotting, Western MH - Breast Neoplasms/*metabolism MH - Cell Division MH - Cell Survival MH - Cysteine Endopeptidases/metabolism MH - Endoplasmic Reticulum MH - Estrogen Receptor alpha MH - Humans MH - Ligands MH - Microscopy, Confocal MH - Microscopy, Fluorescence MH - Multienzyme Complexes/metabolism MH - Peptide Hydrolases/metabolism MH - Phosphoproteins/*metabolism MH - Precipitin Tests MH - Proteasome Endopeptidase Complex MH - Receptors, Estrogen/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction MH - Time Factors MH - Transcription, Genetic MH - Tumor Cells, Cultured MH - Ubiquitin/metabolism EDAT- 2003/06/25 05:00 MHDA- 2003/07/19 05:00 AID - 10.1038/sj.onc.1206436 [doi] AID - 1206436 [pii] PST - ppublish SO - Oncogene 2003 Jun 26;22(26):4007-16. NR -------------------------------------------------------------------------------- 31: van Montfort RL et al. Oxidation state of the active...[PMID: 12802339] Related Articles, Compound via MeSH, Substance via MeSH, Protein, Structure, 3D Domains, OMIM, Cited in PMC, Books, LinkOut PMID- 12802339 OWN - NLM STAT- MEDLINE DA - 20030612 DCOM- 20030714 LR - 20041027 PUBM- Print IS - 0028-0836 VI - 423 IP - 6941 DP - 2003 Jun 12 TI - Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. PG - 773-7 AB - Protein tyrosine phosphatases regulate signal transduction pathways involving tyrosine phosphorylation and have been implicated in the development of cancer, diabetes, rheumatoid arthritis and hypertension. Increasing evidence suggests that the cellular redox state is involved in regulating tyrosine phosphatase activity through the reversible oxidization of the catalytic cysteine to sulphenic acid (Cys-SOH). But how further oxidation to the irreversible sulphinic (Cys-SO2H) and sulphonic (Cys-SO3H) forms is prevented remains unclear. Here we report the crystal structures of the regulatory sulphenic and irreversible sulphinic and sulphonic acids of protein tyrosine phosphatase 1B (PTP1B), an important enzyme in the negative regulation of the insulin receptor and a therapeutic target in type II diabetes and obesity. We also identify a sulphenyl-amide species that is formed through oxidation of its catalytic cysteine. Formation of the sulphenyl-amide causes large changes in the PTP1B active site, which are reversible by reduction with the cellular reducing agent glutathione. The sulphenyl-amide is a protective intermediate in the oxidative inhibition of PTP1B. In addition, it may facilitate reactivation of PTP1B by biological thiols and signal a unique state of the protein. AD - Astex Technology Ltd, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. FAU - van Montfort, Rob L M AU - van Montfort RL FAU - Congreve, Miles AU - Congreve M FAU - Tisi, Dominic AU - Tisi D FAU - Carr, Robin AU - Carr R FAU - Jhoti, Harren AU - Jhoti H LA - eng SI - PDB/1OES SI - PDB/1OET SI - PDB/1OEU SI - PDB/1OEV PT - Journal Article PL - England TA - Nature JID - 0410462 RN - 0 (Amides) RN - 0 (Sulfenic Acids) RN - 0 (Sulfinic Acids) RN - 0 (Sulfonic Acids) RN - 52-90-4 (Cysteine) RN - 70-18-8 (Glutathione) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.1.3.48 (protein tyrosine phosphatase 1B) SB - IM MH - Amides/*metabolism MH - Binding Sites MH - Catalysis MH - Crystallography, X-Ray MH - Cysteine/chemistry/*metabolism MH - Glutathione/metabolism MH - Models, Molecular MH - Oxidation-Reduction MH - Protein Conformation MH - Protein-Tyrosine-Phosphatase/*chemistry/*metabolism MH - Sulfenic Acids/*metabolism MH - Sulfinic Acids/*metabolism MH - Sulfonic Acids/*metabolism EDAT- 2003/06/13 05:00 MHDA- 2003/07/15 05:00 PHST- 2003/01/29 [received] PHST- 2003/04/07 [accepted] AID - 10.1038/nature01681 [doi] AID - nature01681 [pii] PST - ppublish SO - Nature 2003 Jun 12;423(6941):773-7. NR -------------------------------------------------------------------------------- 32: Hamelers IH et al. Interactions between estrogen...[PMID: 12790794] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12790794 OWN - NLM STAT- MEDLINE DA - 20030606 DCOM- 20030904 LR - 20041117 PUBM- Print IS - 1351-0088 VI - 10 IP - 2 DP - 2003 Jun TI - Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. PG - 331-45 AB - Estrogens and insulin-like growth factors (IGFs) act as mitogens promoting cell proliferation in normal breast tissue as well as in breast carcinomas. Both hormones have been shown to play a role in the development of breast cancer and were found to activate multiple signaling pathways leading to proliferation of human breast cancer cell lines in vitro. Originally, it was considered that these agents manifest their mitogenic actions through separate pathways, but a growing body of evidence suggests that the IGF- and estrogen-mediated signaling pathways are intertwined. 17beta-Estradiol (E2) has been shown to enhance IGF signaling at multiple levels. E2 treatment of breast cancer cells alters expression of nearly all of the IGF family members including IGF-I, IGF-II, IGF-binding proteins, IGF type I receptor (IGF-RI), and insulin receptor substrate 1. The ligand-bound estrogen receptor has been reported to bind to and to activate the IGF-RI directly. Vice versa, IGF signaling has been reported to enhance estrogen receptor activation in human breast cancer cells by inducing phosphorylation of the estrogen receptor. Finally, several groups have described synergistic effects of the combination of E2 and IGF-I on S phase entry in breast tumor cell lines. Here, we review recent, often contradictory, reports describing the effects of E2 and IGFs on the proliferation of breast tumor cells, with special emphasis on the synergistic effects of the two hormones. AD - Utrecht Graduate School of Developmental Biology, Department of Physiological Chemistry, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands. FAU - Hamelers, I H L AU - Hamelers IH FAU - Steenbergh, P H AU - Steenbergh PH LA - eng PT - Journal Article PT - Review PL - England TA - Endocr Relat Cancer JID - 9436481 RN - 0 (Somatomedins) RN - 50-28-2 (Estradiol) SB - IM MH - Breast Neoplasms/*metabolism MH - Cell Division MH - Estradiol/*metabolism MH - Female MH - Humans MH - *Signal Transduction MH - Somatomedins/*metabolism MH - Tumor Cells, Cultured RF - 126 EDAT- 2003/06/07 05:00 MHDA- 2003/09/05 05:00 PST - ppublish SO - Endocr Relat Cancer 2003 Jun;10(2):331-45. NR -------------------------------------------------------------------------------- 33: Anneren C et al. The FRK/RAK-SHB signaling cas...[PMID: 12776987] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12776987 OWN - NLM STAT- MEDLINE DA - 20030602 DCOM- 20030711 LR - 20050209 PUBM- Print IS - 1566-5240 VI - 3 IP - 4 DP - 2003 Jun TI - The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation. PG - 313-24 AB - Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where they both induce PC12 cell differentiation and beta-cell proliferation. Furthermore, beta-cell apoptosis is augmented by these proteins under conditions that cause beta-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development. In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase. AD - Howard Hughes Medical Institute, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA. FAU - Anneren, Cecilia AU - Anneren C FAU - Lindholm, Cecilia K AU - Lindholm CK FAU - Kriz, Vitezslav AU - Kriz V FAU - Welsh, Michael AU - Welsh M LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Netherlands TA - Curr Mol Med JID - 101093076 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (Membrane Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Fibroblast Growth Factor) RN - 0 (Receptors, Interleukin-2) RN - 0 (SHB protein, human) RN - 0 (Shb protein, mouse) RN - 0 (Shb protein, rat) RN - 0 (TrkA protein) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.- (FRK protein, human) RN - EC 2.7.1.- (Frk protein, rat) RN - EC 2.7.1.112 (Frk protein, mouse) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, trkA) RN - EC 2.7.1.112 (Receptors, Platelet-Derived Growth Factor) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Animals MH - COS Cells MH - Carrier Proteins/metabolism MH - Cell Differentiation MH - Cell Division MH - Cell Survival MH - Cells, Cultured MH - Embryo/cytology MH - Fibroblasts/metabolism MH - Humans MH - Jurkat Cells MH - Membrane Proteins/metabolism MH - Mice MH - Models, Biological MH - Models, Genetic MH - *Neoplasm Proteins MH - Neurons/metabolism MH - PC12 Cells MH - Phosphorylation MH - Protein Structure, Tertiary MH - Protein-Tyrosine Kinase/*metabolism MH - Proto-Oncogene Proteins/*metabolism MH - Rats MH - *Receptor, trkA MH - Receptors, Fibroblast Growth Factor/metabolism MH - Receptors, Interleukin-2/metabolism MH - Receptors, Platelet-Derived Growth Factor/metabolism MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Tyrosine/metabolism MH - src Homology Domains RF - 64 EDAT- 2003/06/05 05:00 MHDA- 2003/07/12 05:00 PST - ppublish SO - Curr Mol Med 2003 Jun;3(4):313-24. NR -------------------------------------------------------------------------------- 34: del Rincon SV et al. Retinoic acid-induced growth ...[PMID: 12776186] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12776186 OWN - NLM STAT- MEDLINE DA - 20030530 DCOM- 20030626 LR - 20050111 PUBM- Print IS - 0950-9232 VI - 22 IP - 22 DP - 2003 May 29 TI - Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway. PG - 3353-60 AB - In the MCF-7 breast cancer cell line, insulin-like growth factors (IGFs) are known to elicit antiproliferative actions via the insulin receptor substrate-1 (IRS-1)/PI 3-kinase/AKT pathway. All-trans retinoic acid (RA) is a potent inhibitor of MCF-7 cell proliferation, but the mechanism by which growth regulation is achieved remains unclear. We investigated the effects of RA on the regulation of the IGF-IR and its key signaling elements: IRS-1, IRS-2, and SHC. Treatment of MCF-7 cells with RA caused a significant reduction in IRS-1 protein and tyrosine phosphorylation levels at a concentration and time consistent with RA-mediated growth inhibition. IRS-1 regulation is selective, as RA did not influence IRS-2 or SHC levels. Downstream signaling events were also selectively reduced, as RA abrogated IGF-I-stimulated AKT activation but did not alter erk1/2 activation. To confirm the importance of IRS-1 regulation by RA, we examined the response to RA in MCF-7 cells overexpressing IGF-IR and IRS-1. RA resistance was observed in MCF-7 cells overexpressing IRS-1 but not IGF-IR. This suggests that RA-mediated growth inhibition requires the selective downregulation of IRS-1 and AKT. Therapeutic agents targeting the IRS-1/PI 3-kinase/AKT pathway may enhance the cytostatic effects of RA in breast cancer, since overexpression of IRS-1 and AKT have been reported in primary breast tumors. AD - Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Department of Oncology, Montreal, Quebec, Canada. FAU - del Rincon, Sonia V AU - del Rincon SV FAU - Rousseau, Caroline AU - Rousseau C FAU - Samanta, Ratna AU - Samanta R FAU - Miller, Wilson H Jr AU - Miller WH Jr LA - eng PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 302-79-4 (Tretinoin) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/*metabolism MH - Breast Neoplasms/metabolism MH - Cell Division/drug effects MH - Down-Regulation MH - Female MH - Humans MH - In Vitro MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/*metabolism MH - Receptor, IGF Type 1/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Signal Transduction/drug effects/physiology MH - Tretinoin/*metabolism/pharmacology MH - Tumor Cells, Cultured EDAT- 2003/05/31 05:00 MHDA- 2003/06/27 05:00 AID - 10.1038/sj.onc.1206485 [doi] AID - 1206485 [pii] PST - ppublish SO - Oncogene 2003 May 29;22(22):3353-60. NR -------------------------------------------------------------------------------- 35: LeRoith D et al. The insulin-like growth facto...[PMID: 12767520] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12767520 OWN - NLM STAT- MEDLINE DA - 20030527 DCOM- 20030725 LR - 20041117 PUBM- Print IS - 0304-3835 VI - 195 IP - 2 DP - 2003 Jun 10 TI - The insulin-like growth factor system and cancer. PG - 127-37 AB - The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFs play an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causing tumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and its relationship to cancer will be discussed. AD - Diabetes Branch, Room 8D12, Building 10, National Institutes of Health MSC 1758, Bethesda, MD 20892-1758, USA. derek@helix.nih.gov FAU - LeRoith, Derek AU - LeRoith D FAU - Roberts, Charles T Jr AU - Roberts CT Jr LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Ireland TA - Cancer Lett JID - 7600053 RN - 0 (Insulin-Like Growth Factor Binding Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Receptor, IGF Type 2) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Apoptosis/physiology MH - Autocrine Communication MH - Cell Adhesion/physiology MH - Cell Movement/physiology MH - Cell Transformation, Neoplastic/metabolism MH - Dimerization MH - Energy Metabolism MH - Female MH - Humans MH - Insulin-Like Growth Factor Binding Proteins/blood/physiology MH - Insulin-Like Growth Factor I/chemistry/*physiology MH - Insulin-Like Growth Factor II/chemistry/*physiology MH - Male MH - Mice MH - Mice, Transgenic MH - Neoplasm Metastasis MH - Neoplasm Proteins/physiology MH - Neoplasms/blood/*etiology MH - Protein Hybridization MH - Receptor, IGF Type 1/physiology MH - Receptor, IGF Type 2/physiology MH - Receptor, Insulin/physiology MH - Signal Transduction MH - Structure-Activity Relationship RF - 66 EDAT- 2003/05/28 05:00 MHDA- 2003/07/26 05:00 AID - S0304383503001599 [pii] PST - ppublish SO - Cancer Lett 2003 Jun 10;195(2):127-37. DR -------------------------------------------------------------------------------- 36: Wiedmann M et al. Constitutive over-expression ...[PMID: 12763374] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12763374 OWN - NLM STAT- MEDLINE DA - 20030523 DCOM- 20040122 LR - 20041117 PUBM- Print IS - 0168-8278 VI - 38 IP - 6 DP - 2003 Jun TI - Constitutive over-expression of the insulin receptor substrate-1 causes functional up-regulation of Fas receptor. PG - 803-10 AB - BACKGROUND/AIMS: Insulin- and insulin growth factor-1 stimulated signaling through the insulin receptor substrate-1 (IRS-1) promotes hepatocellular proliferation and survival. IRS-1 over-expression in transgenic (Tg) mouse livers caused constitutive activation of Erk mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) resulting in significantly increased levels of DNA synthesis and larger hepatic masses relative to non-transgenic (non-Tg) littermates. However, the livers eventually ceased to grow but remained approximately 25% larger than non-Tg livers. We hypothesized that this growth homeostasis was achieved by parallel activation of pro-apoptosis pathways. METHODS: Since Fas-mediated apoptosis is a common mechanism of hepatocyte destruction, we investigated the potential role of Fas receptor as a regulator of hepatic mass in IRS-1 transgenic mice. RESULTS: Significantly increased Fas-receptor levels were detected in the livers of IRS-1 Tg compared to non-Tg mice by Western blot analysis. Functional activation of Fas-receptor in IRS-1 Tg livers was demonstrated by increased hepatocellular apoptosis caused by intravenous injection of anti-Fas (Jo-2). CONCLUSIONS: These findings suggest that the increased growth caused by IRS-1 over-expression is balanced by constitutive activation of pro-death mechanisms. Failure of the IRS-1 Tg mice to develop liver cancer may be due to preservation of pro-growth, pro-death homeostasis mechanisms. AD - Department of Medicine, Liver Research Center, Rhode Island Hospital, Brown University School of Medicine, 55 Claverick Street 4th floor, Providence, RI 02903, USA. FAU - Wiedmann, Marcus AU - Wiedmann M FAU - Tamaki, Seishu AU - Tamaki S FAU - Silberman, Rebecca AU - Silberman R FAU - de la Monte, Suzanne M AU - de la Monte SM FAU - Cousens, Leslie AU - Cousens L FAU - Wands, Jack R AU - Wands JR LA - eng GR - AA-02666/AA/NIAAA GR - CA-35711/CA/NCI GR - P20 RR-15578/RR/NCRR PT - Journal Article PL - England TA - J Hepatol JID - 8503886 RN - 0 (Antigens, CD95) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) SB - IM MH - Animals MH - Antigens, CD95/*metabolism MH - Apoptosis/genetics MH - Gene Expression MH - Humans MH - In Situ Nick-End Labeling MH - Liver/pathology/physiopathology MH - Mice MH - Mice, Transgenic MH - Phosphoproteins/genetics/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Up-Regulation EDAT- 2003/05/24 05:00 MHDA- 2004/01/24 05:00 AID - S016882780300117X [pii] PST - ppublish SO - J Hepatol 2003 Jun;38(6):803-10. NR -------------------------------------------------------------------------------- 37: Sciacca L et al. Signaling differences from th...[PMID: 12746329] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12746329 OWN - NLM STAT- MEDLINE DA - 20030514 DCOM- 20030625 LR - 20050312 PUBM- Print IS - 0013-7227 VI - 144 IP - 6 DP - 2003 Jun TI - Signaling differences from the A and B isoforms of the insulin receptor (IR) in 32D cells in the presence or absence of IR substrate-1. PG - 2650-8 AB - The A isoform of the insulin receptor (IR) is frequently overexpressed in cancer cells and is activated by IGF-II as well as by insulin, whereas the B isoform is predominant in differentiated tissues and responds poorly to IGF-II. The IR substrate-1 (IRS-1), a docking protein for the IR, is known to send a mitogenic signal and to be a powerful inhibitor of cell differentiation. We have investigated the biological effects of the two IR isoforms in parental 32D hemopoietic cells, which do not express IRS-1, and in 32D-derived cells in which IRS-1 is ectopically expressed. The effects of the two isoforms on cell survival, differentiation markers and nuclear translocation of IRS-1 were compared. The results confirm that the A isoform responds to IGF-II and preferentially sends mitogenic, antiapoptotic signals, whereas the B form, poorly responsive to IGF-II, tends to send differentiation signals. AD - Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, Ospedale Garibaldi, 95123 Catania, Italy. FAU - Sciacca, Laura AU - Sciacca L FAU - Prisco, Marco AU - Prisco M FAU - Wu, An AU - Wu A FAU - Belfiore, Antonino AU - Belfiore A FAU - Vigneri, Riccardo AU - Vigneri R FAU - Baserga, Renato AU - Baserga R LA - eng GR - AG-16291/AG/NIA GR - CA-089640/CA/NCI PT - Journal Article PL - United States TA - Endocrinology JID - 0375040 RN - 0 (Acute-Phase Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (INSR protein, human) RN - 0 (Interleukin-3) RN - 0 (LCN2 protein, human) RN - 0 (Oncogene Proteins) RN - 0 (Phosphoproteins) RN - 0 (Repressor Proteins) RN - 0 (Transcription Factors) RN - 0 (insulin receptor substrate-1 protein) RN - 126469-30-5 (Lcn2 protein, mouse) RN - 146990-20-7 (inhibitor of differentiation protein 2) RN - EC 1.11.1.7 (Peroxidase) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Acute-Phase Proteins/genetics MH - Animals MH - Cell Differentiation/drug effects/physiology MH - Cell Line MH - Cell Nucleus/metabolism MH - Cell Survival MH - DNA-Binding Proteins/genetics MH - Gene Expression/drug effects/physiology MH - Interleukin-3/pharmacology MH - Isomerism MH - Mice MH - Oncogene Proteins/genetics MH - Peroxidase/genetics MH - Phosphoproteins/*metabolism/pharmacology MH - Receptor, Insulin/chemistry/genetics/*metabolism MH - *Repressor Proteins MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*physiology MH - Transcription Factors/genetics EDAT- 2003/05/15 05:00 MHDA- 2003/06/26 05:00 PST - ppublish SO - Endocrinology 2003 Jun;144(6):2650-8. DR -------------------------------------------------------------------------------- 38: Sakai K et al. Glucosamine induces resistanc...[PMID: 12746299] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12746299 OWN - NLM STAT- MEDLINE DA - 20030514 DCOM- 20030625 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 144 IP - 6 DP - 2003 Jun TI - Glucosamine induces resistance to insulin-like growth factor I (IGF-I) and insulin in Hep G2 cell cultures: biological significance of IGF-I/insulin hybrid receptors. PG - 2388-95 AB - IGF-I stimulates insulin-like actions directly through its receptor, and it also enhances sensitivity to insulin-mediated effects in vivo. These studies were undertaken to analyze the role of IGF-I, insulin, and insulin/IGF-I hybrid receptors (HRs) in mediating IGF-I and insulin signaling in cells that had been made insulin-resistant by treatment with glucosamine. Human HepG2 cells, which express IGF-I receptors, insulin receptors (IRs), and IGF-I/insulin HRs, were exposed to 20 mM glucosamine; and the effects of IGF-I and insulin in stimulating glycogen synthesis were determined. An overnight exposure to glucosamine markedly attenuated the effects of insulin and IGF-I in stimulating glycogen synthesis. To determine which receptors were mediating this effect, the ability of insulin and IGF-I to stimulate phosphorylation of their respective receptors was analyzed. An 18-h exposure to glucosamine (20 mM) caused a 75% reduction in the ability of IGF-I to phosphorylate its receptor but no change in receptor abundance. Glucosamine also caused a major reduction in insulin-stimulated receptor phosphorylation, although, unlike IGF-I, there was also a 50% reduction in IR abundance. Exposure to glucosamine also resulted in a reduction in the ability of IGF-I or insulin to stimulate phosphorylation of insulin IGF-I/HRs. The combination of insulin plus IGF-I was a more potent stimulus of HR phosphorylation than either agent alone, and this combination was also more potent in partially reversing the inhibitory effect of glucosamine. Taken together, these findings indicate that glucosamine induces a loss of sensitivity to stimulation of insulin, IGF-I, or HR tyrosine kinase activity by insulin or IGF-I. Although insulin is able to partially reverse the effect of glucosamine on IR phosphorylation, it has a very minimal effect on glucosamine-induced inhibition of HR phosphorylation. However, the combination of IGF-I and insulin induces a major increase in HR phosphorylation, even in the presence of glucosamine, suggesting that it is improving the sensitivity of the HR to insulin activation. AD - Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA. FAU - Sakai, K AU - Sakai K FAU - Clemmons, D R AU - Clemmons DR LA - eng GR - AG-023331/AG/NIA PT - Journal Article PL - United States TA - Endocrinology JID - 0375040 RN - 0 (Hypoglycemic Agents) RN - 11061-68-0 (Insulin) RN - 3416-24-8 (Glucosamine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Carcinoma, Hepatocellular MH - Drug Interactions MH - Glucosamine/*pharmacology MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - Insulin/*pharmacology MH - Insulin-Like Growth Factor I/*pharmacology MH - Liver Neoplasms MH - Phosphorylation/drug effects MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured/drug effects/metabolism EDAT- 2003/05/15 05:00 MHDA- 2003/06/26 05:00 PST - ppublish SO - Endocrinology 2003 Jun;144(6):2388-95. PR -------------------------------------------------------------------------------- 39: Platanias LC. The p38 mitogen-activated pro...[PMID: 12725866] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12725866 OWN - NLM STAT- MEDLINE DA - 20030502 DCOM- 20030904 LR - 20041117 PUBM- Print IS - 0163-7258 VI - 98 IP - 2 DP - 2003 May TI - The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. PG - 129-42 AB - Interferons (IFNs) are pleiotropic cytokines that exhibit multiple biological effects on cells and tissues. IFN receptors are expressed widely in mammalian cells and virtually all different cell types express them on their surface. The Type I IFN receptor has a multichain structure, composed of at least two distinct receptor subunits, IFNalphaR1 and IFNalphaR2. Two Jak-kinases, Tyk-2 and Jak-1, associate with the different receptor subunits and are activated in response to IFNalpha or IFNbeta to regulate engagement of multiple downstream signaling cascades. These include the Stat-pathway, whose function is essential for transcriptional activation of IFN-sensitive genes, and the insulin receptor substrate pathway, which regulates downstream activation of the phosphatidyl-inositol-3' kinase. Members of the Map family of kinases are also activated by the Type I IFN receptor and participate in the generation of IFN signals. The p38 Map kinase pathway appears to play a very important role in the induction of IFN responses. p38 is rapidly activated during engagement of the Type I IFN receptor, and such an activation is regulated by the small G-protein Rac1, which functions as its upstream effector in a tyrosine kinase-dependent manner. The activated form of p38 regulates downstream activation of other serine kinases, notably MapKapK-2 and MapKapK-3, indicating the existence of Type I IFN-dependent signaling cascades activated downstream of p38. Extensive studies have shown that p38 plays a critical role in Type I IFN-dependent transcriptional regulation, without modifying activation of the Stat-pathway. It is now well established that the function of p38 is essential for gene transcription via ISRE or GAS elements, but has no effects on the phosphorylation of Stat-proteins, the formation of Stat-complexes, and their binding to the promoters of IFN-sensitive genes. As Type I IFNs regulate gene expression for proteins with antiviral properties, it is not surprising that pharmacological inhibition of the p38 pathway blocks induction of IFNalpha-antiviral responses. In addition, pharmacological inhibition of p38 abrogates the suppressive effects of Type I IFNs on normal human hematopoietic progenitors, indicating a critical role for this signaling cascade in the induction of the regulatory effects of Type I IFNs on hematopoiesis. p38 is also activated during IFNalpha-treatment of primary leukemia cells from patients with chronic myelogenous leukemia. Such activation is required for IFNalpha-dependent suppression of leukemic cell progenitor growth, indicating that this pathway plays a critical role in the induction of the antileukemic effects of IFNalpha. AD - Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, 303 East Chicago Avenue, Olson Pavilion, Room 8250, Chicago, IL 60611, USA. l-platanias@northwestern.edu FAU - Platanias, Leonidas C AU - Platanias LC LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Pharmacol Ther JID - 7905840 RN - 0 (Receptors, Interferon) RN - 9008-11-1 (Interferons) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - *Gene Expression Regulation MH - Hematopoiesis MH - Humans MH - Interferons/*pharmacology MH - Leukemia, Myeloid, Chronic/drug therapy/physiopathology MH - Mitogen-Activated Protein Kinases/*pharmacology MH - Receptors, Interferon/*physiology MH - Signal Transduction MH - Transcription, Genetic MH - Tumor Cells, Cultured MH - Up-Regulation MH - p38 Mitogen-Activated Protein Kinases RF - 167 EDAT- 2003/05/03 05:00 MHDA- 2003/09/05 05:00 AID - S0163725803000160 [pii] PST - ppublish SO - Pharmacol Ther 2003 May;98(2):129-42. NR -------------------------------------------------------------------------------- 40: Yuan L et al. Chronic hyperinsulinism induc...[PMID: 12674767] Related Articles, Books, LinkOut PMID- 12674767 OWN - NLM STAT- MEDLINE DA - 20030404 DCOM- 20040720 LR - 20041117 PUBM- Print IS - 1672-0733 VI - 22 IP - 4 DP - 2002 TI - Chronic hyperinsulinism induced down-regulation of insulin post-receptor signaling transduction in Hep G2 cells. PG - 313-6 AB - To study the regulatory effect of acute and chronic insulin treatment on insulin post-receptor signaling transduction pathway in a human hepatoma cell line (Hep G2), Hep G2 cells were incubated in the presence or absence of insulin with different concentrations in serum free media for 16 h and then stimulated with 100 nmol/L insulin for 1 min. Protein levels of insulin receptor beta-subunit (IR beta), insulin receptor substrate-1 (IRS-1) and p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) were determined in total cell lysates by Western-immunoblot. Phosphorylated proteins IR beta, IRS-1 and interaction of PI 3-kinase with IRS-1 were determined by immunoprecipitation. Results showed that 1-min insulin stimulation rapidly induced tyrosine phosphorylation of IR beta and IRS-1, which in turn, resulting in association of PI 3-kinase with IRS-1. 1-100 nmol/L chronic insulin treatment induced a dose-dependent decrease in the protein level of IR beta and a slight decrease in the protein level of IRS-1. There was a more marked reduction in the phosphorylation of IR beta, IRS-1, reaching a nadir of 22% (P < 0.01) and 15% (P < 0.01) of control levels, respectively, after 16 h treatment with 100 nmol/L insulin. The association between IRS-1 and PI 3-kinase was decreased by 66% (P < 0.01). There was no significant change in PI 3-kinase protein levels. These data suggest that chronic insulin treatment can induce alterations of IR beta, IRS-1 and PI 3-kinase three early steps in insulin action, which contributes significantly to insulin resistance, and may account for desensitization of insulin action. AD - Department of Endocrinology and Metabolism, University-Hospital Heidelberg, Heidelberg 69115, Germany. FAU - Yuan, Li AU - Yuan L FAU - Ziegler, Reinhard AU - Ziegler R FAU - Hamann, Andreas AU - Hamann A LA - eng PT - Journal Article PL - China TA - J Huazhong Univ Sci Technolog Med Sci JID - 101169627 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Carcinoma, Hepatocellular/*pathology MH - Down-Regulation MH - Humans MH - Hyperinsulinism/*metabolism MH - Insulin Resistance MH - Liver Neoplasms/*pathology MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Receptor, Insulin/antagonists & inhibitors/*metabolism MH - *Signal Transduction/drug effects MH - Tumor Cells, Cultured EDAT- 2003/04/05 05:00 MHDA- 2004/07/21 05:00 PST - ppublish SO - J Huazhong Univ Sci Technolog Med Sci 2002;22(4):313-6. PR -------------------------------------------------------------------------------- 41: Foti D et al. A nucleoprotein complex conta...[PMID: 12665574] Related Articles, Gene, HomoloGene, UniGene, UniSTS, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 12665574 OWN - NLM STAT- MEDLINE DA - 20030331 DCOM- 20030502 LR - 20041117 PUBM- Print IS - 0270-7306 VI - 23 IP - 8 DP - 2003 Apr TI - A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription. PG - 2720-32 AB - HMGI-Y is an architectural transcription factor that regulates gene expression in vivo by controlling the formation of stereospecific multiprotein complexes on the AT-rich regions of certain gene promoters. Recently, we demonstrated that HMGI-Y is required for proper transcription of the insulin receptor (IR) gene. Here we provide evidence that transcriptional activation of the human IR promoter requires the assembly of a transcriptionally active multiprotein-DNA complex which includes, in addition to HMGI-Y, the ubiquitously expressed transcription factor Sp1 and the CCAAT-enhancer binding protein beta (C/EBP beta). Functional integrity of this nucleoprotein complex is required for full transactivation of the IR gene by Sp1 and C/EBP beta in cells readily expressing IRs. We show that HMGI-Y physically interacts with Sp1 and C/EBP beta and facilitates the binding of both factors to the IR promoter in vitro. Furthermore, HMGI-Y is needed for transcriptional synergism between these factors in vivo. Repression of HMGI-Y function adversely affects both Sp1- and C/EBP beta-induced transactivation of the IR promoter. Together, these findings demonstrate that HMGI-Y plays significant molecular roles in the transcriptional activities of these factors in the context of the IR gene and provide concordant support for the hypothesis that, in affected individuals, a putative defect in these nuclear proteins may cause decreased IR expression with subsequent impairment of insulin signaling and action. AD - Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Universita degli Studi di Catanzaro Magna Graecia, 88100 Catanzaro, Italy. FAU - Foti, Daniela AU - Foti D FAU - Iuliano, Rodolfo AU - Iuliano R FAU - Chiefari, Eusebio AU - Chiefari E FAU - Brunetti, Antonio AU - Brunetti A LA - eng PT - Journal Article PL - United States TA - Mol Cell Biol JID - 8109087 RN - 0 (CCAAT-Enhancer-Binding Protein-beta) RN - 0 (Nucleoproteins) RN - 0 (Recombinant Proteins) RN - 0 (Transcription Factor, Sp1) RN - 124544-67-8 (HMGA1a Protein) RN - 9007-49-2 (DNA) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - 3T3 Cells MH - Animals MH - Base Sequence MH - Binding Sites/genetics MH - CCAAT-Enhancer-Binding Protein-beta/genetics/*metabolism MH - Cell Line MH - Cell Transformation, Viral MH - DNA/genetics/metabolism MH - Diabetes Mellitus/genetics/metabolism MH - HMGA1a Protein/genetics/*metabolism MH - Herpesvirus 4, Human MH - Humans MH - Mice MH - Models, Biological MH - Nucleoproteins/metabolism MH - Promoter Regions (Genetics) MH - Receptor, Insulin/*genetics/metabolism MH - Recombinant Proteins/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Transcription Factor, Sp1/genetics/*metabolism MH - Transcription, Genetic EDAT- 2003/04/01 05:00 MHDA- 2003/05/03 05:00 PST - ppublish SO - Mol Cell Biol 2003 Apr;23(8):2720-32. NR -------------------------------------------------------------------------------- 42: Bifulco G et al. Leptin induces mitogenic effe...[PMID: 12657513] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12657513 OWN - NLM STAT- MEDLINE DA - 20030326 DCOM- 20031120 LR - 20041117 PUBM- Print IS - 0143-4004 VI - 24 IP - 4 DP - 2003 Apr TI - Leptin induces mitogenic effect on human choriocarcinoma cell line (JAr) via MAP kinase activation in a glucose-dependent fashion. PG - 385-91 AB - Leptin and glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6m M glucose (LG), proliferation and thymidine incorporation were induced by serum but not by leptin. At variance, at 25m M glucose (HG), proliferation and thymidine incorporation were stimulated by leptin and serum to a comparable extent. HG culturing also enhanced leptin-stimulated insulin receptor substrate 1 (IRS1) and MAPK phosphorylation. Blockage of MAPK activity with PD98059 caused an inhibition of glucose- and leptin-dependent thymidine incorporation. At variance with HG conditions no effects were observed in cells cultured in 6m M glucose upon treatment with PD98059. Neither glucose nor leptin determined a modification in leptin receptors total content.In this study, we provide evidence that in placental cells, leptin, similarly to that observed with insulin, stimulates cell proliferation by inducing the IRS1/MAPK pathway in a glucose-dependent fashion. AD - Dipartimento di Ginecologia, Ostetricia e Fisiopatologia della Riproduzione Umana, Naples, Italy. giuseppebifulco@hotmail.com FAU - Bifulco, G AU - Bifulco G FAU - Trencia, A AU - Trencia A FAU - Caruso, M AU - Caruso M FAU - Tommaselli, G A AU - Tommaselli GA FAU - Miele, C AU - Miele C FAU - di Carlo, C AU - di Carlo C FAU - Beguinot, F AU - Beguinot F FAU - Nappi, C AU - Nappi C LA - eng PT - Journal Article PL - England TA - Placenta JID - 8006349 RN - 0 (Drug Combinations) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Growth Substances) RN - 0 (Leptin) RN - 0 (PD 98059) RN - 0 (TRS1 protein, Human herpesvirus 5) RN - 0 (Viral Proteins) RN - 50-99-7 (Glucose) RN - 9007-49-2 (DNA) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - Cell Division/drug effects MH - Choriocarcinoma MH - DNA/biosynthesis MH - Dose-Response Relationship, Drug MH - Drug Combinations MH - Enzyme Inhibitors/pharmacology MH - Female MH - Flavonoids/pharmacology MH - Glucose/*pharmacology MH - Growth Substances/*pharmacology MH - Humans MH - Leptin/*pharmacology MH - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*biosynthesis MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Trophoblasts/*drug effects/enzymology/pathology MH - Tumor Cells, Cultured/drug effects MH - Uterine Neoplasms MH - Viral Proteins/metabolism EDAT- 2003/03/27 05:00 MHDA- 2003/12/03 05:00 AID - S0143400402909057 [pii] PST - ppublish SO - Placenta 2003 Apr;24(4):385-91. NR -------------------------------------------------------------------------------- 43: von Willebrand M et al. The tyrphostin AG1024 acceler...[PMID: 12649208] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12649208 OWN - NLM STAT- MEDLINE DA - 20030321 DCOM- 20030411 LR - 20041208 PUBM- Print IS - 0008-5472 VI - 63 IP - 6 DP - 2003 Mar 15 TI - The tyrphostin AG1024 accelerates the degradation of phosphorylated forms of retinoblastoma protein (pRb) and restores pRb tumor suppressive function in melanoma cells. PG - 1420-9 AB - Constitutive cell surface receptor kinase signaling and persistent phosphorylation/inactivation of the retinoblastoma (pRb) family of proteins (pRb, p107 and p130, known as pocket proteins) have been implicated in conferring uncontrolled growth to melanoma cells. However, the signals linking receptor kinase activity to neutralization of pocket proteins have not yet been fully elucidated. We therefore used specific chemical inhibitors to examine pRb regulation in melanoma cells. The most efficient agent, AG1024, known as an inhibitor of insulin-like growth factor 1 receptor and insulin receptor, arrested melanoma cell growth in vitro at nanomolar concentrations within 24 h of application. AG1024 inhibited the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and restored pRb tumor suppressive function. The latter was observed by the reduction in the phosphorylated forms of pRb, p107 and p130, and the formation of growth suppressive DNA binding complexes consisting of pRb and E2F1 or E2F3. The loss of phosphorylated forms of pRb at early time points after AG1024 application was not associated with suppression of cyclin-dependent kinases 2 and 4 activity but rather with proteasomal and nonproteasomal degradation. Thus, inhibition of melanoma cell proliferation by AG1024 is mediated by inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase 2 signaling and activation of pRb by a mechanism involving protein degradation. AD - Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. FAU - von Willebrand, Maria AU - von Willebrand M FAU - Zacksenhaus, Eldad AU - Zacksenhaus E FAU - Cheng, Elaine AU - Cheng E FAU - Glazer, Peter AU - Glazer P FAU - Halaban, Ruth AU - Halaban R LA - eng GR - CA44542/CA/NCI PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Cell Cycle Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (E2F transcription factors) RN - 0 (MAP Kinase Signaling System) RN - 0 (Retinoblastoma Protein) RN - 0 (Transcription Factors) RN - 0 (Tyrphostins) RN - 0 (Ubiquitin) RN - 0 (tyrphostin AG 1024) RN - EC 2.7.1.37 (Cyclin-Dependent Kinases) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) SB - IM MH - Animals MH - *Cell Cycle Proteins MH - Cell Division/drug effects MH - Cyclin-Dependent Kinases/metabolism MH - *DNA-Binding Proteins MH - Humans MH - MAP Kinase Signaling System MH - Melanocytes/drug effects/metabolism MH - Melanoma/drug therapy/*metabolism/pathology MH - Mice MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Phosphorylation MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Retinoblastoma Protein/metabolism/*physiology MH - Transcription Factors/metabolism MH - Tyrphostins/*pharmacology MH - Ubiquitin/metabolism EDAT- 2003/03/22 04:00 MHDA- 2003/04/12 05:00 PST - ppublish SO - Cancer Res 2003 Mar 15;63(6):1420-9. DR -------------------------------------------------------------------------------- 44: Chakravarty G et al. p190-B RhoGAP regulates mamma...[PMID: 12637587] Related Articles, Gene, GENSAT, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12637587 OWN - NLM STAT- MEDLINE DA - 20030528 DCOM- 20031218 LR - 20041117 PUBM- Print-Electronic IS - 0888-8809 VI - 17 IP - 6 DP - 2003 Jun TI - p190-B RhoGAP regulates mammary ductal morphogenesis. PG - 1054-65 AB - Previous studies from our laboratory have demonstrated that p190-B RhoGAP (p190-B) is differentially expressed in the Cap cells of terminal end buds (TEBs) and poorly differentiated rodent mammary tumors. Based on these observations we hypothesized that p190-B might play an essential role in invasion of the TEBs into the surrounding fat pad during ductal morphogenesis. To test this hypothesis, mammary development was studied in p190-B-deficient mice. A haploinsufficiency phenotype was observed in p190-B heterozygous mice as indicated by decreased number and rate of ductal outgrowth(s) at 3, 4, and 5 wk of age when compared with their wild-type littermates. This appeared to result from decreased proliferation in the Cap cells of the TEBs, a phenotype remarkably similar to that observed previously in IGF-I receptor null mammary epithelium. Furthermore, decreased expression of insulin receptor substrates 1 and 2 were observed in TEBs of p190-B heterozygous mice. These findings are consistent with decreased IGF signaling observed previously in p190-B-/- mouse embryo fibroblasts. To further assess if this defect was cell autonomous or due to systemic endocrine effects, the mammary anlagen from p190-B+/+, p190-B+/-, and p190-B-/- mice was rescued by transplantation into the cleared fat pad of recipient Rag1-/- mice. Surprisingly, as opposed to 75-80% outgrowths observed using wild-type donor epithelium, only 40% of the heterozygous and none of the p190-B-/- epithelial transplants displayed any outgrowths. Together, these results suggest that p190-B regulates ductal morphogenesis, at least in part, by modulating the IGF signaling axis. AD - Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. FAU - Chakravarty, Geetika AU - Chakravarty G FAU - Hadsell, Darryl AU - Hadsell D FAU - Buitrago, William AU - Buitrago W FAU - Settleman, Jeffrey AU - Settleman J FAU - Rosen, Jeffrey M AU - Rosen JM LA - eng GR - R01-CA-64255/CA/NCI GR - R01-DK-052197-06A1/DK/NIDDK PT - Journal Article DEP - 20030313 PL - United States TA - Mol Endocrinol JID - 8801431 RN - 0 (GAP-associated protein p190) RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (Nuclear Proteins) RN - 0 (Phosphoproteins) RN - 0 (Somatomedins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) SB - IM MH - Analysis of Variance MH - Animals MH - Cell Division/physiology MH - Comparative Study MH - Female MH - Guanine Nucleotide Exchange Factors/genetics/*physiology MH - Heterozygote MH - Mammary Glands, Animal/cytology/*growth & development/metabolism MH - Mice MH - Morphogenesis MH - Nuclear Proteins/genetics/*physiology MH - Phosphoproteins/*metabolism MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Sexual Maturation/genetics/*physiology MH - Signal Transduction MH - Somatomedins/*metabolism EDAT- 2003/03/15 04:00 MHDA- 2003/12/19 05:00 PHST- 2003/03/13 [aheadofprint] AID - 10.1210/me.2002-0428 [doi] AID - me.2002-0428 [pii] PST - ppublish SO - Mol Endocrinol 2003 Jun;17(6):1054-65. Epub 2003 Mar 13. NR -------------------------------------------------------------------------------- 45: Ben-Shlomo I. The polycystic ovary syndrome...[PMID: 12626141] Related Articles, Books, LinkOut PMID- 12626141 OWN - NLM STAT- MEDLINE DA - 20030310 DCOM- 20030708 LR - 20041117 PUBM- Print IS - 1472-6483 VI - 6 IP - 1 DP - 2003 Jan-Feb TI - The polycystic ovary syndrome: what does insulin resistance have to do with it? PG - 36-42 AB - About half of infertility cases are attributable to female factors, of which anovulation is the leading cause. Most cases of anovulation are due to the polycystic ovarian syndrome (PCOS). Clinically PCOS, present in 5% of all women, consists of anovulation, acne, hirsutism, reversed LH-to-FSH ratio and often resistance to insulin. In some cases PCOS appears in familial clusters but its genetic cause is unknown. Several genes were suggested as possible culprits for PCOS but their involvement has not been proven. The central paradox regarding the role of insulin in PCOS is the high responsiveness to insulin by the ovary, as opposed to the resistance of the whole body. On the backdrop of knowledge of several paralogous genes for each of the participating proteins in the insulin signal transduction pathways, it is possible that different paralogues propagate the intracellular signal in the ovary as opposed to peripheral tissues. Studies by microarray techniques of the different gene expression profiles in the two ovarian cells and peripheral cells such as adipocytes could clarify whether the ovarian defect in PCOS is identical to the peripheral defect in insulin signal transduction, or whether serum insulin concentrations simply serve to reveal the ovarian defect. AD - Laboratory for Research in Reproductive Sciences, Department of Obstetrics and Gynecology, Ha'Emek Medical Centre, Afula, Israel. ibs@clalit.org.il FAU - Ben-Shlomo, Izhar AU - Ben-Shlomo I LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Reprod Biomed Online JID - 101122473 RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3.16 (Phosphoprotein Phosphatase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/genetics MH - Female MH - Humans MH - Insulin Resistance/*physiology MH - Ovary/physiology MH - Phosphoprotein Phosphatase/antagonists & inhibitors MH - Polycystic Ovary Syndrome/genetics/*physiopathology MH - Receptor, Insulin/genetics MH - Signal Transduction/genetics/physiology RF - 71 EDAT- 2003/03/11 04:00 MHDA- 2003/07/09 05:00 PST - ppublish SO - Reprod Biomed Online 2003 Jan-Feb;6(1):36-42. NR -------------------------------------------------------------------------------- 46: Sedlaczek N et al. Focal overexpression of insul...[PMID: 12618883] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12618883 OWN - NLM STAT- MEDLINE DA - 20030305 DCOM- 20030417 LR - 20041117 PUBM- Print IS - 0007-0920 VI - 88 IP - 5 DP - 2003 Mar 10 TI - Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis. PG - 733-9 AB - Insulin-like growth factor (IGF)-2 is overexpressed in hepatocellular carcinoma and accompanying dysplastic lesions. IGF-2 signalling is mediated through IGF-1 receptor (IGF-1R), while mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF-2R) controls pericellular levels of free IGF-2. We studied, by in situ hybridisation and immunohistology, 18 liver specimens with cirrhosis of different aetiology without neoplastic or dysplastic lesions. Immunohistology was also performed for insulin receptor IGF-1R and IGF-binding proteins 3 and 4. High focal levels of IGF-2 RNA were found in some hepatocytes of all livers with HBV- or HCV-induced cirrhosis (n=10), but in only one of the cirrhoses with nonviral aetiology (n=8). IGF-2 was overexpressed in biliary duct epithelial cells in one case. Compared with noncirrhotic liver, all cirrhotic specimens showed reduced hepatocellular expression of M6P/IGF-2R protein, which contrasted with enhanced expression in perisinusoidal cells. Immunostaining for the other antigens did not reveal significant differences. Upregulation of IGF-2 in some hepatocytes may lead to high focal IGF-2 levels sufficient to saturate local IGF-2 binding capacities, and may result in an increased susceptibility to cellular dedifferentiation and, ultimately, liver cancer. Downregulation of hepatocellular M6P/IGF-2R and upregulation of IGF-2 seem to be early events in hepatocarcinogenesis prior to the appearance of morphologically distinct dysplastic lesions. Elevated focal IGF-2 transcript levels may therefore indicate an increased risk for hepatocellular and cholangiocellular carcinomas. AD - Institute of Pathology, University of Muenster, Germany. FAU - Sedlaczek, N AU - Sedlaczek N FAU - Hasilik, A AU - Hasilik A FAU - Neuhaus, P AU - Neuhaus P FAU - Schuppan, D AU - Schuppan D FAU - Herbst, H AU - Herbst H LA - eng PT - Journal Article PL - England TA - Br J Cancer JID - 0370635 RN - 67763-97-7 (Insulin-Like Growth Factor II) SB - IM MH - Bile Ducts/*metabolism/pathology MH - Comparative Study MH - Hepatitis, Viral, Human/*complications MH - Hepatocytes/*metabolism MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization MH - Insulin-Like Growth Factor II/*metabolism MH - Liver Cirrhosis/etiology/*metabolism EDAT- 2003/03/06 04:00 MHDA- 2003/04/18 05:00 AID - 10.1038/sj.bjc.6600777 [doi] AID - 6600777 [pii] PST - ppublish SO - Br J Cancer 2003 Mar 10;88(5):733-9. NR -------------------------------------------------------------------------------- 47: Urso B et al. IRS-4 mediated mitogenic sign...[PMID: 12618213] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12618213 OWN - NLM STAT- MEDLINE DA - 20030305 DCOM- 20040105 LR - 20041118 PUBM- Print IS - 0898-6568 VI - 15 IP - 4 DP - 2003 Apr TI - IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors. PG - 385-94 AB - Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells, GH either directly or indirectly via IGF-I production. We have studied a spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show that GH is more potent than insulin, with both GH and insulin dose-response curves for thymidine incorporation being bell-shaped. Binding showed somatogenic rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This phosphorylated IRS-4 associated with PI3-kinase, which was activated along with the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to be involved in insulin-stimulated DNA synthesis. GH induced tyrosine phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells constitute a new model for studying GH and insulin signalling without interference of IGF-1 receptors. AD - Department of Receptor Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. bur@novonordisk.com FAU - Urso, Birgitte AU - Urso B FAU - Ilondo, M Mapoko AU - Ilondo MM FAU - Holst, Patricia A AU - Holst PA FAU - Christoffersen, Claus T AU - Christoffersen CT FAU - Ouwens, Margriet AU - Ouwens M FAU - Giorgetti, Sophie AU - Giorgetti S FAU - Van Obberghen, E AU - Van Obberghen E FAU - Naor, David AU - Naor D FAU - Tornqvist, Hans AU - Tornqvist H FAU - De Meyts, Pierre AU - De Meyts P LA - eng PT - Journal Article PL - England TA - Cell Signal JID - 8904683 RN - 0 (IRS4 protein, human) RN - 0 (Irs4 protein, mouse) RN - 0 (Mitogens) RN - 0 (Phosphoproteins) RN - 11061-68-0 (Insulin) RN - 55520-40-6 (Tyrosine) RN - 9002-72-6 (Growth Hormone) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism MH - Animals MH - Cattle MH - Enzyme Activation MH - Female MH - Growth Hormone/*pharmacology MH - Humans MH - Insulin/*pharmacology MH - Lymphoma, T-Cell MH - Mice MH - Mice, Inbred BALB C MH - Mitogens/*pharmacology MH - Phosphoproteins/*metabolism MH - Phosphorylation/drug effects MH - Receptor, IGF Type 1/deficiency MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured/drug effects/enzymology MH - Tyrosine/metabolism EDAT- 2003/03/06 04:00 MHDA- 2004/01/06 05:00 AID - S0898656802001134 [pii] PST - ppublish SO - Cell Signal 2003 Apr;15(4):385-94. DR -------------------------------------------------------------------------------- 48: Schutt M et al. The HIV protease inhibitor in...[PMID: 12605345] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12605345 OWN - NLM STAT- MEDLINE DA - 20030226 DCOM- 20030930 LR - 20041117 PUBM- Print IS - 0947-7349 VI - 111 IP - 1 DP - 2003 Feb TI - The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells. PG - 16-20 AB - HIV protease inhibitor treatment is associated with insulin resistance. We have recently demonstrated that the HIV protease inhibitor indinavir influences initial insulin signaling steps in HepG2 cells. Here we investigated in the same cell model whether indinavir alters insulin-stimulated glycogen synthesis. Since an altered phosphotyrosine phosphatase activity could represent a mechanism by which insulin signaling is influenced, we also assessed potential indinavir effects on protein tyrosine phosphatase activity directed against tyrosine phosphorylated insulin receptor substrate-1. HepG2 cells were incubated for 48 h without or with indinavir (100 micro mol/l). Subsequently, the insulin-stimulated incorporation of 14C-glucose into glycogen was measured. In indinavir-treated cells the insulin effect on glycogen synthesis was reduced by 30 +/- 4.5 %. Dephosphorylation of immobilized tyrosine-phosphorylated insulin-receptor substrate-1 by the cell extracts was determined using a microwell plate-based method, and indinavir treatment did not alter this dephosphorylation. In conclusion, our data suggest that indinavir affects insulin-stimulation of glycogen synthesis in liver cells, and this may be related to the previously observed alterations in insulin signaling. Direct effects of indinavir on the GLUT4 transport system, that have been suggested from data in other cell systems, are unlikely in HepG2 cells that express no or almost no GLUT4 transport system. Finally, our data do not support the hypothesis that indinavir alters insulin signaling by influencing protein tyrosine phosphatase activity directed against insulin receptor substrate-1. AD - Department of Internal Medicine I, University of Lubeck, Germany. morten.schuett@web.de FAU - Schutt, M AU - Schutt M FAU - Meier, M AU - Meier M FAU - Jost, M M AU - Jost MM FAU - Klein, H H AU - Klein HH LA - eng PT - Journal Article PL - Germany TA - Exp Clin Endocrinol Diabetes JID - 9505926 RN - 0 (HIV Protease Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 11061-68-0 (Insulin) RN - 150378-17-9 (Indinavir) RN - 50-99-7 (Glucose) RN - 9005-79-2 (Glycogen) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - Carcinoma, Hepatocellular/enzymology/*metabolism MH - Glucose/metabolism MH - Glycogen/*biosynthesis MH - HIV Protease Inhibitors/*pharmacology MH - Humans MH - Hypoglycemic Agents/pharmacology MH - Indinavir/*pharmacology MH - Insulin/pharmacology MH - Liver/drug effects/enzymology/metabolism MH - Liver Neoplasms/enzymology/*metabolism MH - Protein-Tyrosine-Phosphatase/metabolism MH - Research Support, Non-U.S. Gov't MH - Stimulation, Chemical MH - Tumor Cells, Cultured EDAT- 2003/02/28 04:00 MHDA- 2003/10/01 05:00 AID - 10.1055/s-2003-37495 [doi] PST - ppublish SO - Exp Clin Endocrinol Diabetes 2003 Feb;111(1):16-20. NR -------------------------------------------------------------------------------- 49: Bohula EA et al. The efficacy of small interfe...[PMID: 12604614] Related Articles, Cited in PMC, Books, LinkOut PMID- 12604614 OWN - NLM STAT- MEDLINE DA - 20030428 DCOM- 20030617 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 278 IP - 18 DP - 2003 May 2 TI - The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. PG - 15991-7 AB - The type 1 insulin-like growth factor receptor (IGF1R) is often overexpressed by tumors and mediates growth and apoptosis protection. We previously showed that antisense reagents complementary to the IGF1R translation start site enhance radio- and chemosensitivity and impair Atm function. However these agents induce relatively modest IGF1R down-regulation and affect insulin receptor levels. To identify alternative sites for molecular targeting, we utilized scanning oligonucleotide arrays to probe the secondary structure of IGF1R mRNA. This strategy enabled selection of antisense oligonucleotides that generated high heteroduplex yield with IGF1R but not insulin receptor transcripts. Antisense oligonucleotides that hybridized strongly to IGF1R mRNA caused IGF1R down-regulation within intact tumor cells, whereas weakly hybridizing oligonucleotides were inactive. Furthermore, the ability of small interfering RNAs (siRNAs) to block IGF1R expression correlated with the accessibility of the target sequence within the transcript. Thus, siRNAs corresponding to weakly hybridizing oligonucleotides caused minor IGF1R down-regulation, whereas siRNAs homologous to accessible targets induced profound sequence-specific IGF1R gene silencing, blocked IGF signaling, and enhanced tumor cell radiosensitivity. This indicates that secondary structure in the target transcript has a major effect on siRNA efficacy. These findings have implications for siRNA design and suggest that IGF1R-targeting agents incorporating this mode of action have potential as anticancer therapy. AD - Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, Headley Way, Headington, Oxford OX3 9DS, United Kingdom. FAU - Bohula, Erin A AU - Bohula EA FAU - Salisbury, Amanda J AU - Salisbury AJ FAU - Sohail, Muhammad AU - Sohail M FAU - Playford, Martin P AU - Playford MP FAU - Riedemann, Johann AU - Riedemann J FAU - Southern, Edwin M AU - Southern EM FAU - Macaulay, Valentine M AU - Macaulay VM LA - eng PT - Journal Article DEP - 20030224 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Gene Silencing MH - Humans MH - Nucleic Acid Conformation MH - RNA, Messenger/*chemistry MH - RNA, Small Interfering/*pharmacology MH - Receptor, IGF Type 1/antagonists & inhibitors/*genetics MH - Research Support, Non-U.S. Gov't MH - Tumor Cells, Cultured EDAT- 2003/02/27 04:00 MHDA- 2003/06/18 05:00 PHST- 2003/02/24 [aheadofprint] AID - 10.1074/jbc.M300714200 [doi] AID - M300714200 [pii] PST - ppublish SO - J Biol Chem 2003 May 2;278(18):15991-7. Epub 2003 Feb 24. NR -------------------------------------------------------------------------------- 50: Sachdev D et al. A chimeric humanized single-c...[PMID: 12566306] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12566306 OWN - NLM STAT- MEDLINE DA - 20030204 DCOM- 20030307 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 63 IP - 3 DP - 2003 Feb 1 TI - A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. PG - 627-35 AB - Insulin-like growth factors (IGFs) stimulate breast cancer proliferation, motility, and survival.The type I IGF receptor (IGF1R) mediates the effects of IGF-I. Thus, inhibition of IGF1R activation could inhibit IGF action in breast cancer cells. A single-chain antibody directed against IGF1R (IGF1R scFv-Fc) has been shown to partially inhibit xenograft growth of MCF-7 cells in athymic mice. In this study, we have examined the effects of scFv-Fc on IGF1R signaling in the estrogen receptor-positive (ER+) MCF-7 breast cancer cells in vitro and in vivo. The antibody stimulated IGF1R activation in vitro in MCF-7 cells and was unable to block IGF-I effects. The antibody also stimulated proliferation of MCF-7 cells in monolayer growth assays. To determine how scFv-Fc could stimulate in vitro growth yet inhibit in vivo tumor growth, we examined the effect of scFv-Fc on IGF1R expression. In MCF-7 cells, scFv-Fc down-regulated IGF1R levels after 2 h, and the levels were greatly reduced after 24 h. In contrast, IGF-I treatment over the same time period did not affect IGF1R levels. Twenty-four-h pretreatment of cells with scFv-Fc blocked IGF-I mediated phosphorylation of insulin receptor substrate-1 and subsequent extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 and phosphatidylinositol 3'-kinase activation. In contrast, cells treated with 5 nM IGF-I for 24 h still retained the ability to further activate downstream signaling pathways in response to IGF-I. Moreover, pretreatment of MCF-7 cells with scFv-Fc rendered them refractory to further proliferation induced by additional IGF-I. Twenty-four-h pretreatment of cells with scFv-Fc also inhibited IGF-I stimulated anchorage-independent growth. scFv-Fc did not enhance antibody-dependent cell-mediated cytotoxicity. In vivo, treatment of mice bearing MCF-7 xenograft tumors with scFv-Fc resulted in near complete down-regulation of IGF1R. Our data show that scFv-Fc stimulates biochemical activation of IGF1R, then causes receptor down-regulation, making MCF-7 cells refractory to additional IGF-I exposure. These results indicate that such chimeric single-chain antibodies against IGF1R have future potential in breast cancer therapy by causing down-regulation of receptor. AD - Department of Medicine, University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA. FAU - Sachdev, Deepali AU - Sachdev D FAU - Li, Shu-Lian AU - Li SL FAU - Hartell, Julie S AU - Hartell JS FAU - Fujita-Yamaguchi, Yoko AU - Fujita-Yamaguchi Y FAU - Miller, Jeffrey S AU - Miller JS FAU - Yee, Douglas AU - Yee D LA - eng GR - P30 CA77398/CA/NCI GR - R01 CA74285/CA/NCI PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Antibodies, Monoclonal) RN - 0 (Chimeric Proteins) RN - 0 (Immunoglobulin Fragments) RN - 0 (Immunoglobulin G) RN - 0 (MAP Kinase Signaling System) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - 3T3 Cells MH - Animals MH - Antibodies, Monoclonal/immunology/pharmacology MH - Breast Neoplasms/immunology/therapy MH - Cell Adhesion/drug effects/physiology MH - Cell Division/drug effects/physiology MH - Chimeric Proteins/immunology/*pharmacology MH - Down-Regulation/drug effects MH - Female MH - Immunoglobulin Fragments/immunology/*pharmacology MH - Immunoglobulin G/immunology/pharmacology MH - Insulin-Like Growth Factor I/*antagonists & inhibitors/pharmacology MH - MAP Kinase Signaling System/drug effects/physiology MH - Mice MH - Mice, Nude MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Receptor, IGF Type 1/*agonists/*immunology/metabolism/physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/physiology MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays EDAT- 2003/02/05 04:00 MHDA- 2003/03/08 04:00 PST - ppublish SO - Cancer Res 2003 Feb 1;63(3):627-35. NR -------------------------------------------------------------------------------- 51: Mamay CL et al. An inhibitory function for JN...[PMID: 12555073] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12555073 OWN - NLM STAT- MEDLINE DA - 20030129 DCOM- 20030212 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 22 IP - 4 DP - 2003 Jan 30 TI - An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer. PG - 602-14 AB - Insulin-like growth factor-I receptor (IGF-IR) is frequently overexpressed in a variety of cancer types. Since many breast tumors and cancer cell lines overexpress IGF-IR, we tested IGF-I effects on chemotherapy-treated breast cancer cells. IGF-I protects from chemotherapy-induced apoptosis, suggesting that overlapping signaling pathways modulate IGF-I and chemotherapy treatment outcomes. Taxol and other chemotherapy drugs induce c-Jun N-terminal kinase (JNK), a kinase that conveys cellular stress and death signals. Notably, in this paper we show that IGF-I alone induces a potent JNK response and this activity is reversed by inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) with LY294002 in MCF-7 but not T47D cells. Cotreatment of cells with chemotherapy and IGF-I leads to additive JNK responses. Using cells overexpressing Akt, we confirm that IGF-I-mediated survival is Akt dependent. In contrast, overexpression of JNK significantly enhances Taxol-induced apoptosis and inhibits IGF-I survival effects. Further, JNK attenuates anchorage-independent growth of MCF-7 cells. The inhibitory effect of JNK appears to be mediated by serine phosphorylation of IRS-1 (insulin receptor substrate) since both Taxol and IGF-I treatment enhanced Ser(312) IRS-1 phosphorylation, while LY294002 blocked IGF-I-mediated phosphorylation. Taken together, these data provide a mechanism whereby stress or growth factors activate JNK to reduce proliferation and/or survival in breast cancer cells. AD - Department of Biological Chemistry, University of California, Davis 95616-8655, USA. FAU - Mamay, Cindy L AU - Mamay CL FAU - Mingo-Sion, Amy M AU - Mingo-Sion AM FAU - Wolf, Doug M AU - Wolf DM FAU - Molina, Marion D AU - Molina MD FAU - Van Den Berg, Carla L AU - Van Den Berg CL LA - eng GR - CA89288A/CA/NCI PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (DNA Primers) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 56-45-1 (Serine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Base Sequence MH - Blotting, Western MH - Breast Neoplasms/*enzymology/pathology MH - Cell Division MH - Cell Survival MH - DNA Primers MH - Humans MH - Insulin-Like Growth Factor I/*metabolism MH - JNK Mitogen-Activated Protein Kinases MH - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/biosynthesis MH - Phosphoproteins/chemistry/metabolism MH - Phosphorylation MH - Precipitin Tests MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Serine/metabolism MH - *Signal Transduction MH - Tumor Cells, Cultured EDAT- 2003/01/30 04:00 MHDA- 2003/02/14 04:00 AID - 10.1038/sj.onc.1206186 [doi] AID - 1206186 [pii] PST - ppublish SO - Oncogene 2003 Jan 30;22(4):602-14. NR -------------------------------------------------------------------------------- 52: Kang S et al. Insulin can block apoptosis b...[PMID: 12534368] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12534368 OWN - NLM STAT- MEDLINE DA - 20030121 DCOM- 20030224 LR - 20041117 PUBM- Print IS - 0804-4643 VI - 148 IP - 1 DP - 2003 Jan TI - Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells. PG - 147-55 AB - OBJECTIVE: Insulin has well-known activities in controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Recently, several studies have suggested that insulin may protect cells from apoptosis in different cell lines; however, little is known about the nature of its anti-apoptotic activity. In many clinical disorders, including type 2 diabetes mellitus, oxidative stress and the production of reactive oxygen species (ROS) is increased. With these facts as a background, we examined here whether insulin protects HepG2 cells from apoptosis by decreasing oxidative stress and, if so, which signaling steps are involved in this process. METHODS: Intracellular DNA content, the degree of nuclear condensation or poly(ADP-ribose) polymerase hydrolysis was measured to verify the occurrence of apoptotic events. Caspase-3 activity and ROS accumulation within cells were also measured. Western blot analysis was performed to identify signaling molecules activated in response to insulin. RESULTS: Serum starvation resulted in a marked accumulation of ROS, activation of caspase-3, and subsequent apoptotic cell death which were, in turn, markedly blocked by the addition of insulin. The anti-apoptotic activity of insulin was sensitive to blockade of two different signaling steps, activations of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated protein kinase (ERK). CONCLUSION: Insulin exerts an anti-apoptotic activity by suppressing the excessive accumulation of ROS within cells through signaling pathways including stimulation of PI3 kinase and ERK in HepG2 cells. AD - Department of Medicine, College of Medicine, Institute of Basic Science and Department of Biology, College of Natural Science, Cheju National University, Ara-1, Cheju, 690-756, South Korea. FAU - Kang, Shinhae AU - Kang S FAU - Song, Jihoon AU - Song J FAU - Kang, Heekyoung AU - Kang H FAU - Kim, Sejae AU - Kim S FAU - Lee, Youngki AU - Lee Y FAU - Park, Deokbae AU - Park D LA - eng PT - Journal Article PL - England TA - Eur J Endocrinol JID - 9423848 RN - 0 (Culture Media, Serum-Free) RN - 0 (Hypoglycemic Agents) RN - 0 (MAP Kinase Signaling System) RN - 0 (Reactive Oxygen Species) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 3.4.22.- (Caspases) RN - EC 3.4.22.- (caspase-3) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism MH - Apoptosis/*drug effects/physiology MH - Caspases/metabolism MH - Culture Media, Serum-Free/pharmacology MH - Enzyme Activation/drug effects MH - Hepatoblastoma MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - Insulin/*pharmacology MH - Liver Neoplasms MH - MAP Kinase Signaling System/drug effects MH - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism MH - Oxidative Stress/drug effects MH - Reactive Oxygen Species/metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Tumor Cells, Cultured EDAT- 2003/01/22 04:00 MHDA- 2003/02/25 04:00 PST - ppublish SO - Eur J Endocrinol 2003 Jan;148(1):147-55. DR -------------------------------------------------------------------------------- 53: Lornejad-Schafer MR et al. Osmotic regulation of insulin...[PMID: 12529177] Related Articles, Gene, HomoloGene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12529177 OWN - NLM STAT- MEDLINE DA - 20030404 DCOM- 20030703 LR - 20041117 PUBM- Print IS - 0264-6021 VI - 371 IP - Pt 2 DP - 2003 Apr 15 TI - Osmotic regulation of insulin-induced mitogen-activated protein kinase phosphatase (MKP-1) expression in H4IIE rat hepatoma cells. PG - 609-19 AB - A contribution of intracellular dehydration to insulin resistance has been established in human subjects and in different experimental systems. Here the effect of hyperosmolarity (405 mosmol/l) on insulin-induced mitogen-activated protein (MAP) kinase phosphatase (MKP)-1 expression was studied in H4IIE rat hepatoma cells. Insulin induces robust MKP-1 expression which correlates with a vanadate-sensitive decay of extracellular-signal-regulated kinase (Erk-1/Erk-2) activity. Hyperosmolarity delays MKP-1 accumulation by insulin and this corresponds to impaired MKP-1 synthesis, whereas MKP-1 degradation remains unaffected by hyperosmolarity. Rapamycin, which inhibits signalling downstream from the mammalian target of rapamycin (mTOR) and a peptide inhibiting protein kinase C (PKC) zeta/lambda abolish insulin-induced MKP-1 protein but not mRNA expression, suggesting the involvement of the p70 ribosomal S6 protein kinase (p70S6-kinase) and/or the eukaryotic initiation factor 4E-binding proteins (4E-BPs) as well as atypical PKCs in MKP-1 translation. Hyperosmolarity induces sustained suppression of p70S6-kinase and 4E-BP1 hyperphosphorylation by insulin, whereas insulin-induced tyrosine phosphorylation of the insulin receptor (IR) beta subunit and the IR substrates IRS1 and IRS2, recruitment of the phosphoinositide 3-kinase (PI 3-kinase) regulatory subunit p85 to the receptor substrates as well as PI 3-kinase activation, and Ser-473 phosphorylation of protein kinase B and Thr-410/403 phosphorylation of PKC zeta/lambda are largely unaffected under hyperosmotic conditions. The hyperosmotic impairment of both, MKP-1 expression and p70S6-kinase hyperphosphorylation by insulin is insensitive to K(2)CrO(4), calyculin A and vanadate, and inhibition of the Erk-1/Erk-2 and p38 pathways. The suppression of MKP-1 may further contribute to insulin resistance under dehydrating conditions by allowing unbalanced MAP kinase activation. AD - Medizinische Einrichtungen der Heinrich-Heine Universitat, Klinik fur Gastroenterologie, Hepatologie und Infektiologie, Moorenstrasse 5, D-40225 Dusseldorf, Germany. FAU - Lornejad-Schafer, Mohammad Reza AU - Lornejad-Schafer MR FAU - Schafer, Christine AU - Schafer C FAU - Graf, Dirk AU - Graf D FAU - Haussinger, Dieter AU - Haussinger D FAU - Schliess, Freimut AU - Schliess F LA - eng PT - Journal Article PL - England TA - Biochem J JID - 2984726R RN - 0 (Cell Cycle Proteins) RN - 0 (Immediate-Early Proteins) RN - 0 (MAP Kinase Signaling System) RN - 0 (RNA, Messenger) RN - 11061-68-0 (Insulin) RN - 146888-90-6 (3CH134 protein) RN - EC 3.1.3.16 (Phosphoprotein Phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - Animals MH - Carcinoma, Hepatocellular MH - *Cell Cycle Proteins MH - Enzyme Induction/drug effects MH - Gene Expression Regulation, Enzymologic MH - Gene Expression Regulation, Neoplastic/*physiology MH - Immediate-Early Proteins/biosynthesis/*genetics MH - Insulin/*pharmacology MH - Kinetics MH - Liver Neoplasms MH - MAP Kinase Signaling System MH - Osmolar Concentration MH - *Phosphoprotein Phosphatase MH - Protein-Tyrosine-Phosphatase/biosynthesis/*genetics MH - RNA, Messenger/genetics MH - Rats MH - Transcription, Genetic MH - Tumor Cells, Cultured EDAT- 2003/01/17 04:00 MHDA- 2003/07/04 05:00 PHST- 2003/01/15 [accepted] PHST- 2003/01/10 [revised] PHST- 2002/08/29 [received] AID - 10.1042/BJ20021357 [doi] AID - BJ20021357 [pii] PST - ppublish SO - Biochem J 2003 Apr 15;371(Pt 2):609-19. PR -------------------------------------------------------------------------------- 54: Yuan L et al. Metformin modulates insulin p...[PMID: 12511230] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12511230 OWN - NLM STAT- MEDLINE DA - 20030103 DCOM- 20031001 LR - 20041117 PUBM- Print IS - 1671-4083 VI - 24 IP - 1 DP - 2003 Jan TI - Metformin modulates insulin post-receptor signaling transduction in chronically insulin-treated Hep G2 cells. PG - 55-60 AB - AIM: To study the effect of chronic insulin treatment on insulin post-receptor signaling transduction and whether the effects of metformin are transmitted throughout the cascade of insulin signaling intermediates in a human hepatoma cell line (Hep G2). METHODS: Hep G2 cells were incubated in serum free media containing either insulin 100 nmol/L or insulin 100 nmol/L plus different concentrations (0.01-10 mmol/L) of metformin for 16 h and then were stimulated with insulin 100 nmol/L for 1 min. RESULTS: Chronic treatment of insulin 100 nmol/L induced a significant reduction in the phosphorylation and protein expression of IR?, IRS1 and IRS2, which therefore resulted in a downregulation of association of PI3K with IRS. Therapeutic concentrations (0.01-0.1 mmol/L) of metformin prevented the changes induced by chronic insulin treatment in these post-receptor components of insulin signaling pathway. Tyrosine phosphorylation of IR?, IRS1, and IRS2 was increased by 2.7 fold (P < 0.01), 6.8 fold (P < 0.01), and 2.3 fold (P <0.01) of chronically insulin-treated cells alone, respectively, after metformin 0.1 mmol/L was added. The association of p85 with IRS1 and IRS2 was also increased from 34 % to 86 % (P <0.01) and from 30 % to 92 % (P <0.01), respectively. In contrast, metformin in pharmacological concentration (1-10 mmol/L) further inhibited tyrosine phosphorylation of IR?, IRS1, IRS2 and the interaction of PI3K with IRS. The association of IRS1 with p85 was further decreased by 58 % (P >0.05) and of IRS2 by 30 % (P <0.05). CONCLUSION: Chronic insulin exposure of Hep G2 cells induces the downregulation of insulin signal transduction via PI3K pathway. The effect of metformin on insulin signaling transduction represent a primary mechanism of metformin action in insulin resistant state. AD - Department of Endocrinology and Metabolism in Hospital of University Heidelberg, Heidelberg 69115, Germany. yuanli18cn@yahoo.com.cn FAU - Yuan, Li AU - Yuan L FAU - Ziegler, Reinhard AU - Ziegler R FAU - Hamann, Andreas AU - Hamann A LA - eng PT - Journal Article PL - China TA - Acta Pharmacol Sin JID - 100956087 RN - 0 (Hypoglycemic Agents) RN - 657-24-9 (Metformin) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Carcinoma, Hepatocellular/pathology MH - Humans MH - Hypoglycemic Agents/*pharmacology MH - Insulin Resistance MH - Liver Neoplasms/pathology MH - Metformin/*pharmacology MH - Receptor, Insulin/antagonists & inhibitors/*metabolism MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured EDAT- 2003/01/04 04:00 MHDA- 2003/10/02 05:00 PST - ppublish SO - Acta Pharmacol Sin 2003 Jan;24(1):55-60. PR -------------------------------------------------------------------------------- 55: Clampit JE et al. Reduction of protein-tyrosine...[PMID: 12504077] Related Articles, Gene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12504077 OWN - NLM STAT- MEDLINE DA - 20021230 DCOM- 20030225 LR - 20050111 PUBM- Print IS - 0006-291X VI - 300 IP - 2 DP - 2003 Jan 10 TI - Reduction of protein-tyrosine phosphatase-1B increases insulin signaling in FAO hepatoma cells. PG - 261-7 AB - Protein-tyrosine phosphatase-1B (PTP1B) has been implicated as a negative regulator of insulin signaling. PTP1B dephosphorylates the insulin receptor and insulin receptor substrates (IRS-1/2), inhibiting the insulin-signaling pathway. PTP1B has been reported to be elevated in diabetes and insulin-resistant states. Conversely, PTP1B null mice have increased insulin sensitivity. To further investigate the effect of PTP1B reduction on insulin signaling, FAO rat hepatoma cells were transfected, by electroporation, with a specific PTP1B antisense oligonucleotide (ASO), or a control oligonucleotide. The PTP1B ASO caused a 50-70% reduction in PTP1B protein expression as measured by Western blot analysis. Upon insulin stimulation, an increase in the phosphorylation of the insulin receptor and insulin receptor substrates was observed, without any change in protein expression levels. Reduction of PTP1B expression in FAO cells also caused an increase in insulin-stimulated phosphorylation of PKB and GSK3, without any change in protein expression. These results demonstrate that reduction of PTP1B can modulate key insulin signaling events downstream of the insulin receptor. AD - Insulin Signaling, Metabolic Diseases Research, Global Pharmaceutical Research Division, Abbott Laboratories, Department 47R, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60064-6009, USA. FAU - Clampit, Jill E AU - Clampit JE FAU - Meuth, Joseph L AU - Meuth JL FAU - Smith, Harriet T AU - Smith HT FAU - Reilly, Regina M AU - Reilly RM FAU - Jirousek, Michael R AU - Jirousek MR FAU - Trevillyan, James M AU - Trevillyan JM FAU - Rondinone, Cristina M AU - Rondinone CM LA - eng PT - Journal Article PL - United States TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (Oligonucleotides, Antisense) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Glycogen Synthase Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.1.3.48 (protein tyrosine phosphatase 1B) SB - IM MH - Animals MH - Carcinoma, Hepatocellular MH - Dose-Response Relationship, Drug MH - Glycogen Synthase Kinase 3/metabolism MH - Insulin/*pharmacology MH - Mitogen-Activated Protein Kinases/metabolism MH - Oligonucleotides, Antisense/genetics MH - Phosphoproteins/metabolism MH - Phosphorylation MH - *Protein-Serine-Threonine Kinases MH - Protein-Tyrosine-Phosphatase/genetics/*physiology MH - Proto-Oncogene Proteins/metabolism MH - Rats MH - Receptor, Insulin/metabolism MH - *Signal Transduction MH - Tumor Cells, Cultured EDAT- 2002/12/31 04:00 MHDA- 2003/02/26 04:00 AID - S0006291X02028395 [pii] PST - ppublish SO - Biochem Biophys Res Commun 2003 Jan 10;300(2):261-7. PR -------------------------------------------------------------------------------- 56: Schnyder B et al. Mono- or dual-phosphorylation...[PMID: 12503617] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12503617 OWN - NLM STAT- MEDLINE DA - 20021230 DCOM- 20030605 LR - 20050111 PUBM- Print IS - 1079-9893 VI - 22 IP - 1-4 DP - 2002 Feb-Nov TI - Mono- or dual-phosphorylation of akt kinase is regulated by distinct receptors that involve the common insulin receptor substrate. PG - 213-28 AB - We have previously shown that the interleukin (IL)-4 signal transduction involves the Insulin Receptor Substrate (IRS) in human colorectal carcinoma cells LS513. In the present study it was tested whether IL-4 counters Insulin-like Growth Factor (IGF)-1 through competition at the IRS signal transduction pathway and, thus, induces a molecular "insulin resistance" or whether IL-4 invokes an alternative signal transduction. The activated receptors of IL-4 and IGF-I both docked to IRS-1 and IRS-2 and invoked IRS complex formation with phosphatidylinositol (PI) 3-kinase, as assessed by immunoprecipitation and detection of the precipitated compounds by immunoblot analysis. Both, IL-4 and IGF-1, signaling pathways induced phosphorylation of Akt kinase in a PI 3-kinase-dependent manner, as assessed by addition of the PI 3-kinase inhibitor Ly294002. Interleukin-4 stimulation induced mono-phosphorylation at serine residue S473 of Akt kinase but failed to activate the kinase. Insulin-like growth factor-1 stimulation invoked dual-phosphorylation at S473 and T308 of Akt kinase and subsequent activation of the kinase. When LS513 cells were treated with IL-4 to induce mono-phosphorylation of Akt, dual- phosphorylation and activation of Akt kinase in response to IGF-1 were still intact. Interleukin-4 yet reduced cell growth by at least 50% both, in the absence and presence of growth factor IGF-1. In the LS513 cells, IL-4 stimulated phosphorylation of Jak2, an adapter molecule at the IL-4 receptor, and phosphorylation of transcription factor Stat6 both, in the absence and presence of IGF-1. We found a similar IL-4 signal transduction and growth suppression in multiple human cell cultures, including primary cells. Our findings indicate that the molecular mechanism underlying growth suppression by IL-4 may depend on gene-expression but not on "insulin/growth factor resistance" at IRS. AD - University of Fribourg, Department of Medicine, Fribourg, Switzerland. bruno.schnyder@unifr.ch FAU - Schnyder, Bruno AU - Schnyder B FAU - Lahm, Harald AU - Lahm H FAU - Pittet, Martine AU - Pittet M FAU - Schnyder-Candrian, Silvia AU - Schnyder-Candrian S LA - eng PT - Journal Article PL - United States TA - J Recept Signal Transduct Res JID - 9509432 RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 207137-56-2 (Interleukin-4) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism MH - Cell Division/drug effects MH - Chromones/pharmacology MH - Colorectal Neoplasms/*metabolism/pathology MH - Enzyme Inhibitors/pharmacology MH - Humans MH - Immunoblotting MH - Insulin Resistance MH - Insulin-Like Growth Factor I/*metabolism MH - Interleukin-4/*metabolism MH - Morpholines/pharmacology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Precipitin Tests MH - *Protein-Serine-Threonine Kinases MH - Protein-Tyrosine Kinase/metabolism MH - Proto-Oncogene Proteins/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Trans-Activators/metabolism MH - Tumor Cells, Cultured/drug effects/metabolism EDAT- 2002/12/31 04:00 MHDA- 2003/06/06 05:00 PST - ppublish SO - J Recept Signal Transduct Res 2002 Feb-Nov;22(1-4):213-28. NR -------------------------------------------------------------------------------- 57: Matheson SL et al. Differential responses of EGF...[PMID: 12497201] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12497201 OWN - NLM STAT- MEDLINE DA - 20021223 DCOM- 20030225 LR - 20041117 PUBM- Print-Electronic IS - 0344-5704 VI - 51 IP - 1 DP - 2003 Jan TI - Differential responses of EGFR-/AGT-expressing cells to the "combi-triazene" SMA41. PG - 11-20 AB - PURPOSE: Previous studies have demonstrated enhanced potency associated with the binary [DNA/epidermal growth factor receptor (EGFR)] targeting properties of SMA41 (a chimeric 3-(alkyl)-1,2,3-triazene linked to a 4-anilinoquinazoline backbone) in the A431 (epidermal carcinoma of the vulva) cell line. We now report on the dependence of its antiproliferative effects (e.g. DNA damage, cell survival) on the EGFR and the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) contents of 12 solid tumor cell lines, two of which, NIH3T3 and NIH3T3 HER14 (engineered to overexpress EGFR), were isogenic. METHODS: Receptor type specificity was determined using ELISA for competitive binding, as well as growth factor-stimulation assays. DNA damage was studied using single-cell microelectrophoresis (comet) assays, and levels of EGFR were determined by Western blotting. The effects of SMA41 on the cell cycle of NIH3T3 cells were investigated using univariate flow cytometry. RESULTS: Studies of receptor type specificity showed that SMA41: (a) preferentially inhibited the kinase activity of EGFR over those of Src, insulin receptor and protein kinase C (PKC, a serine/threonine kinase), (b) induced stronger inhibition of growth stimulated with EGF than of growth stimulated with platelet-derived growth factor (PDGF) or fetal bovine serum (FBS). Despite the EGFR specificity of SMA41, there was an absence of a linear correlation between the EGFR status of our solid tumor cell lines and levels of DNA damage induced by the alkylating component. Similarly, EGFR levels did not correlate with IC(50) values. The antiproliferative activities of SMA41 correlated more with the AGT status of these cells and paralleled those of the clinical triazene temozolomide (TEM). However, throughout the panel, tumor cell sensitivity to SMA41 was consistently stronger than to its closest analogue TEM. Experiments performed with the isogenic cells showed that SMA41 was capable of inducing twofold higher levels of DNA damage in the EGFR transfectant and delayed cell entry to G(2)/M in both cell types. When the cells were starved and growth-stimulated with FBS (conditions under which both cell types were growth-stimulated), in contrast to TEM, SMA41 and its hydrolytic metabolite SMA52 exhibited approximately nine- and threefold stronger inhibition of growth of the EGFR transfectant. CONCLUSIONS: These results suggest that, in addition to its ability to induce DNA damage and cell cycle perturbations, SMA41 is capable of selectively targeting the cells with a growth advantage conferred by EGFR transfection. When compared with the monoalkyltriazene prodrug TEM, its potency may be further enhanced by its ability to hydrolyze to another signal transduction inhibitor (SMA52) plus a DNA alkylating agent that may further contribute to chemosensitivity. Thus, our new "combi-targeting" strategy may well represent a tandem approach to selectively blocking receptor tyrosine kinase-mediated growth signaling while inducing significant levels of cytotoxic DNA lesions in refractory tumors. AD - Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Rm. M 7.15, Montreal, Quebec, H3A 1A1, Canada. FAU - Matheson, Stephanie L AU - Matheson SL FAU - McNamee, James P AU - McNamee JP FAU - Jean-Claude, Bertrand J AU - Jean-Claude BJ LA - eng PT - Journal Article DEP - 20021122 PL - Germany TA - Cancer Chemother Pharmacol JID - 7806519 RN - 0 (Antineoplastic Agents) RN - 0 (Quinazolines) RN - 0 (SMA-41) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.1.1.63 (O(6)-Methylguanine-DNA Methyltransferase) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) SB - IM MH - 3T3 Cells MH - Animals MH - Antineoplastic Agents/*pharmacology MH - Cell Cycle/drug effects MH - Cell Division/drug effects MH - *DNA Damage MH - Epidermal Growth Factor/pharmacology MH - Humans MH - Mice MH - O(6)-Methylguanine-DNA Methyltransferase/*physiology MH - Quinazolines/*pharmacology MH - Receptor, Epidermal Growth Factor/analysis/*antagonists & inhibitors MH - Research Support, Non-U.S. Gov't MH - Tumor Cells, Cultured EDAT- 2002/12/24 04:00 MHDA- 2003/02/26 04:00 PHST- 2002/05/19 [received] PHST- 2002/08/23 [accepted] PHST- 2002/11/22 [aheadofprint] AID - 10.1007/s00280-002-0525-4 [doi] PST - ppublish SO - Cancer Chemother Pharmacol 2003 Jan;51(1):11-20. Epub 2002 Nov 22. DR -------------------------------------------------------------------------------- 58: Del Valle L et al. Insulin-like growth factor I ...[PMID: 12491166] Related Articles, Cited in PMC, Cited in Books, Books, LinkOut PMID- 12491166 OWN - NLM STAT- MEDLINE DA - 20021219 DCOM- 20030303 LR - 20041117 PUBM- Print IS - 1355-0284 VI - 8 Suppl 2 DP - 2002 Dec TI - Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas. PG - 138-47 AB - Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum, affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that both the cellular protein insulin-like growth factor I (IGF-I) and the early protein of the human polyomavirus JC (JCV T antigen) may contribute to the development of these tumors. The results of this study show a potential functional cooperation between these two proteins in the process of malignant transformation. Both medulloblastoma cell lines and medulloblastoma biopsies are characterized by the abundant presence of the IGF-I receptor (IGF-IR) and its major signaling molecule, insulin receptor substrate 1 (IRS-1). Importantly, IRS-1 is translocated to the nucleus in the presence of the JCV T antigen. Nuclear IRS-1 was detected in T antigen-positive cell lines and in T antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JCV T antigen binding was localized within the N-terminal portion of IRS-1 molecule and the competition for IRS-1 T antigen binding by a dominant-negative mutant of IRS-1 inhibited growth and survival of JCV T antigen-transformed cells in anchorage-independent culture condition. AD - Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania 19122, USA. FAU - Del Valle, Luis AU - Del Valle L FAU - Wang, Jin Ying AU - Wang JY FAU - Lassak, Adam AU - Lassak A FAU - Peruzzi, Francesca AU - Peruzzi F FAU - Croul, Sidney AU - Croul S FAU - Khalili, Kamel AU - Khalili K FAU - Reiss, Krzysztof AU - Reiss K LA - eng GR - P01 NS36466/NS/NINDS GR - R01 CA95518-01/CA/NCI PT - Journal Article PT - Review PL - United States TA - J Neurovirol JID - 9508123 RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Brain Neoplasms/*virology MH - Cerebellar Neoplasms/virology MH - Humans MH - *JC Virus MH - Medulloblastoma/virology MH - Neuroectodermal Tumors, Primitive/*virology MH - Polyomavirus Infections/complications/*physiopathology MH - Receptor, IGF Type 1/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/physiology MH - Tumor Virus Infections/complications/*physiopathology RF - 34 EDAT- 2002/12/20 04:00 MHDA- 2003/03/04 04:00 AID - 10.1080/13550280290101111 [doi] PST - ppublish SO - J Neurovirol 2002 Dec;8 Suppl 2:138-47. NR -------------------------------------------------------------------------------- 59: Allende ML et al. Lubricating cell signaling pa...[PMID: 12464309] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12464309 OWN - NLM STAT- MEDLINE DA - 20021204 DCOM- 20030326 LR - 20031114 PUBM- Print IS - 0959-440X VI - 12 IP - 5 DP - 2002 Oct TI - Lubricating cell signaling pathways with gangliosides. PG - 587-92 AB - Gangliosides--glycosphingolipids that contain sialic acid--are concentrated in plasma membrane lipid domains that are specialized for cell signaling. Recent evidence indicates that gangliosides have two different roles in cell signaling. They can act in cis to modulate tyrosine kinase receptor function and in trans as ligands for receptors that facilitate communication between cells. These signaling functions of gangliosides may be potential therapeutic targets in cancer, diabetes and nerve regeneration. AD - Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1821, USA. FAU - Allende, Maria Laura AU - Allende ML FAU - Proia, Richard L AU - Proia RL LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Curr Opin Struct Biol JID - 9107784 RN - 0 (Gangliosides) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.2.1.18 (Neuraminidase) SB - IM MH - Animals MH - Cell Membrane/physiology MH - Gangliosides/biosynthesis/*physiology MH - Membrane Microdomains/physiology MH - Mice MH - Mice, Knockout MH - Neuraminidase/metabolism MH - Receptor Protein-Tyrosine Kinases/metabolism MH - Receptor, Epidermal Growth Factor/metabolism MH - Receptor, Insulin/metabolism MH - Signal Transduction/*physiology RF - 56 EDAT- 2002/12/05 04:00 MHDA- 2003/03/27 05:00 AID - S0959440X02003767 [pii] PST - ppublish SO - Curr Opin Struct Biol 2002 Oct;12(5):587-92. PR -------------------------------------------------------------------------------- 60: Le MN et al. Dual mechanism of signal tran...[PMID: 12456798] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12456798 OWN - NLM STAT- MEDLINE DA - 20021128 DCOM- 20030609 LR - 20041217 PUBM- Print IS - 0888-8809 VI - 16 IP - 12 DP - 2002 Dec TI - Dual mechanism of signal transducer and activator of transcription 5 activation by the insulin receptor. PG - 2764-79 AB - Insulin stimulates signal transducer and activator of transcription 5 (Stat5) activation in insulin receptor (IR)-overexpressing cell lines and in insulin target tissues of mice. Stat5b and insulin receptor substrate 1 (IRS-1) interact with the same autophosphorylation site in the IR [phosphotyrosine (pY) 972] in yeast two-hybrid assays, and the IR phosphorylates Stat5b in vitro. These data suggest that Stat5 proteins might be recruited to, and phosphorylated by, the activated IR in vivo. Nevertheless, insulin activates Janus kinases (JAKs) in IR-overexpressing cell lines and in insulin target tissues. To determine whether Stat5 proteins must be recruited to the pY972LSA motif in the IR for insulin-stimulated activation in mammalian cells, we generated and tested a series of IR mutants. The L973R/A975D mutation abolishes the ability of the IR to induce Stat5 activation, whereas IRS-1 phosphorylation is unaffected. In contrast, the N969A/P970A mutation in the IR has no effect on Stat5 activation but significantly reduces IRS-1 phosphorylation. In coimmunoprecipitation assays, insulin-stimulated Stat5 activation correlates with Stat5 recruitment to the IR. We also find that insulin stimulates tyrosine phosphorylation of JAKs that are constitutively associated with the IR. Expression of dominant-negative (DN) JAKs, the JAK inhibitor suppressor of cytokine signaling 1, or pretreatment with the JAK inhibitor, AG490, reduces, but does not eliminate, insulin-induced Stat5 activation. Expression of the appropriate pair of DN JAKs in each of the singly JAK-deficient cell lines further establishes a component of insulin-stimulated Stat5 activation that is JAK independent. This likely represents phosphorylation of Stat5 proteins by the IR, as we find that IR kinase domain phosphorylates Stat5b in vitro on Y699 as efficiently as JAK2. Increasing the concentration of Stat5 proteins in cells favors the direct phosphorylation of Stat5 by the IR kinase where the DN-JAK inhibition of insulin-stimulated Stat5 activation becomes insignificant. At physiological levels of Stat5 however, we propose that JAKs and the IR both contribute to the insulin-induced phosphorylation of Stat5. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA. FAU - Le, Maithao N AU - Le MN FAU - Kohanski, Ronald A AU - Kohanski RA FAU - Wang, Lu-Hai AU - Wang LH FAU - Sadowski, Henry B AU - Sadowski HB LA - eng GR - CA 29339/CA/NCI GR - CA 55054/CA/NCI GR - DK 53000/DK/NIDDK PT - Journal Article PL - United States TA - Mol Endocrinol JID - 8801431 RN - 0 (Carrier Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (Enzyme Inhibitors) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Milk Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Repressor Proteins) RN - 0 (SOCS1 protein, human) RN - 0 (Socs1 protein, rat) RN - 0 (Stat5 protein) RN - 0 (Trans-Activators) RN - 0 (Tyrphostins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (tyrphostin AG-490) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - EC 1.13.12.- (Luciferases) RN - EC 2.7.1.112 (Janus kinase 1) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Baculoviridae/genetics MH - COS Cells MH - Carrier Proteins/pharmacology MH - DNA-Binding Proteins/*metabolism MH - Enzyme Activation/drug effects MH - Enzyme Inhibitors/pharmacology MH - Gene Expression MH - Humans MH - Immunosorbent Techniques MH - Insulin/pharmacology MH - *Intracellular Signaling Peptides and Proteins MH - Liver Neoplasms, Experimental/metabolism MH - Luciferases/genetics MH - *Milk Proteins MH - Mutagenesis MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Protein-Tyrosine Kinase/antagonists & inhibitors/deficiency/metabolism MH - *Proto-Oncogene Proteins MH - Rats MH - Receptor, Insulin/genetics/*physiology MH - *Repressor Proteins MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Trans-Activators/*metabolism MH - Transfection MH - Tumor Cells, Cultured MH - Tyrphostins/pharmacology EDAT- 2002/11/29 04:00 MHDA- 2003/06/10 05:00 PST - ppublish SO - Mol Endocrinol 2002 Dec;16(12):2764-79. PR -------------------------------------------------------------------------------- 61: Sciacca L et al. In IGF-I receptor-deficient l...[PMID: 12447687] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12447687 OWN - NLM STAT- MEDLINE DA - 20021126 DCOM- 20021213 LR - 20050111 PUBM- Print IS - 0950-9232 VI - 21 IP - 54 DP - 2002 Nov 28 TI - In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. PG - 8240-50 AB - One of the two isoforms of the human insulin receptor (isoform A or IR-A) binds IGF-II with high affinity and is predominantly expressed in fetal tissues and malignant cells. We evaluated the biological relevance of IR-A in human myosarcoma cells. Six myosarcoma cell lines were studied. All produced high amounts of IGF-II and five of them predominantly expressed IR-A. SKUT-1 leiomyosarcoma cells, that do not express the IGF-IR, were identified as a suitable model to study the effects of IR-A in the absence of the interference of IGF-IR. In these cells, which express high levels of IR with an IR-A relative abundance of approximately 95%, IGF-II elicits biological effects exclusively via IR-A activation and IGF-I is almost ineffective. Blockade of autocrine IGF-II reduced unstimulated cell viability and migration. Although both insulin and IGF-II activate IR-A, these two ligands showed a different ability to activate different intracellular signaling pathways and to elicit different biological effects. Insulin was more potent than IGF-II in activating the PI3-K/Akt pathway and in protecting cells from apoptosis. In contrast, IGF-II was more potent than insulin in activating the Shc/ERK pathway and in stimulating cell migration. These data indicate that IGF-II sensitive IR-A is the predominant IR isoform in a variety of myosarcoma cells. In SKUT-1 leiomyoma cells this fetal IR isoform may vicariate the IGF-IR for cell response to both insulin and IGF-II. Acting on the same IR-A receptor IGF-II is more potent than insulin in stimulating cancer cell migration. AD - Dipartimento di Medicina Interna e Medicina Specialistica, University of Catania, Ospedale Garibaldi, 95123 Catania, Italy. FAU - Sciacca, Laura AU - Sciacca L FAU - Mineo, Rossana AU - Mineo R FAU - Pandini, Giuseppe AU - Pandini G FAU - Murabito, Antonella AU - Murabito A FAU - Vigneri, Riccardo AU - Vigneri R FAU - Belfiore, Antonino AU - Belfiore A LA - eng PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (DNA Primers) RN - 0 (INSR protein, human) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Messenger) RN - 0 (TRS1 protein, Human herpesvirus 5) RN - 0 (Viral Proteins) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - Apoptosis/*physiology MH - Base Sequence MH - DNA Primers MH - Enzyme-Linked Immunosorbent Assay MH - Insulin-Like Growth Factor II/*physiology MH - Leiomyosarcoma/*metabolism/pathology MH - Phosphorylation MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - RNA, Messenger/genetics MH - Receptor, IGF Type 1/genetics/*physiology MH - Receptor, Insulin/genetics/metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tumor Cells, Cultured MH - Viral Proteins/metabolism EDAT- 2002/11/26 04:00 MHDA- 2002/12/17 04:00 PHST- 2002/05/15 [received] PHST- 2002/09/17 [revised] PHST- 2002/09/19 [accepted] AID - 10.1038/sj.onc.1206058 [doi] PST - ppublish SO - Oncogene 2002 Nov 28;21(54):8240-50. DR -------------------------------------------------------------------------------- 62: Zhao WQ et al. Secretion of Annexin II via a...[PMID: 12431980] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 12431980 OWN - NLM STAT- MEDLINE DA - 20030203 DCOM- 20030321 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 278 IP - 6 DP - 2003 Feb 7 TI - Secretion of Annexin II via activation of insulin receptor and insulin-like growth factor receptor. PG - 4205-15 AB - Annexin II is secreted into the extracellular environment, where, via interactions with specific proteases and extracellular matrix proteins, it participates in plasminogen activation, cell adhesion, and tumor metastasis and invasion. However, mechanisms regulating annexin II transport across the cellular membrane are unknown. In this study, we used coimmunoprecipitation to show that Annexin-II was bound to insulin and insulin-like growth factor-1 (IGF-1) receptors in PC12 cells and NIH-3T3 cells overexpressing insulin (NIH-3T3(IR)) or IGF-1 receptor (NIH-3T3(IGF-1R)). Stimulation of insulin and IGF-1 receptors by insulin caused a temporary dissociation of annexin II from these receptors, which was accompanied by an increased amount of extracellular annexin II detected in the media of PC12, NIH-3T3(IR), and NIH-3T3(IGF-1R) cells but not in that of untransfected NIH-3T3 cells. Activation of a different growth factor receptor, the platelet-derived growth factor receptor, did not produce such results. Tyrphostin AG1024, a tyrosine kinase inhibitor of insulin and IGF-1 receptor, was shown to inhibit annexin II secretion along with reduced receptor phosphorylation. Inhibitors of a few downstream signaling enzymes including phosphatidylinositol 3-kinase, pp60c-Src, and protein kinase C had no effect on insulin-induced annexin II secretion, suggesting a possible direct link between receptor activation and annexin II secretion. Immunocytochemistry revealed that insulin also induced transport of the membrane-bound form of annexin II to the outside layer of the cell membrane and appeared to promote cell aggregation. These results suggest that the insulin receptor and its signaling pathways may participate in molecular mechanisms mediating annexin II secretion. AD - Laboratory of Adaptive Systems, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA. zhaow@brni-jhu.org FAU - Zhao, Wei-Qin AU - Zhao WQ FAU - Chen, Gina H AU - Chen GH FAU - Chen, Hui AU - Chen H FAU - Pascale, Alessia AU - Pascale A FAU - Ravindranath, Lakshmi AU - Ravindranath L FAU - Quon, Michael J AU - Quon MJ FAU - Alkon, Daniel L AU - Alkon DL LA - eng PT - Journal Article DEP - 20021112 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Annexin A2) RN - 0 (Tyrphostins) RN - 0 (tyrphostin AG 1024) RN - 11061-68-0 (Insulin) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - 3T3 Cells MH - Animals MH - Annexin A2/chemistry/metabolism/*secretion MH - Blotting, Western MH - Immunohistochemistry MH - Insulin/metabolism MH - Kinetics MH - Mice MH - PC12 Cells MH - Phosphorylation MH - Precipitin Tests MH - Rats MH - Receptor, IGF Type 1/antagonists & inhibitors/*physiology MH - Receptor, Insulin/*physiology MH - Signal Transduction MH - Tyrosine/metabolism MH - Tyrphostins/pharmacology EDAT- 2002/11/15 04:00 MHDA- 2003/03/22 04:00 PHST- 2002/11/12 [aheadofprint] AID - 10.1074/jbc.M210545200 [doi] AID - M210545200 [pii] PST - ppublish SO - J Biol Chem 2003 Feb 7;278(6):4205-15. Epub 2002 Nov 12. DR -------------------------------------------------------------------------------- 63: Chang Q et al. Constitutive activation of in...[PMID: 12414625] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12414625 OWN - NLM STAT- MEDLINE DA - 20021104 DCOM- 20021210 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 62 IP - 21 DP - 2002 Nov 1 TI - Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications. PG - 6035-8 AB - Insulin receptor substrate 1 (IRS-1) is a major substrate of insulin, insulin-like growth factors, and cytokine signaling and plays an important role in mediating apoptosis, cell differentiation, and cell transformation. We found that IRS-1 is constitutively activated in a variety of solid tumors, including breast cancers, leiomyomas, Wilms' tumors, rhabdomyosarcomas, liposarcomas, leiomyosarcomas, and adrenal cortical carcinomas. Blocking the constitutively activated IRS-1 signaling in breast cancer cells with a dominant-negative IRS-1, an IRS-1 with all 18 potential tyrosine-phosphorylation sites replaced by phenylalanines (F18), dramatically reduced cancer cell growth. Breast cancer cells that expressed F18 also formed smaller and far fewer colonies in soft agar culture than did the cells that did not express F18. These studies suggest that constitutive IRS-1 activation is a common phenomenon in tumors and that activated IRS-1 may present an attractive therapeutic target. AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. FAU - Chang, Qing AU - Chang Q FAU - Li, Yu AU - Li Y FAU - White, Morris F AU - White MF FAU - Fletcher, Jonathan A AU - Fletcher JA FAU - Xiao, Sheng AU - Xiao S LA - eng PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Breast Neoplasms/metabolism/pathology MH - Cell Division/physiology MH - Humans MH - Neoplasms/*metabolism/pathology MH - Phosphoproteins/genetics/metabolism/*physiology MH - Phosphorylation MH - Receptor, IGF Type 1/metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/physiology MH - Transfection EDAT- 2002/11/05 04:00 MHDA- 2002/12/11 04:00 PST - ppublish SO - Cancer Res 2002 Nov 1;62(21):6035-8. PR -------------------------------------------------------------------------------- 64: Chan CM et al. Molecular changes associated ...[PMID: 12361723] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12361723 OWN - NLM STAT- MEDLINE DA - 20021003 DCOM- 20021202 LR - 20041203 PUBM- Print IS - 0960-0760 VI - 81 IP - 4-5 DP - 2002 Aug TI - Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation. PG - 333-41 AB - The growth dependence of many breast cancers on oestrogen has been exploited therapeutically by oestrogen deprivation, but almost all patients eventually develop resistance largely by unknown mechanisms. Wild-type (WT) MCF-7 cells were cultured in oestrogen-deficient medium for 90 weeks in order to establish a long-term oestrogen-deprived MCF-7 (LTED) which eventually became independent of exogenous oestrogen for growth. After 15 weeks of quiescence (LTED-Q), basal growth rate increased in parallel with increasing oestrogen sensitivity. While 10(-9)M oestradiol (E2) maximally stimulated WT growth, the hypersensitive LTED (LTED-H) were maximally growth stimulated by 10(-13)M E2. By week 50, hypersensitivity was apparently lost and the cells became oestrogen independent (LTED-I), although the pure antioestrogen ICI182780 still inhibited cell growth and reversed the inhibitory effect of 10(-9)M E2 at 10(-12) to 10(-7)M. Tamoxifen (10(-7) to 10(-6)M) had a partial agonist effect on WT, but had no stimulatory effect on LTED. Whilst LTED cells have a low progesterone receptor (PgR) expression in all phases, oestrogen receptor (ER) a expression was, on average, elevated five- and seven-fold in LTED-H and LTED-I, respectively, and serine118 was phosphorylated. ERbeta expression was up-regulated and the levels of insulin receptor substrate 1 (IRS-1) remained low throughout all phases. The levels of RIP140mRNA appeared to decrease to approximately 50% of the WT message in LTED-Q and remained constant into the hypersensitive phase. No significant changes were observed in the expression of SUG-1, TIF-1 and SMRT in LTED. The overall changes in nuclear receptor interacting proteins do not appear to be involved in the hypersensitivity. Thus, the resistance of these human breast cancer cells to oestrogen-deprivation appears to be due to acquired hypersensitivity which may be explained in part by increased levels of and phosphorylated ERalpha. AD - Department of Academic Biochemistry, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK. FAU - Chan, Christina M W AU - Chan CM FAU - Martin, Lesley-Ann AU - Martin LA FAU - Johnston, Stephen R D AU - Johnston SR FAU - Ali, Simak AU - Ali S FAU - Dowsett, Mitch AU - Dowsett M LA - eng PT - Journal Article PL - England TA - J Steroid Biochem Mol Biol JID - 9015483 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (Estrogen Antagonists) RN - 0 (Estrogen Receptor Modulators) RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogen Receptor beta) RN - 0 (Estrogens) RN - 0 (Nuclear Proteins) RN - 0 (Phosphoproteins) RN - 0 (Protozoan Proteins) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, Progesterone) RN - 0 (Repressor Proteins) RN - 0 (SMRT protein) RN - 0 (SUG1 protein, mammalian) RN - 0 (TIF1 protein, Tetrahymena thermophila) RN - 0 (Transcription Factors) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (receptor interacting protein, 140 kDa) RN - 0 (thyroid-hormone-receptor interacting protein) RN - 10540-29-1 (Tamoxifen) RN - 129453-61-8 (fulvestrant) RN - 50-28-2 (Estradiol) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Blotting, Northern MH - Blotting, Western MH - Breast Neoplasms/*drug therapy/metabolism MH - Carrier Proteins/genetics/metabolism MH - Cell Division/*drug effects MH - DNA-Binding Proteins/genetics/metabolism MH - *Drug Resistance, Neoplasm MH - Estradiol/*analogs & derivatives/pharmacology MH - Estrogen Antagonists/pharmacology MH - Estrogen Receptor Modulators/pharmacology MH - Estrogen Receptor alpha MH - Estrogen Receptor beta MH - Estrogens/deficiency/*pharmacology MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Nuclear Proteins/genetics/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation/drug effects MH - *Protozoan Proteins MH - RNA, Messenger/metabolism MH - Receptors, Estrogen/metabolism MH - Receptors, Progesterone/metabolism MH - Repressor Proteins/genetics/metabolism MH - Tamoxifen/pharmacology MH - *Transcription Factors MH - Tumor Cells, Cultured/*drug effects/metabolism EDAT- 2002/10/04 04:00 MHDA- 2002/12/03 04:00 AID - S0960076002000742 [pii] PST - ppublish SO - J Steroid Biochem Mol Biol 2002 Aug;81(4-5):333-41. NR -------------------------------------------------------------------------------- 65: Bompard G et al. Protein-tyrosine phosphatase ...[PMID: 12354757] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12354757 OWN - NLM STAT- MEDLINE DA - 20021128 DCOM- 20030204 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 49 DP - 2002 Dec 6 TI - Protein-tyrosine phosphatase PTPL1/FAP-1 triggers apoptosis in human breast cancer cells. PG - 47861-9 AB - Studies in Jurkat leukemia cells have suggested that protein-tyrosine phosphatase PTPL1/FAP-1 rescues Fas-induced cell death. However, we have previously shown that this enzyme triggers 4-hydroxytamoxifen-induced growth inhibition in human breast cancer cells. The present study addresses the role of PTPL1/FAP-1 in antiestrogen-regulated apoptotic effect and insulin-like growth factor-I survival action in MCF7 cells and further identifies the impacted signaling pathway. By terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and cytoplasmic nucleosome enzyme-linked immunosorbent assay, we demonstrated that 4-hydroxytamoxifen-induced apoptosis was totally lost in PTPL1/FAP-1 antisense transfectants in which enzyme expression was abrogated, revealing the crucial role of this phosphatase in the apoptotic process in human breast cancer cells. Time-dependent expression of PTPL1/FAP-1 in MCF7 cells completely abolished the survival action of insulin-like growth factor-I. This effect occurred through a highly significant reduction in phosphatidylinositol 3-kinase/Akt pathway activation (80% reduction in phosphatidylinositol 3-kinase activity, 55% inhibition of Akt activation) accompanied by a 65% decrease in insulin receptor substrate-1 growth factor-induced tyrosine phosphorylation. These results provide the first evidence that PTPL1/FAP-1 has a key role in the apoptotic process in human breast cancer cells independent of Fas but associated with an early inhibition of the insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway. Our data therefore suggest new therapeutic routes and strengthen the importance of identifying endogenous regulators and substrates of this phosphatase in breast tumors. AD - Inserm, Unit 540, Molecular and Cellular Endocrinology of Cancers, 60 rue de Navacelles, 34090 Montpellier, France. FAU - Bompard, Guillaume AU - Bompard G FAU - Puech, Carole AU - Puech C FAU - Prebois, Christine AU - Prebois C FAU - Vignon, Francoise AU - Vignon F FAU - Freiss, Gilles AU - Freiss G LA - eng PT - Journal Article DEP - 20020926 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Carrier Proteins) RN - 0 (Oligonucleotides, Antisense) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.3.1.3- (Fas-associated phosphatase-1) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - *Apoptosis MH - Blotting, Western MH - Breast Neoplasms/*metabolism MH - Carrier Proteins/*metabolism/*physiology MH - Cell Survival MH - DNA Fragmentation MH - Enzyme-Linked Immunosorbent Assay MH - Humans MH - In Situ Nick-End Labeling MH - Oligonucleotides, Antisense/pharmacology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Binding MH - Protein-Tyrosine-Phosphatase/*metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Time Factors MH - Transfection MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2002/10/02 04:00 MHDA- 2003/02/05 04:00 PHST- 2002/09/26 [aheadofprint] AID - 10.1074/jbc.M208950200 [doi] AID - M208950200 [pii] PST - ppublish SO - J Biol Chem 2002 Dec 6;277(49):47861-9. Epub 2002 Sep 26. NR -------------------------------------------------------------------------------- 66: Velasquez E. [Chronic complications of pol...[PMID: 12229282] Related Articles, Books, LinkOut PMID- 12229282 OWN - NLM STAT- MEDLINE DA - 20020916 DCOM- 20021021 LR - 20041117 PUBM- Print IS - 0535-5133 VI - 43 IP - 3 DP - 2002 Sep TI - [Chronic complications of polycystic ovary syndrome. Review] PG - 205-13 AB - In addition to neuroendocrine abnormalities, women with polycystic ovary syndrome have insulin resistance and beta-cell dysfunction associated with a high frequency of metabolic syndrome components, such as glucose intolerance, type 2 diabetes mellitus (DM-2), dyslipidemia and a higher risk for endothelial dysfunction, haemostatic abnormalities, hypertension and cardiovascular disease. Obesity, a common finding in this disorder, plays an important role in the development of metabolic and cardiovascular disorders. Early identification of patients and prompt initiation of insulin sensitizing therapy by pharmacological agents or changes in life style such diet and exercise might improve the metabolic and endocrine abnormalities and reduce the risk of DM-2 and cardiovascular disease in these patients. AD - Unidad de Endocrinologia, Facultad de Medicina, Hospital Universitario de Los Andes, Merida, Venezuela. elsyvm@yahoo.com FAU - Velasquez, Elsy AU - Velasquez E LA - spa PT - Journal Article PT - Review PT - Review, Tutorial TT - Complicaciones cronicas del sindrome de ovarios poliquisticos. Revision. PL - Venezuela TA - Invest Clin JID - 0421531 RN - 0 (Hypoglycemic Agents) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Cardiovascular Diseases/etiology/prevention & control MH - Diabetes Mellitus, Type 2/etiology/prevention & control MH - Diabetes, Gestational/etiology MH - English Abstract MH - Female MH - Humans MH - Hyperandrogenism/etiology/physiopathology MH - Hyperlipidemia/etiology MH - Hypoglycemic Agents/therapeutic use MH - Insulin Resistance/physiology MH - Metabolic Syndrome X/etiology/prevention & control MH - Obesity/etiology/prevention & control MH - Phosphoproteins/deficiency MH - Polycystic Ovary Syndrome/*complications/physiopathology/therapy MH - Pregnancy MH - Receptor, Insulin/physiology MH - Signal Transduction RF - 70 EDAT- 2002/09/17 10:00 MHDA- 2002/10/22 04:00 PST - ppublish SO - Invest Clin 2002 Sep;43(3):205-13. NR -------------------------------------------------------------------------------- 67: Li M et al. Decreased insulin receptor (I...[PMID: 12213853] Related Articles, Books, LinkOut PMID- 12213853 OWN - NLM STAT- MEDLINE DA - 20020905 DCOM- 20021003 LR - 20041117 PUBM- Print IS - 0021-972X VI - 87 IP - 9 DP - 2002 Sep TI - Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. PG - 4088-93 AB - Insulin resistance is characteristic of many patients with polycystic ovary syndrome (PCOS). Several studies have suggested that a decrease in insulin receptor (IR) autophosphorylation is a significant component of this resistance. In this study, we have used a highly sensitive ELISA to measure IR tyrosine phosphorylation in fibroblasts from patients with PCOS and healthy control women. After the stimulation of intact fibroblasts with insulin, IR tyrosine phosphorylation in cells from the PCOS patients was decreased by approximately 40% when compared with controls. However, when IR were first immunocaptured from fibroblasts and then stimulated with insulin, neither basal nor insulin-stimulated IR autophosphorylation was different between the two groups, suggesting that a factor independent of the IR was involved. To examine the role of increased serine kinase activity in decreased IR autophosphorylation in PCOS, fibroblasts from PCOS patients were pretreated with inhibitors of serine kinases before insulin stimulation. Pretreatment with H7, a nonspecific protein kinase inhibitor, completely reversed the decrease in insulin-stimulated IR autophosphorylation. Pretreatment with H89, an inhibitor of protein kinase A, partially reversed this function, whereas pretreatment with Go6983, an inhibitor of protein kinase C, was without effect. We next studied the effects of two small molecule activators of the IR tyrosine kinase: TLK16998 and Merck L7. Both TLK16998 and Merck L7 were able to reverse the impaired insulin-stimulated IR autophosphorylation. In summary, a factor(s) extrinsic to the IR cause impaired IR signaling in fibroblasts from patients with PCOS. Reversal of the impaired IR signaling by inhibitors of serine kinase activity suggests that serine kinase-mediated pathways may be involved in the insulin resistance. Moreover, the observation that TLK16998 and Merck L7 improved IR tyrosine phosphorylation in fibroblasts from patients with PCOS suggests that specific pharmacological therapies might be developed to treat the insulin resistance in PCOS. AD - University of California at San Francisco, Mount Zion Medical Center, San Francisco, California 94143, USA. FAU - Li, Ming AU - Li M FAU - Youngren, Jack F AU - Youngren JF FAU - Dunaif, Andrea AU - Dunaif A FAU - Goldfine, Ira D AU - Goldfine ID FAU - Maddux, Betty A AU - Maddux BA FAU - Zhang, Bei B AU - Zhang BB FAU - Evans, Joseph L AU - Evans JL LA - eng PT - Journal Article PL - United States TA - J Clin Endocrinol Metab JID - 0375362 RN - 0 (Azo Compounds) RN - 0 (Enzyme Inhibitors) RN - 0 (Naphthalenes) RN - 0 (TLK 16998) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) SB - AIM SB - IM CIN - J Clin Endocrinol Metab. 2002 Sep;87(9):4085-7. PMID: 12213851 MH - Adolescent MH - Adult MH - Azo Compounds/*pharmacology MH - Cell Line MH - Cells, Cultured MH - Comparative Study MH - Enzyme Inhibitors/*pharmacology MH - Female MH - Fibroblasts/*metabolism MH - Humans MH - Insulin Resistance/*physiology MH - Kinetics MH - Naphthalenes/*pharmacology MH - Phosphorylation MH - Polycystic Ovary Syndrome/*metabolism MH - Protein-Serine-Threonine Kinases/*antagonists & inhibitors MH - Receptor, Insulin/drug effects/*metabolism MH - Reference Values MH - Research Support, Non-U.S. Gov't EDAT- 2002/09/06 10:00 MHDA- 2002/10/04 04:00 PST - ppublish SO - J Clin Endocrinol Metab 2002 Sep;87(9):4088-93. NR -------------------------------------------------------------------------------- 68: Pender C et al. Regulation of insulin recepto...[PMID: 12213804] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 12213804 OWN - NLM STAT- MEDLINE DA - 20021111 DCOM- 20030102 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 46 DP - 2002 Nov 15 TI - Regulation of insulin receptor function by a small molecule insulin receptor activator. PG - 43565-71 AB - In type 2 diabetes mellitus, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. TLK19780, a non-peptide small molecule, is a new member of a novel class of anti-diabetic agents that function as activators of the insulin receptor (IR) beta-subunit tyrosine kinase. In HTC-IR cells, 20 microm TLK19780 enhanced maximal insulin-stimulated IR autophosphorylation 2-fold and increased insulin sensitivity 2-3-fold. In contrast, TLK19780 did not potentiate the action of insulin-like growth factor-1, indicating the selectivity of TLK19780 toward the IR. The predominant effect of TLK19780 was to increase the number of IR that underwent autophosphorylation. Kinetic studies indicated that TLK19780 acted very rapidly, with a maximal effect observed 2 min after addition to insulin-stimulated cells. In 3T3-L1 adipocytes, 5 microm TLK19780 enhanced insulin-stimulated glucose transport, increasing both the sensitivity and maximal responsiveness to insulin. These studies indicate that at low micromolar levels small IR activator molecules can enhance insulin action in various cultured cells and suggest that this effect is mediated by increasing the number of IR that are tyrosine-phosphorylated in response to insulin. These studies suggest that these types of molecules could be developed to treat type 2 diabetes and other clinical conditions associated with insulin resistance. AD - Mount Zion Medical Center, University of California, San Francisco 94143-1616, USA. FAU - Pender, Celia AU - Pender C FAU - Goldfine, Ira D AU - Goldfine ID FAU - Manchem, Vara Prasad AU - Manchem VP FAU - Evans, Joseph L AU - Evans JL FAU - Spevak, Wayne R AU - Spevak WR FAU - Shi, Songyuan AU - Shi S FAU - Rao, Sandhya AU - Rao S FAU - Bajjalieh, Sonia AU - Bajjalieh S FAU - Maddux, Betty A AU - Maddux BA FAU - Youngren, Jack F AU - Youngren JF LA - eng PT - Journal Article DEP - 20020903 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Sulfanilic Acids) RN - 0 (TLK 19780) RN - 50-99-7 (Glucose) RN - 55520-40-6 (Tyrosine) RN - 57-13-6 (Urea) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - 3T3 Cells MH - Adipocytes/metabolism MH - Animals MH - Biological Transport MH - Blotting, Western MH - CHO Cells MH - Carcinoma, Hepatocellular/metabolism MH - Cells, Cultured MH - Dose-Response Relationship, Drug MH - Dose-Response Relationship, Radiation MH - Enzyme-Linked Immunosorbent Assay MH - Glucose/metabolism MH - Hamsters MH - Kinetics MH - Mice MH - Models, Chemical MH - Phosphorylation MH - Rats MH - Receptor, Insulin/*metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - Sulfanilic Acids/pharmacology MH - Time Factors MH - Tyrosine/metabolism MH - Urea/analogs & derivatives/pharmacology EDAT- 2002/09/06 10:00 MHDA- 2003/01/03 04:00 PHST- 2002/09/03 [aheadofprint] AID - 10.1074/jbc.M202426200 [doi] AID - M202426200 [pii] PST - ppublish SO - J Biol Chem 2002 Nov 15;277(46):43565-71. Epub 2002 Sep 3. PR -------------------------------------------------------------------------------- 69: Kalli KR et al. Functional insulin receptors ...[PMID: 12193537] Related Articles, Gene, HomoloGene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12193537 OWN - NLM STAT- MEDLINE DA - 20020823 DCOM- 20020923 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 143 IP - 9 DP - 2002 Sep TI - Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. PG - 3259-67 AB - The insulin receptor mediates a proliferative response in certain transformed cells, but little is known about its function in ovarian cancer. We used human epithelial ovarian carcinoma cell lines and lifespan-extended normal ovarian surface epithelial (OSE) cells to examine (125)I-insulin binding and mitogenic responses to insulin. All cancer cell and OSE cultures specifically bound (125)I-insulin. Except for OV202, the carcinoma lines had elevated insulin binding compared with OSE cells. All carcinoma lines except OV202 expressed insulin receptor as detected by flow cytometry and increased (3)H-thymidine incorporation or cell number in response to 0.1-10 nM insulin. Interestingly, similar concentrations of IGF-II also induced proliferation of the insulin-responsive cancer cell lines and displaced (125)I-insulin binding. Direct binding of (125)I-IGF-II to the insulin receptor was visualized by cross-linking and immunoprecipitation. Binding of IGF-II to the insulin receptor and a proliferative effect of insulin suggest the presence of insulin receptor isoform A. Real-time PCR analyses confirm that insulin receptor isoform A expression predominates over isoform B expression in the ovarian carcinoma cell lines. This report suggests that the insulin receptor may play a role in the regulation of ovarian cancer cell growth. AD - Division of Endocrinology and Metabolism, Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. FAU - Kalli, Kimberly R AU - Kalli KR FAU - Falowo, Oluwole I AU - Falowo OI FAU - Bale, Laurie K AU - Bale LK FAU - Zschunke, Michael A AU - Zschunke MA FAU - Roche, Patrick C AU - Roche PC FAU - Conover, Cheryl A AU - Conover CA LA - eng PT - Journal Article PL - United States TA - Endocrinology JID - 0375040 RN - 0 (Cross-Linking Reagents) RN - 0 (Iodine Radioisotopes) RN - 0 (Protein Isoforms) RN - 0 (RNA, Messenger) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Alternative Splicing MH - *Cell Division MH - Cross-Linking Reagents MH - Electrophoresis, Polyacrylamide Gel MH - Epithelial Cells/metabolism/pathology MH - Female MH - Flow Cytometry MH - Gene Expression MH - Humans MH - Insulin/metabolism/pharmacology MH - Insulin-Like Growth Factor I/metabolism MH - Insulin-Like Growth Factor II/*pharmacology MH - Iodine Radioisotopes MH - Ovarian Neoplasms/*metabolism/*pathology MH - Polymerase Chain Reaction MH - Protein Isoforms/analysis/genetics MH - RNA, Messenger/analysis MH - Receptor, IGF Type 1/metabolism MH - Receptor, Insulin/*analysis/genetics/physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - *Signal Transduction MH - Tumor Cells, Cultured EDAT- 2002/08/24 10:00 MHDA- 2002/09/24 06:00 PST - ppublish SO - Endocrinology 2002 Sep;143(9):3259-67. DR -------------------------------------------------------------------------------- 70: Shen WH et al. Proinflammatory cytokines blo...[PMID: 12183434] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12183434 OWN - NLM STAT- MEDLINE DA - 20020816 DCOM- 20020925 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 62 IP - 16 DP - 2002 Aug 15 TI - Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor. PG - 4746-56 AB - Neutralization of endogenous growth factors and administration of exogenous bioactive cytokines are two distinct biological antitumor strategies that show promise for treatment of cancer patients. In this report, we provide evidence to link both strategies as an integrative approach to cancer therapy. We tested the hypothesis that proinflammatory cytokines block growth of transformed cells by inhibiting key intracellular signaling events after activation of the insulin-like growth factor-I (IGF-I) tyrosine kinase receptor. IGF-I stimulates DNA synthesis in MCF-7 cells by 15-fold. This increase is significantly inhibited by TNF (tumor necrosis factor) -alpha at 0.1 ng/ml and is reduced by 80% at 100 ng/ml. Similarly, both IL (interleukin) -1beta and IL-6 significantly reduce the ability of IGF-I to promote DNA synthesis. Flow cytometry confirmed that all three of the cytokines inhibit IGF-I-induced DNA synthesis by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Although none of the cytokines alone are cytotoxic to transformed epithelial cells in the absence of serum, TNF-alpha significantly inhibits the antiapoptotic property of IGF-I in protecting MCF-7 cells from DNA fragmentation. TNF-alpha and IL-1beta act by inhibiting the IGF-I receptor from tyrosine phosphorylating insulin receptor substrate-1 without affecting tyrosine kinase activity of the IGF-IR itself. These data support the novel idea that the major inhibitory properties of proinflammatory cytokines on growth of breast cancer cells are manifested prominently in the presence of growth factors. These data also highlight growth factor receptor adaptor molecules, such as insulin receptor substrate-1, rather than the receptors themselves as targets for antitumor therapeutic strategies. AD - Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, USA. FAU - Shen, Wen-Hong AU - Shen WH FAU - Zhou, Jian-Hua AU - Zhou JH FAU - Broussard, Suzanne R AU - Broussard SR FAU - Freund, Gregory G AU - Freund GG FAU - Dantzer, Robert AU - Dantzer R FAU - Kelley, Keith W AU - Kelley KW LA - eng GR - AI50442/AI/NIAID GR - MH-51569/MH/NIMH PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (DNA, Neoplasm) RN - 0 (Interleukin-1) RN - 0 (Interleukin-6) RN - 0 (Phosphoproteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Adenocarcinoma/drug therapy/genetics/metabolism/*pathology MH - Apoptosis/drug effects/physiology MH - Breast Neoplasms/drug therapy/genetics/metabolism/*pathology MH - Cell Cycle/drug effects/physiology MH - Cell Division/drug effects/physiology MH - DNA, Neoplasm/biosynthesis MH - Humans MH - Insulin-Like Growth Factor I/*antagonists & inhibitors/physiology MH - Interleukin-1/*pharmacology MH - Interleukin-6/*pharmacology MH - Phosphoproteins/metabolism MH - Phosphorylation/drug effects MH - Receptor, IGF Type 1/antagonists & inhibitors/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured MH - Tumor Necrosis Factor-alpha/*pharmacology MH - Tyrosine/metabolism EDAT- 2002/08/17 10:00 MHDA- 2002/09/26 06:00 PST - ppublish SO - Cancer Res 2002 Aug 15;62(16):4746-56. NR -------------------------------------------------------------------------------- 71: Morrison KB et al. ETV6-NTRK3 transformation req...[PMID: 12173038] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 12173038 OWN - NLM STAT- MEDLINE DA - 20020812 DCOM- 20020910 LR - 20050610 PUBM- Print IS - 0950-9232 VI - 21 IP - 37 DP - 2002 Aug 22 TI - ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation. PG - 5684-95 AB - Congenital fibrosarcoma (CFS) and cellular mesoblastic nephroma (CMN) are pediatric spindle cell malignancies that share two specific cytogenetic abnormalities: trisomy of chromosome 11 and a t(12;15)(p13;q25) translocation. The t(12;15) rearrangement creates a transcriptionally active fusion gene that encodes a chimeric oncoprotein, ETV6-NTRK3 (EN). EN transforms NIH3T3 fibroblasts through constitutive activation of both the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3'kinase (PI3K)-Akt pathway. However, the role of trisomy 11 in CFS and CMN remains unknown. In this study we demonstrate elevated expression of the chromosome 11p15.5 insulin-like growth factor 2 gene (IGF2) in CFS and CMN tumors. Moreover, we present evidence that an intact IGF signaling axis is essential for in vitro EN-mediated transformation. EN only very weakly transformed so-called R-murine fibroblasts derived from mice with a targeted disruption of the IGF1 receptor gene (IGFRI), but transformation activity was fully restored in R- cells engineered to re-express IGFRI (R+ cells). We also observed that the major IGFRI substrate, insulin-receptor substrate-1 (IRS-1), was constitutively tyrosine phosphorylated and could be co-immunoprecipitated with EN in either R- or R+ cells expressing the EN oncoprotein. IRS-1 association with Grb2 and PI3K p85, which link IGFRI to the Ras-MAPK and PI3K-Akt pathways, respectively, was enhanced in both cell types in the presence of EN. However, activation of the Ras-MAPK and PI3K-Akt pathways was markedly attenuated in EN-expressing R- cells compared to EN-transformed R+ cells. This suggests that IRS-1 may be functioning as an adaptor in EN signal transduction, but that a link to EN transformation pathways requires the presence of IGFRI. Our findings indicate that an intact IGF signaling axis is essential for EN transformation, and are consistent with a role for trisomy 11 in augmenting this pathway in EN expressing tumors. AD - Department of Pathology, BC Research Institute for Children's and Women's Health, and the University of British Columbia, Vancouver, BC V5Z 4H4, Canada. FAU - Morrison, Kevin B AU - Morrison KB FAU - Tognon, Cristina E AU - Tognon CE FAU - Garnett, Mathew J AU - Garnett MJ FAU - Deal, Cheri AU - Deal C FAU - Sorensen, Poul H B AU - Sorensen PH LA - eng PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (DNA-Binding Proteins) RN - 0 (ETS translocation variant 6 protein) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Repressor Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 55520-40-6 (Tyrosine) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.- (MAP Kinase Kinase 1) RN - EC 2.7.1.- (MAP Kinase Kinase 2) RN - EC 2.7.1.- (Map2k1 protein, mouse) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, trkC) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Animals MH - *Cell Transformation, Neoplastic MH - DNA-Binding Proteins/*physiology MH - Insulin-Like Growth Factor II/genetics MH - MAP Kinase Kinase 1 MH - MAP Kinase Kinase 2 MH - Mice MH - Mitogen-Activated Protein Kinase Kinases/metabolism MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Protein-Serine-Threonine Kinases/metabolism MH - Protein-Tyrosine Kinase/metabolism MH - Proteins/physiology MH - Proto-Oncogene Proteins/metabolism MH - Receptor, IGF Type 1/*physiology MH - Receptor, trkC/*physiology MH - Repressor Proteins/*physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tyrosine/metabolism EDAT- 2002/08/13 10:00 MHDA- 2002/09/11 10:01 PHST- 2002/02/18 [received] PHST- 2002/05/09 [revised] PHST- 2002/05/14 [accepted] AID - 10.1038/sj.onc.1205669 [doi] PST - ppublish SO - Oncogene 2002 Aug 22;21(37):5684-95. NR -------------------------------------------------------------------------------- 72: Zhang X et al. Insulin-like growth factor bi...[PMID: 12154042] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12154042 OWN - NLM STAT- MEDLINE DA - 20020802 DCOM- 20020911 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 62 IP - 15 DP - 2002 Aug 1 TI - Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits breast cancer cell motility. PG - 4369-75 AB - The breast cancer malignant phenotype is regulated by steroid hormones and peptide growth factors. We have shown previously that insulin-like growth factor-I (IGF-I) stimulates cell motility in a metastatic cell line, MDA-231BO. In this study, we show that neutralization of IGF action by a type I IGF receptor (IGFR1) blocking antibody or neutralization of IGF-I by IGFBP-1 reduced cell motility. However, in addition to inhibiting IGF effects, IGFBP-1 also diminished basal motility. Because IGFBP-1 contains a RGD motif important in binding of fibronectin to its alpha 5 beta 1 integrin receptor, we examined the effect of inhibiting integrin function on cell motility. As expected, disruption of fibronectin-integrin interactions interrupted basal motility in MDA-231BO cells. In addition, disruption of integrin function by an alpha 5 beta 1 blocking peptide also inhibited IGF stimulation of cell motility. To determine whether integrin function could interfere with IGF signaling, we used an alpha 5 beta 1 blocking peptide to show that in MDA-231BO cells integrin occupancy appeared necessary for phosphorylation of insulin receptor substrate-2 but not for IGFR1 activation. We conclude that IGFR1 and integrin action are linked in these breast cancer cells as disruption of integrin binding to its receptor influences IGF signaling pathways. Moreover, IGFBP-1 could have dual effects on cancer cell motility by disrupting both receptor systems. AD - University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, USA. FAU - Zhang, Xihong AU - Zhang X FAU - Yee, Douglas AU - Yee D LA - eng GR - P30 CA77398/CA/NCI GR - R01 CA74285/CA/NCI PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Antibodies) RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 0 (Integrins) RN - 0 (Oligopeptides) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Vitronectin) RN - 0 (Recombinant Proteins) RN - 0 (insulin receptor substrate-2 protein) RN - 0 (integrin alphavbeta1) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 99896-85-2 (arginyl-glycyl-aspartic acid) SB - IM MH - Antibodies/pharmacology MH - Breast Neoplasms/*pathology MH - Cell Movement/*drug effects/physiology MH - Humans MH - Insulin-Like Growth Factor Binding Protein 1/metabolism/*pharmacology/physiology MH - Insulin-Like Growth Factor I/antagonists & inhibitors/pharmacology/physiology MH - Integrins/antagonists & inhibitors/immunology/metabolism MH - Oligopeptides/pharmacology MH - Phosphoproteins/antagonists & inhibitors/metabolism MH - Phosphorylation/drug effects MH - *Receptors, Vitronectin MH - Recombinant Proteins/pharmacology MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 2002/08/03 10:00 MHDA- 2002/09/12 10:01 PST - ppublish SO - Cancer Res 2002 Aug 1;62(15):4369-75. NR -------------------------------------------------------------------------------- 73: Lingohr MK et al. Dichloroacetate stimulates gl...[PMID: 12151648] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12151648 OWN - NLM STAT- MEDLINE DA - 20020801 DCOM- 20021223 LR - 20050111 PUBM- Print IS - 1096-6080 VI - 68 IP - 2 DP - 2002 Aug TI - Dichloroacetate stimulates glycogen accumulation in primary hepatocytes through an insulin-independent mechanism. PG - 508-15 AB - Dichloroacetate (DCA), a by-product of water chlorination, causes liver cancer in B6C3F1 mice. A hallmark response observed in mice exposed to carcinogenic doses of DCA is an accumulation of hepatic glycogen content. To distinguish whether the in vivo glycogenic effect of DCA was dependent on insulin and insulin signaling proteins, experiments were conducted in isolated hepatocytes where insulin concentrations could be controlled. In hepatocytes isolated from male B6C3F1 mice, DCA increased glycogen levels in a dose-related manner, independently of insulin. The accumulation of hepatocellular glycogen induced by DCA was not the result of decreased glycogenolysis, since DCA had no effect on the rate of glucagon-stimulated glycogen breakdown. Glycogen accumulation caused by DCA treatment was not hindered by inhibitors of extracellular-regulated protein kinase kinase (Erk1/2 kinase or MEK) or p70 kDa S6 protein kinase (p70(S6K)), but was completely blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin. Similarly, insulin-stimulated glycogen deposition was not influenced by the Erk1/2 kinase inhibitor, PD098509, or the p70(S6K) inhibitor, rapamycin. Unlike DCA-stimulated glycogen deposition, PI3K-inhibition only partially blocked the glycogenic effect of insulin. DCA did not cause phosphorylation of the downstream PI3K target protein, protein kinase B (PKB/Akt). The phosphorylation of PKB/Akt did not correlate to insulin-stimulated glycogenesis either. Similar to insulin, DCA in the medium decreased IR expression in isolated hepatocytes. The results indicate DCA increases hepatocellular glycogen accumulation through a PI3K-dependent mechanism that does not involve PKB/Akt and is, at least in part, different from the classical insulin-stimulated glycogenesis pathway. Somewhat surprisingly, insulin-stimulated glycogenesis also appears not to involve PKB/Akt in isolated murine hepatocytes. AD - Washington State University, Pullman, Washington 99164-6510, USA. FAU - Lingohr, Melissa K AU - Lingohr MK FAU - Bull, Richard J AU - Bull RJ FAU - Kato-Weinstein, Junko AU - Kato-Weinstein J FAU - Thrall, Brian D AU - Thrall BD LA - eng PT - Journal Article PL - United States TA - Toxicol Sci JID - 9805461 RN - 0 (Androstadienes) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 0 (Proto-Oncogene Proteins) RN - 11061-68-0 (Insulin) RN - 13425-80-4 (Dichloroacetate) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 19545-26-7 (wortmannin) RN - 9005-79-2 (Glycogen) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors MH - Androstadienes/pharmacology MH - Animals MH - Cells, Cultured MH - Chromones/pharmacology MH - Dichloroacetate/*toxicity MH - Drug Interactions MH - Enzyme Inhibitors/pharmacology MH - Glycogen/*metabolism MH - Hepatocytes/*drug effects/metabolism MH - Insulin/pharmacology/*physiology MH - Mice MH - Mice, Inbred Strains MH - Morpholines/pharmacology MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/antagonists & inhibitors MH - Receptor, Insulin/metabolism MH - Research Support, U.S. Gov't, Non-P.H.S. EDAT- 2002/08/02 10:00 MHDA- 2002/12/27 04:00 PST - ppublish SO - Toxicol Sci 2002 Aug;68(2):508-15. PR -------------------------------------------------------------------------------- 74: Varma H et al. Antiestrogen ICI 182,780 decr...[PMID: 12124331] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12124331 OWN - NLM STAT- MEDLINE DA - 20020718 DCOM- 20020813 LR - 20050111 PUBM- Print IS - 0008-5472 VI - 62 IP - 14 DP - 2002 Jul 15 TI - Antiestrogen ICI 182,780 decreases proliferation of insulin-like growth factor I (IGF-I)-treated MCF-7 cells without inhibiting IGF-I signaling. PG - 3985-91 AB - Previous studies have suggested that antiestrogens inhibit MCF-7 cell proliferation by alteringthe expression or activity of components of the insulin-like growth factor I (IGF-I) signaling pathway, including IGF-I receptor, insulin receptor substrate 1, and phosphatidylinositol 3-kinase. In this report, we examine the effects of the pure antiestrogen ICI 182,780 (ICI) on various targets of IGF-I signaling in MCF-7 cells. ICI treatment led to decreases in the absolute levels of cyclin D1 and cyclin A expression, retinoblastoma protein phosphorylation, and DNA synthesis in IGF-I-treated cells. However, IGF-I retained the ability to induce these events in the presence of ICI, suggesting that ICI treatment did not completely block IGF-I signaling. Consistent with this suggestion, IGF-I-induced phosphorylation of extracellular signal-regulated kinase, AKT, and insulin receptor substrate 1 was unaffected by ICI treatment. Finally, transient expression of either constitutively active phosphatidylinositol 3-kinase or AKT was unable to induce proliferation in ICI-treated MCF-7 cells. Together, these results indicate that ICI can inhibit proliferation without blocking IGF-I signaling and suggest a model in which both estrogen receptor and IGF-I signaling regulate cell cycle components and are required for MCF-7 cell proliferation. AD - Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA. FAU - Varma, Hemant AU - Varma H FAU - Conrad, Susan E AU - Conrad SE LA - eng GR - CA76647/CA/NCI PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (Estrogen Receptor Modulators) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Estrogen) RN - 0 (insulin receptor substrate-1 protein) RN - 129453-61-8 (fulvestrant) RN - 136601-57-5 (Cyclin D1) RN - 50-28-2 (Estradiol) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Antineoplastic Agents, Hormonal/pharmacology MH - Breast Neoplasms/drug therapy/metabolism/*pathology MH - Cell Division/drug effects MH - Cyclin D1/biosynthesis/genetics MH - Drug Resistance, Neoplasm MH - Enzyme Activation MH - Estradiol/analogs & derivatives/*pharmacology MH - Estrogen Receptor Modulators/*pharmacology MH - Humans MH - Insulin-Like Growth Factor I/*antagonists & inhibitors/pharmacology/physiology MH - Mitogen-Activated Protein Kinase Kinases/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation/drug effects MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - RNA, Messenger/biosynthesis/genetics MH - Receptors, Estrogen/physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured EDAT- 2002/07/19 10:00 MHDA- 2002/08/14 10:01 PST - ppublish SO - Cancer Res 2002 Jul 15;62(14):3985-91. NR -------------------------------------------------------------------------------- 75: Waltner-Law ME et al. Epigallocatechin gallate, a c...[PMID: 12118006] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12118006 OWN - NLM STAT- MEDLINE DA - 20020916 DCOM- 20021024 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 38 DP - 2002 Sep 20 TI - Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. PG - 34933-40 AB - Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70(s6k) activity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent. AD - Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA. FAU - Waltner-Law, Mary E AU - Waltner-Law ME FAU - Wang, Xiaohui L AU - Wang XL FAU - Law, Brian K AU - Law BK FAU - Hall, Robert K AU - Hall RK FAU - Nawano, Masao AU - Nawano M FAU - Granner, Daryl K AU - Granner DK LA - eng GR - DK02887/DK/NIDDK GR - DK35107/DK/NIDDK PT - Journal Article DEP - 20020712 PL - United States TA - J Biol Chem JID - 2985121R RN - 11061-68-0 (Insulin) RN - 154-23-4 (Catechin) RN - 50-99-7 (Glucose) RN - 55520-40-6 (Tyrosine) RN - 616-91-1 (Acetylcysteine) RN - 989-51-5 (epigallocatechin gallate) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.7.1.- (phosphoenolpyruvate carboxylase kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 3.1.3.9 (Glucose-6-Phosphatase) SB - IM MH - Acetylcysteine/pharmacology MH - Animals MH - Catechin/analogs & derivatives/*pharmacology MH - Gene Expression Regulation, Enzymologic/drug effects MH - Gluconeogenesis/*drug effects MH - Glucose/*biosynthesis MH - Glucose-6-Phosphatase/genetics MH - Insulin/pharmacology MH - Liver/*drug effects/enzymology/metabolism MH - Liver Neoplasms, Experimental/enzymology/metabolism/pathology MH - Phosphorylation MH - Protein-Serine-Threonine Kinases/genetics MH - Rats MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Superoxide Dismutase/pharmacology MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2002/07/16 10:00 MHDA- 2002/10/31 04:00 PHST- 2002/07/12 [aheadofprint] AID - 10.1074/jbc.M204672200 [doi] AID - M204672200 [pii] PST - ppublish SO - J Biol Chem 2002 Sep 20;277(38):34933-40. Epub 2002 Jul 12. PR -------------------------------------------------------------------------------- 76: Najib S et al. Sam68 associates with the SH3...[PMID: 12112020] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12112020 OWN - NLM STAT- MEDLINE DA - 20020711 DCOM- 20021217 LR - 20041117 PUBM- Print IS - 0730-2312 VI - 86 IP - 1 DP - 2002 TI - Sam68 associates with the SH3 domains of Grb2 recruiting GAP to the Grb2-SOS complex in insulin receptor signaling. PG - 99-106 AB - The 68 kDa Src substrate associated during mitosis (Sam68) is an RNA binding protein with Src homology (SH) 2 and 3 domain binding sites. We have recently found that Sam68 is a substrate of the insulin receptor (IR) that translocates from the nucleus to the cytoplasm and that Tyr-phosphorylated Sam68 associates with the SH2 domains of p85 PI3K and GAP, in vivo and in vitro. In the present work, we have further demonstrated the cytoplasmic localization of Sam68, which is increased in cells overexpressing IR. Besides, we sought to further study the association of Sam68 with the Ras-GAP pathway by assessing the interactions with SH3 domains of Grb2. We employed GST-fusion proteins containing the SH3 domains of Grb2 (N or C), and recombinant Sam68 for in vitro studies. In vivo studies of protein-protein interaction were assessed by co-immunoprecipitation experiments with specific antibodies against Sam68, GAP, Grb2, SOS, and phosphotyrosine; and by affinity precipitation with the fusion proteins (SH3-Grb2). Insulin stimulation of HTC-IR cells promotes phosphorylation of Sam68 and its association with the SH2 domains of GAP. Sam68 is constitutively associated with the SH3 domains of Grb2 and it does not change upon insulin stimulation, but Sam68 is Tyr-phosphorylated and promotes the association of GAP with the Grb2-SOS complex. In vitro studies with fusion proteins showed that Sam68 association with Grb2 is preferentially mediated by the C-terminal SH3 domains of Grb2. In conclusion, Sam68 is a substrate of the IR and may have a role as a docking protein in IR signaling, recruiting GAP to the Grb2-SOS complex, and in this way it may modulate Ras activity. CI - Copyright 2002 Wiley-Liss, Inc. AD - Department of Medical Biochemistry and Molecular Biology, Medical School, Investigation Unit, Virgen Macarena University Hospital, Seville, Spain. FAU - Najib, Souad AU - Najib S FAU - Sanchez-Margalet, Victor AU - Sanchez-Margalet V LA - eng PT - Journal Article PL - United States TA - J Cell Biochem JID - 8205768 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (GTPase-Activating Proteins) RN - 0 (Macromolecular Substances) RN - 0 (Proteins) RN - 0 (RNA-Binding Proteins) RN - 0 (SRC-associated p68 protein) RN - 0 (Son of Sevenless Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Animals MH - Carcinoma, Hepatocellular/metabolism/pathology MH - Cell Nucleus/metabolism MH - Cytoplasm/metabolism MH - GTPase-Activating Proteins/*metabolism MH - Humans MH - Macromolecular Substances MH - Protein Transport MH - Proteins/*chemistry/*metabolism MH - RNA-Binding Proteins/*metabolism MH - Rats MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Son of Sevenless Proteins/*metabolism MH - Tumor Cells, Cultured MH - *src Homology Domains EDAT- 2002/07/12 10:00 MHDA- 2002/12/18 04:00 AID - 10.1002/jcb.10198 [doi] PST - ppublish SO - J Cell Biochem 2002;86(1):99-106. PR -------------------------------------------------------------------------------- 77: Pugeat M. [Genetics of the polycystic o...[PMID: 12089937] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12089937 OWN - NLM STAT- MEDLINE DA - 20020701 DCOM- 20021112 LR - 20041117 PUBM- Print IS - 0300-8738 VI - 104 IP - 4 DP - 2000 Oct-Dec TI - [Genetics of the polycystic ovarian syndrome and therapeutic perspectives ] PG - 11-9 AB - PCOS is the most frequent endocrine disorder of premenopausal women. The common clinical signs of PCOS are hirsutism, menstrual irregularities with chronic anovulation and a trend toward overweight or obesity. Diagnosis is based upon high plasma levels of androgens and the ultrasound image of polycystic ovaries. The high prevalence of PCOS at first degree female relatives suggest an important genetic component of this syndrome. Linking studies in sisters presenting phenotypical traits of PCOS and in their parents allowed the investigation of certain candidate genes presumed to be involved in the physiopathology of PCOS. The genes encoding enzymes involved in androgen synthesis, protein transducers of insulin signals and the paracrine regulating factors of gonadotrophins and ovarian function have been analysed. To date, no determinant gene mutation was reported. However, several loci were detected, especially a locus within the insulin receptor. Mutations or gene polymorphisms and their function remain to be identified. These research attempts should explain the physiopathology of PCOS and open new therapeutic perspectives. The usage of medication increasing the sensitivity to insulin action is an example of applying these particular aspects. AD - Hospices Civils de Lyon Federation d'Endocrinologie l'Hopital de l'Antiquaille INSERM unite 329-69321. FAU - Pugeat, M AU - Pugeat M LA - fre PT - Journal Article PT - Review PT - Review, Tutorial TT - Genetique du syndrome des ovaires polykystiques et nouvelles perspectives therapeutiques. PL - Romania TA - Rev Med Chir Soc Med Nat Iasi JID - 0413735 RN - 0 (Androgens) RN - 0 (Gonadotropins, Pituitary) RN - 0 (Hypoglycemic Agents) RN - 657-24-9 (Metformin) RN - 6917-35-7 (Inositol) SB - IM MH - Androgens/metabolism MH - Diet, Reducing MH - English Abstract MH - Female MH - Gonadotropins, Pituitary/metabolism MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Inositol/therapeutic use MH - Metformin/therapeutic use MH - Phenotype MH - Polycystic Ovary Syndrome/*genetics/metabolism/*therapy RF - 34 EDAT- 2002/07/02 10:00 MHDA- 2002/11/26 04:00 PST - ppublish SO - Rev Med Chir Soc Med Nat Iasi 2000 Oct-Dec;104(4):11-9. NR -------------------------------------------------------------------------------- 78: Gooch JL et al. STAT6 mediates interleukin-4 ...[PMID: 12082548] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 12082548 OWN - NLM STAT- MEDLINE DA - 20020625 DCOM- 20030214 LR - 20041217 PUBM- Print IS - 1522-8002 VI - 4 IP - 4 DP - 2002 Jul-Aug TI - STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. PG - 324-31 AB - In addition to acting as a hematopoietic growth factor, interleukin-4 (IL-4) inhibits growth of some transformed cells in vitro and in vivo. In this study, we show that insulin receptor substrate (IRS)-1, IRS-2, and signal transducer and activator of transcription 6 (STAT6) are phosphorylated following IL-4 treatment in MCF-7 breast cancer cells. STAT6 DNA binding is enhanced by IL-4 treatment. STAT6 activation occurs even after IRS-1 depletion, suggesting the two pathways are independent. To examine the role of STAT6 in IL-4-mediated growth inhibition and apoptosis, a full-length STAT6 cDNA was transfected into MCF-7 cells. Transient overexpression of STAT6 resulted in both cytoplasmic and nuclear expression of the protein, increased DNA binding in response to IL-4, and increased transactivation of an IL-4 responsive promoter. In STAT6-transfected cells, basal proliferation was reduced whereas apoptosis was increased. Finally, stable expression of STAT6 resulted in reduced foci formation compared to vector-transfected cells alone. These results suggest STAT6 is required for IL-4-mediated growth inhibition and induction of apoptosis in human breast cancer cells. AD - Department of Medicine, Division of Oncology, University of Texas Health Science Center, San Antonio, TX 78284, USA. FAU - Gooch, Jennifer L AU - Gooch JL FAU - Christy, Barbara AU - Christy B FAU - Yee, Douglas AU - Yee D LA - eng GR - P30 CA 54174/CA/NCI GR - R01 CA 74285/CA/NCI PT - Journal Article PL - United States TA - Neoplasia JID - 100886622 RN - 0 (DNA, Complementary) RN - 0 (Growth Inhibitors) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 207137-56-2 (Interleukin-4) SB - IM MH - Adenocarcinoma/metabolism/*pathology MH - Apoptosis/drug effects/physiology MH - Breast Neoplasms/metabolism/*pathology MH - Cell Division/drug effects/physiology MH - DNA, Complementary/genetics MH - Female MH - Growth Inhibitors/*pharmacology MH - Humans MH - Interleukin-4/*pharmacology MH - Neoplasm Proteins/*physiology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Processing, Post-Translational/drug effects MH - Recombinant Fusion Proteins/physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Trans-Activation (Genetics) MH - Trans-Activators/genetics/*physiology MH - Transfection MH - Tumor Cells, Cultured/drug effects/pathology EDAT- 2002/06/26 10:00 MHDA- 2003/02/15 04:00 PHST- 2001/12/06 [received] PHST- 2002/02/14 [accepted] AID - 10.1038/sj.neo.7900248 [doi] PST - ppublish SO - Neoplasia 2002 Jul-Aug;4(4):324-31. NR -------------------------------------------------------------------------------- 79: Del Valle L et al. Insulin-like growth factor I ...[PMID: 12060623] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12060623 OWN - NLM STAT- MEDLINE DA - 20020612 DCOM- 20021227 LR - 20050111 PUBM- Print IS - 1078-0432 VI - 8 IP - 6 DP - 2002 Jun TI - Insulin-like growth factor I receptor activity in human medulloblastomas. PG - 1822-30 AB - Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that insulin-like growth factor I (IGF-I) may contribute to the development of these tumors. Results of this study show that the majority of cases examined were characterized by the abundant presence of the receptor for IGF-I (IGF-IR) protein (16 of 20 cases), and its major signaling molecule, insulin receptor substrate 1 (IRS-1; 15 of 20). Protein levels for IGF-IR and IRS-1, determined by Western blot and immunohistochemistry, were significantly higher in medulloblastoma biopsies than in control cerebellar tissue. By immunohistochemistry, 10 of 17 biopsies examined were also positive for the anti-pY1316 antibody staining that specifically recognizes the phosphorylated (active) form of the IGF-IR. These findings correlate with the fact that phosphorylated forms of the downstream-signaling molecules Erk-1, Erk-2, and Akt/protein kinase B were found in medulloblastoma biopsies but not in control cerebellar tissue. Importantly, there is a strong inverse correlation between biopsies that are positive for anti-pY1316 and for anti-Trk-C immunoreactivity. These observations direct our attention to the IGF-IR system as a potential therapeutic target in medulloblastomas and suggest a possibility of using the anti-pY1316 antibody as a potential prognostic marker for medulloblastomas. AD - Center for Neurovirology and Cancer Biology, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA. FAU - Del Valle, Luis AU - Del Valle L FAU - Enam, Sahnila AU - Enam S FAU - Lassak, Adam AU - Lassak A FAU - Wang, Jin Yiang AU - Wang JY FAU - Croul, Sidney AU - Croul S FAU - Khalili, Kamel AU - Khalili K FAU - Reiss, Krzysztof AU - Reiss K LA - eng GR - P01 NS 36466/NS/NINDS PT - Journal Article PL - United States TA - Clin Cancer Res JID - 9502500 RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Adolescent MH - Animals MH - Biopsy MH - Blotting, Western MH - Cell Division/physiology MH - Cerebellar Neoplasms/*metabolism/pathology MH - Child MH - Child, Preschool MH - Down-Regulation MH - Female MH - Fibroblasts/metabolism MH - Humans MH - Immunoenzyme Techniques MH - Infant MH - Insulin-Like Growth Factor I/pharmacology MH - Male MH - Medulloblastoma/*metabolism/pathology MH - Mice MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/metabolism MH - Paraffin Embedding MH - Phosphoproteins/metabolism MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - Receptor, IGF Type 1/genetics/*metabolism/physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*physiology MH - Tumor Cells, Cultured EDAT- 2002/06/13 10:00 MHDA- 2002/12/28 04:00 PST - ppublish SO - Clin Cancer Res 2002 Jun;8(6):1822-30. NR -------------------------------------------------------------------------------- 80: Garrouste F et al. Prevention of cytokine-induce...[PMID: 12058282] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12058282 OWN - NLM STAT- MEDLINE DA - 20020611 DCOM- 20030114 LR - 20050209 PUBM- Print IS - 1350-9047 VI - 9 IP - 7 DP - 2002 Jul TI - Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules in HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism. PG - 768-79 AB - We have previously established that insulin-like growth factor (IGF)-I, -II and insulin exert a strong protective effect against tumor necrosis factor-alpha (TNF)-induced apoptosis in interferon-gamma (IFN)-sensitized HT29-D4 human colon carcinoma cells. In this study, we report that this effect was still operative when cells were cultured in the absence of integrin- and E-cadherin-mediated cell-extracellular matrix and cell-cell interactions. In this model, IGF-I did not activate the focal adhesion kinase, whereas it induced tyrosine phosphorylation of the insulin receptor substrate-1 and activation of the extracellular signal-related kinase 1 and 2, p38, phosphatidylinositol 3'-kinase and protein kinase B/Akt. However, the use of specific inhibitors indicated that these pathways did not play a role in the adhesion-independent IGF-I anti-apoptotic signal. In contrast, inhibition of the NF-kappaB activation induced a complete reversal of the IGF-I anchorage-independent protective effect. Correspondingly, IGF-I markedly enhanced the TNF- and IFN/TNF-induced NF-kappaB-dependent interleukin-8 production. Our results provide evidence that IGF-I induces resistance against cytokine-induced cell death even in the absence of cell adhesion-mediated signaling. NF-kappaB appears to be a key mediator of this anti-apoptotic effect that should contribute to the resistance of colon cancer cells to immune-destruction during metastasis. AD - UMR CNRS 6032, Facultes de Medecine et de Pharmacie, Universite de la Mediterranee, Marseille, France. FAU - Garrouste, F AU - Garrouste F FAU - Remacle-Bonnet, M AU - Remacle-Bonnet M FAU - Fauriat, C AU - Fauriat C FAU - Marvaldi, J AU - Marvaldi J FAU - Luis, J AU - Luis J FAU - Pommier, G AU - Pommier G LA - eng PT - Journal Article PL - England TA - Cell Death Differ JID - 9437445 RN - 0 (Cell Adhesion Molecules) RN - 0 (Interleukin-8) RN - 0 (NF-kappa B) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 82115-62-6 (Interferon Type II) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - *Apoptosis MH - Cell Adhesion Molecules/metabolism MH - Cell Communication MH - Cell Survival MH - Drug Resistance MH - Extracellular Matrix/metabolism MH - HT29 Cells MH - Humans MH - Insulin/pharmacology MH - Insulin-Like Growth Factor I/*metabolism/pharmacology MH - Interferon Type II/pharmacology MH - Interleukin-8/biosynthesis MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/metabolism MH - NF-kappa B/*metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - *Protein-Serine-Threonine Kinases MH - Protein-Tyrosine Kinase/metabolism MH - Proto-Oncogene Proteins/metabolism MH - *Signal Transduction MH - Tumor Necrosis Factor-alpha/pharmacology MH - p38 Mitogen-Activated Protein Kinases EDAT- 2002/06/12 10:00 MHDA- 2003/01/15 04:00 PHST- 2001/07/17 [received] PHST- 2001/12/13 [revised] PHST- 2002/01/10 [accepted] AID - 10.1038/sj.cdd.4401022 [doi] PST - ppublish SO - Cell Death Differ 2002 Jul;9(7):768-79. NR -------------------------------------------------------------------------------- 81: Li L et al. Overexpression of insulin rec...[PMID: 12055235] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12055235 OWN - NLM STAT- MEDLINE DA - 20020610 DCOM- 20020716 LR - 20041117 PUBM- Print IS - 0022-1767 VI - 168 IP - 12 DP - 2002 Jun 15 TI - Overexpression of insulin receptor substrate-1, but not insulin receptor substrate-2, protects a T cell hybridoma from activation-induced cell death. PG - 6215-23 AB - The insulin receptor substrate (IRS) family of signaling molecules is expressed in lymphocytes, although their functions in these cells is largely unknown. To investigate the role of IRS in the protection of T cells from activation-induced cell death (AICD), we transfected the T cell hybridoma A1.1, which is IL-4 responsive but lacks expression of IRS family members with cDNA encoding IRS1 or IRS2. Stimulation of these clones with immobilized anti-CD3-induced expression of CD69 to the same level as the parental A1.1 cells. However, the A1.1 IRS1-expressing cells were markedly resistant to AICD, while the A1.1 IRS2-expressing cells were not. Inhibition of phosphatidylinositol 3'-kinase in the A1.1 IRS1-expressing cells did not abrogate their resistance to AICD. Fas mRNA was induced similarly by anti-CD3 in A1.1, A1.1 IRS1-expressing, and A1.1 IRS2-expressing cells. However, induction of Fas ligand (FasL) mRNA and functional FasL protein was delayed and decreased in IRS1-expressing cells, but not in IRS2-expressing cells. The induction of transcription from a 500-bp FasL promoter and a minimal 16-mer early growth response element linked to luciferase was also impaired in the IRS1-expressing cells. These results suggest that overexpression of IRS1, but not IRS2, protects A1.1 cells from AICD by diminishing FasL transcription through a pathway that is independent of the tyrosine phosphorylation of IRS1 and phosphatidylinositol 3'-kinase activity. AD - Department of Immunology, Jerome Holland Laboratories, American Red Cross, Rockville, MD 20852, USA. FAU - Li, Li AU - Li L FAU - Qi, Xiulan AU - Qi X FAU - Williams, Mark AU - Williams M FAU - Shi, Yufang AU - Shi Y FAU - Keegan, Achsah D AU - Keegan AD LA - eng GR - AI43384/AI/NIAID GR - AI45662/AI/NIAID PT - Journal Article PL - United States TA - J Immunol JID - 2985117R RN - 0 (Antigens, CD95) RN - 0 (FasL protein) RN - 0 (Membrane Glycoproteins) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Transcription Factors) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/physiology MH - Animals MH - Antigens, CD95/biosynthesis/genetics/metabolism MH - Cell Death/genetics/immunology MH - Comparative Study MH - Hybridomas/cytology/*immunology/metabolism MH - Leukemia L1210 MH - *Lymphocyte Activation/genetics MH - Membrane Glycoproteins/biosynthesis/genetics MH - Mice MH - Phosphoproteins/*biosynthesis/genetics/physiology MH - Receptor, Insulin/*metabolism MH - Receptors, Antigen, T-Cell/physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/genetics/immunology MH - T-Lymphocytes/cytology/*immunology/metabolism MH - Transcription Factors/metabolism MH - Transfection EDAT- 2002/06/11 10:00 MHDA- 2002/07/18 10:01 PST - ppublish SO - J Immunol 2002 Jun 15;168(12):6215-23. DR -------------------------------------------------------------------------------- 82: Stoll BA. Upper abdominal obesity, insu...[PMID: 12037643] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12037643 OWN - NLM STAT- MEDLINE DA - 20020530 DCOM- 20020719 LR - 20041117 PUBM- Print IS - 0307-0565 VI - 26 IP - 6 DP - 2002 Jun TI - Upper abdominal obesity, insulin resistance and breast cancer risk. PG - 747-53 AB - PURPOSE: A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined. MECHANISMS: Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity. CONCLUSION: Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations. AD - Oncology Department, St Thomas' Hospital, London, UK. FAU - Stoll, B A AU - Stoll BA LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Int J Obes Relat Metab Disord JID - 9313169 RN - 11061-68-0 (Insulin) SB - IM MH - Abdomen MH - Adipocytes/physiology MH - Adipose Tissue MH - Body Constitution MH - *Breast Neoplasms/epidemiology/etiology MH - Female MH - Humans MH - Hyperinsulinism MH - Insulin MH - *Insulin Resistance MH - Life Style MH - Male MH - *Obesity/complications/epidemiology MH - Postmenopause MH - Risk Factors MH - Signal Transduction RF - 87 EDAT- 2002/05/31 10:00 MHDA- 2002/07/20 10:01 PHST- 2001/03/08 [received] PHST- 2001/11/21 [revised] PHST- 2001/12/20 [accepted] AID - 10.1038/sj.ijo.0801998 [doi] PST - ppublish SO - Int J Obes Relat Metab Disord 2002 Jun;26(6):747-53. NR -------------------------------------------------------------------------------- 83: Goberdhan DC et al. Insulin receptor-mediated org...[PMID: 12012234] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12012234 OWN - NLM STAT- MEDLINE DA - 20020515 DCOM- 20021119 LR - 20050111 PUBM- Print-Electronic IS - 0949-944X VI - 212 IP - 4 DP - 2002 May TI - Insulin receptor-mediated organ overgrowth in Drosophila is not restricted by body size. PG - 196-202 AB - Recent studies have demonstrated that insulin receptor (Inr) signalling plays an important role in determining organ size and maintaining proportionality in normal animals. However, it is unclear whether the activity of this pathway in a developing organ is invariably a dominant determinant of its mass or whether size can be restricted by other non-autonomous growth regulatory mechanisms if a tissue starts to outgrow the rest of the body. To test this in Drosophila, we induced excess Inr-dependent growth by removal of the Inr signalling antagonist, DPTEN, in the eyes of flies with dramatically different body sizes. Although our data suggest a very limited level of growth competition between organs in animals with giant eyes, there do not appear to be mechanisms by which neighbouring structures substantially inhibit eye overgrowth, even when the resulting organ is many times enlarged relative to the rest of the animal. Overall, our results support a simple model in which organs are normally maintained in proportion to each other, primarily because they all respond similarly to levels of insulin-like factors and other growth regulators. Given the evolutionarily conserved role of insulin receptor signalling in growth control, our data may also help to explain why this pathway is so frequently hyperactivated in mammalian tumours. AD - Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. FAU - Goberdhan, Deborah C I AU - Goberdhan DC FAU - Wilson, Clive AU - Wilson C LA - eng PT - Journal Article DEP - 20020329 PL - Germany TA - Dev Genes Evol JID - 9613264 RN - 0 (Carrier Proteins) RN - 0 (Drosophila Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Tumor Suppressor Proteins) RN - 0 (chico protein, Drosophila) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTEN protein) SB - IM MH - Animals MH - Body Constitution/genetics MH - *Carrier Proteins MH - Drosophila/*growth & development MH - Drosophila Proteins/genetics MH - Epistasis, Genetic MH - Eye/growth & development MH - *Intracellular Signaling Peptides and Proteins MH - Mosaicism/genetics MH - Phosphoric Monoester Hydrolases/genetics/*physiology MH - Receptor, Insulin/*physiology MH - Research Support, Non-U.S. Gov't MH - Tumor Suppressor Proteins/genetics/*physiology EDAT- 2002/05/16 10:00 MHDA- 2002/11/26 04:00 PHST- 2001/09/19 [received] PHST- 2002/02/20 [accepted] PHST- 2002/03/29 [aheadofprint] AID - 10.1007/s00427-002-0226-3 [doi] PST - ppublish SO - Dev Genes Evol 2002 May;212(4):196-202. Epub 2002 Mar 29. DR -------------------------------------------------------------------------------- 84: Falcone S et al. Nitric oxide regulates oestro...[PMID: 11978177] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11978177 OWN - NLM STAT- MEDLINE DA - 20020806 DCOM- 20021008 LR - 20041117 PUBM- Print IS - 0264-6021 VI - 366 IP - Pt 1 DP - 2002 Aug 15 TI - Nitric oxide regulates oestrogen-activated signalling pathways at multiple levels through cyclic GMP-dependent recruitment of insulin receptor substrate 1. PG - 165-73 AB - The gaseous messenger nitric oxide (NO) contributes to biological effects of oestrogen in target tissues, including reproductive organs, bone, cardiovascular and central nervous systems. Vasodilation and anti-atherosclerotic properties of NO have been shown to play a role in these effects. The possibility that NO acts also through regulation of the signal transduction cascade triggered by oestrogen, instead, has never been investigated. To study this we have used the MCF-7 human breast cancer cell line, an established model for oestrogen signalling. Exposure of these cells to 17-beta-oestradiol (E(2)) in the presence of NO gave rise to activation of signalling events additional to those triggered by E(2) alone, namely tyrosine phosphorylation of specific proteins, including the insulin receptor substrate-1, with recruitment to this adapter of the phosphatidylinositol 3'-kinase and persistent activation of Akt (protein kinase B). Active Akt, in turn, prevented E(2) from activating p42/44 extracellular signal-regulated kinases (ERK 1/2). These effects of NO, which were mediated through generation of cyclic GMP and activation of the cGMP-dependent protein kinase I, initiated in the first minutes after administration of oestrogen. The consequences, however, were long lasting, as modulation of Akt and ERK 1/2 activities by NO was responsible for inhibition of E(2)-triggered cell growth and regulation of oestrogen responsive-element dependent gene transcription. Generation of NO is stimulated by both E(2) and growth factors known to contribute to the complex network of intracellular events regulating the biological actions of oestrogen. It is conceivable, therefore, that modulation by NO of E(2) early signalling, here described for the first time, has broad significance in regulating cellular responses to the hormone. AD - Department of Pharmacology, University of Milano, 20129 Milano, Italy. FAU - Falcone, Sestina AU - Falcone S FAU - Mauro, Loredana AU - Mauro L FAU - de Rose, Giacinta AU - de Rose G FAU - Paolucci, Clara AU - Paolucci C FAU - Sciorati, Clara AU - Sciorati C FAU - Ando, Sebastiano AU - Ando S FAU - Clementi, Emilio AU - Clementi E LA - eng PT - Journal Article PL - England TA - Biochem J JID - 2984726R RN - 0 (MAP Kinase Signaling System) RN - 0 (Phosphoproteins) RN - 0 (Protein Isoforms) RN - 0 (insulin receptor substrate-1 protein) RN - 10102-43-9 (Nitric Oxide) RN - 50-28-2 (Estradiol) RN - 55520-40-6 (Tyrosine) RN - 7665-99-8 (Cyclic GMP) RN - EC 1.13.12.- (Luciferases) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Blotting, Western MH - Cell Division MH - Cyclic GMP/*physiology MH - Enzyme Activation MH - Estradiol/*pharmacology MH - Humans MH - Luciferases/metabolism MH - MAP Kinase Signaling System MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/metabolism MH - Nitric Oxide/*physiology MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Precipitin Tests MH - Protein Isoforms MH - Protein Transport MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Transfection MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2002/04/30 10:00 MHDA- 2002/10/09 04:00 PHST- 2002/04/29 [accepted] PHST- 2002/04/02 [revised] PHST- 2002/01/03 [received] AID - 10.1042/BJ20020017 [doi] AID - BJ20020017 [pii] PST - ppublish SO - Biochem J 2002 Aug 15;366(Pt 1):165-73. NR -------------------------------------------------------------------------------- 85: Kiely PA et al. RACK1 is an insulin-like grow...[PMID: 11964397] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11964397 OWN - NLM STAT- MEDLINE DA - 20020617 DCOM- 20020719 LR - 20050111 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 25 DP - 2002 Jun 21 TI - RACK1 is an insulin-like growth factor 1 (IGF-1) receptor-interacting protein that can regulate IGF-1-mediated Akt activation and protection from cell death. PG - 22581-9 AB - The insulin receptor and insulin-like growth factor 1 receptor (IGF-1R), activated by their ligands, control metabolism, cell survival, and proliferation. Although the signaling pathways activated by these receptors are well characterized, regulation of their activity is poorly understood. To identify regulatory proteins we undertook a two-hybrid screen using the IGF-1R beta-chain as bait. This screen identified Receptor for Activated C Kinases (RACK1) as an IGF-1R-interacting protein. RACK1 also interacted with the IGF-1R in fibroblasts and MCF-7 cells and with endogenous insulin receptor in COS cells. Interaction with the IGF-1R did not require tyrosine kinase activity or receptor autophosphorylation but did require serine 1248 in the C terminus. Overexpression of RACK1 in either R+ fibroblasts or MCF-7 cells inhibited IGF-1-induced phosphorylation of Akt, whereas it enhanced phosphorylation of Erks and Jnks. Src, the p85 subunit of phosphatidylinositol 3-kinase, and SHP-2 were all associated with RACK1 in these cells. Interestingly, the proliferation of MCF-7 cells was enhanced by overexpression of RACK1, whereas IGF-1-mediated protection from etoposide killing was greatly reduced. Altogether the data indicate that RACK1 is an IGF-1R-interacting protein that can modulate receptor signaling and suggest that RACK1 has a particular role in regulating Akt activation and cell survival. AD - Cell Biology Laboratory, Department of Biochemistry and Bioscience Institute, National University of Ireland, Lee Maltings Cork, Ireland. FAU - Kiely, Patrick A AU - Kiely PA FAU - Sant, Anagha AU - Sant A FAU - O'Connor, Rosemary AU - O'Connor R LA - eng PT - Journal Article DEP - 20020418 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Neoplasm Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RACK1 protein, human) RN - 0 (Recombinant Proteins) RN - 56-41-7 (Alanine) RN - 56-45-1 (Serine) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Alanine/chemistry MH - Animals MH - Blotting, Western MH - COS Cells MH - Cell Death MH - Cell Division MH - Cell Survival MH - Cloning, Molecular MH - Enzyme Activation MH - Fibroblasts/metabolism MH - Humans MH - Mutation MH - Neoplasm Proteins/*metabolism MH - Phosphorylation MH - Precipitin Tests MH - Protein Binding MH - Protein Structure, Tertiary MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/*metabolism MH - Receptor, IGF Type 1/*metabolism MH - Recombinant Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Serine/chemistry MH - Time Factors MH - Transfection MH - Tumor Cells, Cultured MH - Two-Hybrid System Techniques EDAT- 2002/04/20 10:00 MHDA- 2002/07/20 10:01 PHST- 2002/04/18 [aheadofprint] AID - 10.1074/jbc.M201758200 [doi] AID - M201758200 [pii] PST - ppublish SO - J Biol Chem 2002 Jun 21;277(25):22581-9. Epub 2002 Apr 18. DR -------------------------------------------------------------------------------- 86: Hermanto U et al. RACK1, an insulin-like growth...[PMID: 11884618] Related Articles, Gene, GENSAT, HomoloGene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 11884618 OWN - NLM STAT- MEDLINE DA - 20020308 DCOM- 20020403 LR - 20050209 PUBM- Print IS - 0270-7306 VI - 22 IP - 7 DP - 2002 Apr TI - RACK1, an insulin-like growth factor I (IGF-I) receptor-interacting protein, modulates IGF-I-dependent integrin signaling and promotes cell spreading and contact with extracellular matrix. PG - 2345-65 AB - The insulin-like growth factor I (IGF-I) receptor (IGF-IR) is known to regulate a variety of cellular processes including cell proliferation, cell survival, cell differentiation, and cell transformation. IRS-1 and Shc, substrates of the IGF-IR, are known to mediate IGF-IR signaling pathways such as those of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), which are believed to play important roles in some of the IGF-IR-dependent biological functions. We used the cytoplasmic domain of IGF-IR in a yeast two-hybrid interaction trap to identify IGF-IR-interacting molecules that may potentially mediate IGF-IR-regulated functions. We identified RACK1, a WD repeat family member and a Gbeta homologue, and demonstrated that RACK1 interacts with the IGF-IR but not with the closely related insulin receptor (IR). In several types of mammalian cells, RACK1 interacted with IGF-IR, protein kinase C, and beta1 integrin in response to IGF-I and phorbol 12-myristate 13-acetate stimulation. Whereas most of RACK1 resides in the cytoskeletal compartment of the cytoplasm, transformation of fibroblasts and epithelial cells by v-Src, oncogenic IR or oncogenic IGF-IR, but not by Ros or Ras, resulted in a significantly increased association of RACK1 with the membrane. We examined the role of RACK1 in IGF-IR-mediated functions by stably overexpressing RACK1 in NIH 3T3 cells that expressed an elevated level of IGF-IR. RACK1 overexpression resulted in reduced IGF-I-induced cell growth in both anchorage-dependent and anchorage-independent conditions. Overexpression of RACK1 also led to enhanced cell spreading, increased stress fibers, and increased focal adhesions, which were accompanied by increased tyrosine phosphorylation of focal adhesion kinase and paxillin. While IGF-I-induced activation of IRS-1, Shc, PI3K, and MAPK pathways was unaffected, IGF-I-inducible beta1 integrin-associated kinase activity and association of Crk with p130(CAS) were significantly inhibited by RACK1 overexpression. In RACK1-overexpressing cells, delayed cell cycle progression in G(1) or G(1)/S was correlated with retinoblastoma protein hypophophorylation, increased levels of p21(Cip1/WAF1) and p27(Kip1), and reduced IGF-I-inducible Cdk2 activity. Reduction of RACK1 protein expression by antisense oligonucleotides prevented cell spreading and suppressed IGF-I-dependent monolayer growth. Our data suggest that RACK1 is a novel IGF-IR signaling molecule that functions as a positive mediator of cell spreading and contact with extracellular matrix, possibly through a novel IGF-IR signaling pathway involving integrin and focal adhesion signaling molecules. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. FAU - Hermanto, Ulrich AU - Hermanto U FAU - Zong, Cong S AU - Zong CS FAU - Li, Weiqun AU - Li W FAU - Wang, Lu-Hai AU - Wang LH LA - eng GR - CA29339/CA/NCI GR - CA55054/CA/NCI GR - T32GM07280/GM/NIGMS PT - Journal Article PL - United States TA - Mol Cell Biol JID - 8109087 RN - 0 (Antigens, CD29) RN - 0 (Cell Cycle Proteins) RN - 0 (Cyclins) RN - 0 (Cytoskeletal Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (RACK1 protein, human) RN - 0 (cyclin-dependent kinase Inhibitor p21) RN - 0 (paxillin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM MH - Animals MH - Antigens, CD29/*metabolism MH - Cell Cycle Proteins/metabolism MH - Cell Division MH - Cell Line MH - Cell Line, Transformed MH - Cell Size/drug effects MH - Chickens MH - Cyclins/metabolism MH - Cytoskeletal Proteins/metabolism MH - Extracellular Matrix/drug effects/*metabolism MH - Focal Adhesions/drug effects/metabolism MH - Humans MH - Insulin-Like Growth Factor I/*pharmacology MH - Mice MH - Neoplasm Proteins/biosynthesis/genetics/*metabolism MH - Oncogenes/physiology MH - Phosphoproteins/metabolism MH - Protein Binding/drug effects MH - Protein Kinase C/metabolism MH - Protein-Tyrosine Kinase/metabolism MH - Receptor, IGF Type 1/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*drug effects MH - Stress Fibers/drug effects/metabolism MH - Two-Hybrid System Techniques EDAT- 2002/03/09 10:00 MHDA- 2002/04/04 10:01 PST - ppublish SO - Mol Cell Biol 2002 Apr;22(7):2345-65. NR -------------------------------------------------------------------------------- 87: Haimsohn M et al. Aurintricarboxylic acid induc...[PMID: 11861505] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11861505 OWN - NLM STAT- MEDLINE DA - 20020225 DCOM- 20020321 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 143 IP - 3 DP - 2002 Mar TI - Aurintricarboxylic acid induces a distinct activation of the IGF-I receptor signaling within MDA-231 cells. PG - 837-45 AB - Aurintricarboxylic acid (ATA), a polymeric carboxylated triphenylmethane derivate, prevents apoptotic death in a variety of cell systems. Recently, we have shown that the survival promoting effect of ATA is transduced via activation of the IGF-I receptor (IGF-IR) signaling pathway. In breast cancer MDA-231 cells exposed either to the protein synthesis inhibitors cycloheximide or ricin or to the anticancer drug adriamycin, we have found that ATA, but not IGF-1, is a powerful antiapoptotic agent. The purpose of this study was to compare the ability of ATA and IGF-I to activate the IGF-IR signaling cascade and to correlate this ability to their survival potency. MDA-231 cells were exposed to ATA or IGF-I, up to 7 h, and the dynamics of activation of the IGF-IR signaling cascade was evaluated. Our results show that: 1) The amount of tyrosine phosphorylated IGF-IR proteins was greater after exposure to ATA, compared with IGF-I. 2) Two phosphorylated IGF-IR beta-subunits (a 95-kDa and a 75-kDa) were induced after exposure to ATA, whereas IGF-1 induced only the 95-kDa form. Immunoprecipitation of both receptor forms by antibodies against the alpha-subunit and against the carboxy terminus of the beta-subunit of the IGF-IR suggests that the 75-kDa form could be the beta-chain truncated at the amino terminus above the alpha-beta disulphide bridges. 3) The ATA-activated IGF-IR forms underwent slow dephosphorylation, compared with a rapid dephosphorylation of the IGF-I activated receptor. 4) The insulin receptor substrate-1/2-associated PI3K, Shc proteins, and the kinases Akt and Erk1/2, downstream mediators of the antiapoptotic signaling by IGF-IR, were activated to a higher extent and for a longer time period by ATA, compared with IGF-I. Taken together, the sustained activation of the IGF-IR signaling pathway by ATA may explain its stronger antiapoptotic effect. We suggest that this enhanced activity, and the different susceptibility of the IGF-IR to certain proteases and phosphatases, may indicate a distinct conformation of the ATA-activated IGF-IR. AD - Institue of Endocrinology, Sheba Medical Center, Tel Hashomer, 52621, Israel. FAU - Haimsohn, Michal AU - Haimsohn M FAU - Beery, Rachel AU - Beery R FAU - Karasik, Avraham AU - Karasik A FAU - Kanety, Hannah AU - Kanety H FAU - Geier, Avraham AU - Geier A LA - eng PT - Journal Article PL - United States TA - Endocrinology JID - 0375040 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Protein Synthesis Inhibitors) RN - 23214-92-8 (Doxorubicin) RN - 4431-00-9 (Aurintricarboxylic Acid) RN - 66-81-9 (Cycloheximide) RN - 9009-86-3 (Ricin) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - AIM SB - IM MH - Antibiotics, Antineoplastic/pharmacology MH - Apoptosis/drug effects MH - Aurintricarboxylic Acid/*pharmacology MH - Breast Neoplasms/metabolism MH - Cell Death/drug effects MH - Cycloheximide/pharmacology MH - Doxorubicin/pharmacology MH - Female MH - Humans MH - Phosphorylation MH - Protein Synthesis Inhibitors/pharmacology MH - Receptor, IGF Type 1/*drug effects MH - Ricin/pharmacology MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured EDAT- 2002/02/28 10:00 MHDA- 2002/03/22 10:01 PST - ppublish SO - Endocrinology 2002 Mar;143(3):837-45. NR -------------------------------------------------------------------------------- 88: Livingstone C et al. Sex steroids and insulin resi...[PMID: 11834135] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11834135 OWN - NLM STAT- MEDLINE DA - 20020208 DCOM- 20020408 LR - 20041117 PUBM- Print IS - 0143-5221 VI - 102 IP - 2 DP - 2002 Feb TI - Sex steroids and insulin resistance. PG - 151-66 AB - There is extensive experimental evidence that sex steroids and insulin interact in their actions on tissues. At physiological levels, testosterone and oestradiol are thought to be involved in maintaining normal insulin sensitivity. However, outside this 'physiological window' these steroids may promote insulin resistance. Considerable research has been carried out on polycystic ovarian syndrome, a common disorder associated with excessive androgen production and insulin resistance. Hyperinsulinaemia in patients with this condition is believed to stimulate ovarian androgen production, and there is also evidence that androgens act directly on peripheral tissues to promote insulin resistance. There is the potential for a vicious circle to develop with increasing androgen production and insulin resistance. The molecular basis of this insulin resistance has been reported to involve reduced insulin receptor autophosphorylation, reduced expression and translocation of insulin-responsive glucose transporters and defects of the insulin signalling pathway distal to the insulin receptor. These defects await full characterization. Insulin-sensitizing agents can reverse many of the effects of insulin resistance and may have a future place in the treatment of polycystic ovarian syndrome and other conditions associated with steroid-induced insulin resistance. Recognition and treatment of sex steroid-associated insulin resistance at an early stage in patients may reduce their risk of developing Type II (non-insulin-dependent) diabetes mellitus, hypertension and dyslipidaemia, and so may improve fertility and reduce cardiovascular risk. Here we review the interplay between sex steroids and insulin resistance, and consider the implications this has for clinical conditions. AD - Centre for Clinical Science and Measurement, School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 5XH, UK. clivingstone@royalsurrey.nhs.uk FAU - Livingstone, Callum AU - Livingstone C FAU - Collison, Mary AU - Collison M LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Clin Sci (Lond) JID - 7905731 RN - 0 (Gonadal Steroid Hormones) RN - 0 (Monosaccharide Transport Proteins) RN - 11061-68-0 (Insulin) RN - 50-28-2 (Estradiol) RN - 58-22-0 (Testosterone) SB - IM MH - Animals MH - Diabetes Mellitus, Type 2/physiopathology MH - Estradiol/physiology MH - Female MH - Gonadal Steroid Hormones/*physiology MH - Humans MH - Insulin/physiology MH - Insulin Resistance/*physiology MH - Male MH - Monosaccharide Transport Proteins/physiology MH - Polycystic Ovary Syndrome/physiopathology MH - Pregnancy MH - Rats MH - Testosterone/physiology RF - 136 EDAT- 2002/02/09 10:00 MHDA- 2002/04/09 10:01 PST - ppublish SO - Clin Sci (Lond) 2002 Feb;102(2):151-66. NR -------------------------------------------------------------------------------- 89: Ducluzeau PH et al. [Resistance to insulin and po...[PMID: 11787441] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11787441 OWN - NLM STAT- MEDLINE DA - 20020111 DCOM- 20020213 LR - 20041117 PUBM- Print IS - 1262-3636 VI - 27 IP - 4 Pt 2 DP - 2001 Sep TI - [Resistance to insulin and polycystic ovary syndrome] PG - S7-12 AD - Federation d'Endocrinologie, Hopital de l'Antiquaille, Hospices Civils de Lyon. michel.pugeat@chu-lyon.fr FAU - Ducluzeau, P H AU - Ducluzeau PH FAU - Laville, M AU - Laville M FAU - Vidal, H AU - Vidal H FAU - Pugeat, M AU - Pugeat M LA - fre PT - Journal Article PT - Review PT - Review, Tutorial TT - Resistance a l'insuline et syndrome des ovaires polykystiques. PL - France TA - Diabetes Metab JID - 9607599 RN - 11061-68-0 (Insulin) RN - 57-83-0 (Progesterone) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Diabetes Mellitus, Type 2/epidemiology/etiology/prevention & control MH - Female MH - Glucose Intolerance/epidemiology/etiology MH - Homeostasis MH - Humans MH - Insulin/*physiology MH - *Insulin Resistance MH - Polycystic Ovary Syndrome/*physiopathology MH - Pregnancy MH - Pregnancy Complications/physiopathology MH - Progesterone/physiology MH - Protein-Tyrosine Kinase/metabolism MH - Receptor, Insulin/physiology MH - Reproduction MH - Risk MH - Risk Factors MH - Signal Transduction RF - 49 EDAT- 2002/01/15 10:00 MHDA- 2002/02/14 10:01 PST - ppublish SO - Diabetes Metab 2001 Sep;27(4 Pt 2):S7-12. NR -------------------------------------------------------------------------------- 90: Burroughs KD et al. Dysregulation of IGF-I signal...[PMID: 11786376] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11786376 OWN - NLM STAT- MEDLINE DA - 20020111 DCOM- 20020215 LR - 20041117 PUBM- Print IS - 0022-0795 VI - 172 IP - 1 DP - 2002 Jan TI - Dysregulation of IGF-I signaling in uterine leiomyoma. PG - 83-93 AB - IGF-I expression has been observed in human uterine leiomyomas. To examine whether autocrine IGF-I signaling plays a role in the growth of these tumors, we used an animal model of uterine leiomyoma (the Eker rat) to investigate regulation of IGF-I and the IGF-I receptor (IGF-IR) expression in tumors and normal myometrium. During the normal estrous cycle, myometrial IGF-I expression peaked on the day of proestrus when the rate of proliferation in this tissue is greatest. In leiomyomas, the expression of IGF-I was increased 7.5-fold compared with the age-matched normal tissue. The level of IGF-IR mRNA in both tumor and non-tumor tissues was found to inversely correlate with that of IGF-I. Changes observed in IGF-I signaling components correlated with the activation state of the signal-transducing protein insulin receptor substrate-1 (IRS-1). During diestrus and proestrus when IGF-I levels were increasing, tyrosine phosphorylation of IRS-1 was increased up to 5.7-fold in the normal myometrium relative to estrus, when IGF-I levels were the lowest. Additionally, IRS-1 phosphorylation was 4-fold greater in leiomyomas relative to age-matched normal myometrium. Autocrine stimulation of the IGF-IR may, therefore, play a role in regulating the normal growth of the myometrium, and dysregulation of IGF-I signaling could contribute to the neoplastic growth of uterine leiomyomas. AD - Department of Carcinogenesis, The University of Texas, MD Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA. FAU - Burroughs, K D AU - Burroughs KD FAU - Howe, S R AU - Howe SR FAU - Okubo, Y AU - Okubo Y FAU - Fuchs-Young, R AU - Fuchs-Young R FAU - LeRoith, D AU - LeRoith D FAU - Walker, C L AU - Walker CL LA - eng GR - CA16672/CA/NCI GR - CA72253/CA/NCI GR - ES07784/ES/NIEHS GR - ES08263/ES/NIEHS PT - Journal Article PL - England TA - J Endocrinol JID - 0375363 RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Somatomedin) RN - 0 (insulin receptor substrate-1 protein) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Animals MH - Autocrine Communication MH - Blotting, Western MH - *Cell Communication MH - Cell Division/genetics MH - Female MH - Genes, Tumor Suppressor MH - Insulin-Like Growth Factor I/genetics/*metabolism MH - Leiomyoma/*metabolism MH - Myometrium/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - RNA, Messenger/analysis MH - Rats MH - Rats, Mutant Strains MH - Receptors, Somatomedin/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction MH - Tyrosine/metabolism MH - Uterine Neoplasms/*metabolism EDAT- 2002/01/12 10:00 MHDA- 2002/02/16 10:01 AID - JOE04403 [pii] PST - ppublish SO - J Endocrinol 2002 Jan;172(1):83-93. NR -------------------------------------------------------------------------------- 91: Thordarson G et al. Growth and characterization o...[PMID: 11751437] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11751437 OWN - NLM STAT- MEDLINE DA - 20011225 DCOM- 20020204 LR - 20041117 PUBM- Print IS - 0143-3334 VI - 22 IP - 12 DP - 2001 Dec TI - Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats. PG - 2039-47 AB - It is well established that 85-90% of chemically induced mammary tumors in rats will disappear or diminish significantly in size after the ovaries are removed from the animal. However, it is less well established whether a high percentage of these mammary tumors will grow back with prolonged time after ovariectomy. It is also not known what changes in gene expression take place in the tumors as they develop an independence from hormones for growth. This study was carried out to investigate this. Virgin, 50-day-old female Sprague-Dawley rats were injected with N-methyl-N-nitrosourea (MNU) at the dose of 50 mg MNU/kg body wt. When at least one mammary tumor had grown to 1.0-1.5 cm in one dimension, the animal was bilaterally ovariectomized and reduction and then re-growth of the tumors monitored. Control animals were treated identically except they were not ovariectomized when tumors appeared. Re-growths and new tumors and tumors that developed in the control rats were removed when they reached 1.0-1.5 cm in diameter and all animals were killed 25 weeks after the MNU injection. All the animals in the study (100%) developed mammary tumors after MNU injection with an average latency of 56.5 days. After ovariectomy, 93% of the tumors showed 50% or more reduction in size and 76% of the tumors could not be detected by palpation. However, in 96% of the animals where tumor reduction or disappearance occurred, a re-growth or new mammary tumor development took place with an average latency period of 52.8 days from the day of ovariectomy. Of these post-ovariectomy tumors, 36% occurred at a location where tumors had developed prior to ovariectomy, but 64% appeared at new locations. The circulating levels of 17beta-estradiol (E2) was undetectable in the ovariectomized (OVX) rats and significant reduction was seen in the serum concentrations of progesterone (P4), prolactin (PRL), growth hormone (GH) and insulin-like growth factor-I (IGF-I). The tumors from the OVX rats showed indications of progression as evident from loss of differentiation and invasive characteristics. Comparison between tumors from OVX and intact rats revealed a significantly increased expression of P450 aromatase and elevated activation of extracellular signal-regulated kinase 1 and 2, but reduced levels of the progesterone receptor and cyclin D1 in OVX rats. However, the estrogen receptor (ER) content remained similar in tumors from both groups, at least at the protein level, and so did the expression of IGF-I, IGF-II, insulin receptor substrate-1 (IRS1), IRS-2 and epidermal growth factor receptor. IGF-I receptor (IGF-IR) and ErbB-2 were expressed, respectively, in 50 and 70% of the tumors from the OVX animals, whereas these genes were expressed in 100% of the tumors from the intact rats. It is concluded that chemically induced rat mammary tumors may still depend on the ER and local syntheses of E2 and growth factors for growth initially after ovariectomy. However, as these tumors progress, they develop a more aggressive phenotype and lose their dependency on the ER and possibly growth factors. AD - Department of Molecular, Cell and Developmental Biology, Sinsheimer Laboratories, University of California, Santa Cruz, CA 95064, USA. gummi@biology.ucsc.edu FAU - Thordarson, G AU - Thordarson G FAU - Lee, A V AU - Lee AV FAU - McCarty, M AU - McCarty M FAU - Van Horn, K AU - Van Horn K FAU - Chu, O AU - Chu O FAU - Chou, Y C AU - Chou YC FAU - Yang, J AU - Yang J FAU - Guzman, R C AU - Guzman RC FAU - Nandi, S AU - Nandi S FAU - Talamantes, F AU - Talamantes F LA - eng GR - CA-71590/CA/NCI GR - CA-72598/CA/NCI PT - Journal Article PL - England TA - Carcinogenesis JID - 8008055 RN - 0 (Estrogen Receptor alpha) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, Progesterone) RN - 0 (Somatomedins) RN - 136601-57-5 (Cyclin D1) RN - 50-28-2 (Estradiol) RN - 684-93-5 (Methylnitrosourea) RN - 9002-62-4 (Prolactin) RN - 9002-72-6 (Growth Hormone) RN - EC 1.14.14.1 (Aromatase) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, erbB-2) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 3.1.- (Ribonucleases) SB - IM MH - Animals MH - Aromatase/metabolism MH - Cell Differentiation MH - Cyclin D1/metabolism MH - Estradiol/blood/metabolism MH - Estrogen Receptor alpha MH - Female MH - Growth Hormone/blood MH - Mammary Neoplasms, Experimental/*chemically induced/enzymology/metabolism/*pathology MH - Methylnitrosourea/*toxicity MH - Mitogen-Activated Protein Kinases/metabolism MH - *Ovariectomy MH - Prolactin/blood MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, Epidermal Growth Factor/metabolism MH - Receptor, IGF Type 1/metabolism MH - Receptor, erbB-2/metabolism MH - Receptors, Estrogen/metabolism MH - Receptors, Progesterone/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Ribonucleases/metabolism MH - Somatomedins/metabolism EDAT- 2001/12/26 10:00 MHDA- 2002/02/05 10:01 PST - ppublish SO - Carcinogenesis 2001 Dec;22(12):2039-47. NR -------------------------------------------------------------------------------- 92: Ostlund P et al. Altered insulin receptor proc...[PMID: 11750072] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 11750072 OWN - NLM STAT- MEDLINE DA - 20011225 DCOM- 20020321 LR - 20041117 PUBM- Print IS - 0169-328X VI - 97 IP - 2 DP - 2001 Dec 30 TI - Altered insulin receptor processing and function in scrapie-infected neuroblastoma cell lines. PG - 161-70 AB - The underlying neurochemical changes contributing to prion-induced neurodegeneration remain largely unknown. This study shows that scrapie infection induced a 2-fold increase of insulin receptor (IR) protein and aberrantly processed IR beta-chain in scrapie-infected N2a neuroblastoma cells (ScN2a) as measured by Western blot of immunoprecipitated IR, in the absence of increased IR mRNA. Elevated IR protein level was further confirmed in an independently scrapie-infected neuroblastoma cell line N1E-115 (ScN1E-115). Proliferation studies showed that the increased IR level in ScN2a did not result in an increased insulin-mediated cell growth compared to normal N2a cells. Binding studies indicated that this apparent paradox was due to a 65% decrease in specific [(125)I]insulin binding sites in ScN2a when compared to the amount of immunoreactive IR, although the IR binding affinity was unchanged. Analysis of insulin stimulated IR tyrosine phosphorylation showed a slight but not significant reduction in ScN2a, when related to the increased level of immunoreactive IR. However, comparing the IR tyrosine phosphorylation to the loss of binding sites in ScN2a, we demonstrated an increased IR tyrosine phosphorylation of the remaining functional IR. In addition to these differences in IR properties, the basal extracellular signal regulated kinase-2 (ERK2) phosphorylation detected by Western blot, was significantly elevated and the insulin stimulated ERK2 phosphorylation was subsequently decreased in ScN2a. Together, these data show that scrapie infection affects the level and processing of the IR and signal transduction mediated by the IR in neuroblastoma cells, as well as induces an elevated basal ERK2 phosphorylation. Aberrant regulation of neuroprotective receptors may contribute to neurodegeneration in prion diseases. AD - Department of Neurochemistry and Neurotoxicology, University of Stockholm, Svante Arrhenius v. 21A, S-10691 Stockholm, Sweden. FAU - Ostlund, P AU - Ostlund P FAU - Lindegren, H AU - Lindegren H FAU - Pettersson, C AU - Pettersson C FAU - Bedecs, K AU - Bedecs K LA - eng PT - Journal Article PL - Netherlands TA - Brain Res Mol Brain Res JID - 8908640 RN - 0 (Hypoglycemic Agents) RN - 0 (Iodine Radioisotopes) RN - 0 (Prions) RN - 11061-68-0 (Insulin) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) SB - IM MH - Animals MH - Blotting, Western MH - Cell Division/drug effects MH - Gene Expression/physiology MH - Hypoglycemic Agents/pharmacology MH - Insulin/pharmacology MH - Iodine Radioisotopes/diagnostic use MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Nerve Degeneration/metabolism/physiopathology MH - Neuroblastoma MH - Phosphorylation MH - Prions/metabolism MH - Receptor, Insulin/analysis/*genetics/*metabolism MH - Research Support, Non-U.S. Gov't MH - Scrapie/*metabolism/*physiopathology MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2001/12/26 10:00 MHDA- 2002/03/22 10:01 AID - S0169328X01003163 [pii] PST - ppublish SO - Brain Res Mol Brain Res 2001 Dec 30;97(2):161-70. PR -------------------------------------------------------------------------------- 93: Meyer GE et al. Insulin-like growth factor I ...[PMID: 11709726] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11709726 OWN - NLM STAT- MEDLINE DA - 20011115 DCOM- 20011207 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 20 IP - 51 DP - 2001 Nov 8 TI - Insulin-like growth factor I stimulates motility in human neuroblastoma cells. PG - 7542-50 AB - Motility is an important process that contributes to cancer cell spread. Growth factors are key regulators of motility in many cell types. Insulin-like growth factor I (IGF-I) causes SH-SY5Y human neuroblastoma cells to undergo dynamic morphological changes, leading to the extension of lamellipodia. IGF-I stimulated lamellipodia extension requires signaling through both phosphatidylinositol 3-kinase (PI3-K) and MAP kinase pathways. IGF-I, over a period of hours, stimulates SH-SY5Y and SHEP neuroblastoma cells to become more motile. While SH-SY5Y and SHEP cells use different insulin receptor substrate (IRS) isoforms to transduce signals from the IGF-I receptor, IGF-I has the same relative effect on the motility of both cell lines. Blocking the PI3-K and MAP kinase pathways attenuates the ability of IGF-I to increase motility. Overexpression of PTEN also attenuates IGF-I mediated motility. These results delineate some of the proximal events in the signaling mechanism utilized by IGF-I to stimulate cell motility. AD - Neuroscience Program, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI 48109, USA. FAU - Meyer, G E AU - Meyer GE FAU - Shelden, E AU - Shelden E FAU - Kim, B AU - Kim B FAU - Feldman, E L AU - Feldman EL LA - eng GR - 5T32 CA 09676/CA/NCI GR - 5T32 GM 07863/GM/NIGMS GR - RO1 NS 38849/NS/NINDS PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (Culture Media, Serum-Free) RN - 0 (MAP Kinase Signaling System) RN - 0 (Protein Isoforms) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Cell Division MH - Cell Line MH - Cell Movement MH - Culture Media, Serum-Free MH - Dose-Response Relationship, Drug MH - Humans MH - Immunoblotting MH - Insulin-Like Growth Factor I/*metabolism/*physiology MH - MAP Kinase Signaling System MH - Microscopy, Video MH - Neuroblastoma/*metabolism MH - Precipitin Tests MH - Protein Isoforms MH - Pseudopodia/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Time Factors MH - Tumor Cells, Cultured EDAT- 2001/12/26 10:00 MHDA- 2002/01/05 10:01 PHST- 2001/04/11 [received] PHST- 2001/08/09 [revised] PHST- 2001/08/15 [accepted] AID - 10.1038/sj/onc/1204927 [doi] PST - ppublish SO - Oncogene 2001 Nov 8;20(51):7542-50. NR -------------------------------------------------------------------------------- 94: Murata M et al. Ghrelin modulates the downstr...[PMID: 11724768] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11724768 OWN - NLM STAT- MEDLINE DA - 20020211 DCOM- 20020321 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 7 DP - 2002 Feb 15 TI - Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. PG - 5667-74 AB - Ghrelin was identified in the stomach as an endogenous ligand specific for the growth hormone secretagogue receptor (GHS-R). GHS-R is found in various tissues, but its function is unknown. Here we show that GHS-R is found in hepatoma cells. Exposure of these cells to ghrelin caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, mitogen-activated protein kinase activity, and cell proliferation. Unlike insulin, ghrelin inhibited Akt kinase activity as well as up-regulated gluconeogenesis. These findings raise the possibility that ghrelin modulates insulin activities in humans. AD - Third Division and Second Division, Department of Medicine and the Department of Basic Allied Medicine, Kobe University School of Medicine, Kobe, Japan. FAU - Murata, Masahiro AU - Murata M FAU - Okimura, Yasuhiko AU - Okimura Y FAU - Iida, Keiji AU - Iida K FAU - Matsumoto, Michihiro AU - Matsumoto M FAU - Sowa, Hideaki AU - Sowa H FAU - Kaji, Hidesuke AU - Kaji H FAU - Kojima, Masayasu AU - Kojima M FAU - Kangawa, Kenji AU - Kangawa K FAU - Chihara, Kazuo AU - Chihara K LA - eng PT - Journal Article DEP - 20011127 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Culture Media, Serum-Free) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Ligands) RN - 0 (MAP Kinase Signaling System) RN - 0 (PD 98059) RN - 0 (Peptide Hormones) RN - 0 (Peptides) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Cell Surface) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (ghrelin) RN - 0 (growth hormone secretagogue receptor) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Animals MH - Blotting, Western MH - Carcinoma, Hepatocellular/*metabolism MH - Cell Division MH - Cell Line MH - Cells, Cultured MH - Culture Media, Serum-Free/pharmacology MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/pharmacology MH - Flavonoids/pharmacology MH - Humans MH - Insulin/*metabolism MH - Ligands MH - MAP Kinase Signaling System MH - Models, Biological MH - *Peptide Hormones MH - Peptides/*metabolism/*physiology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Binding MH - RNA, Messenger/metabolism MH - Rats MH - Receptors, Cell Surface/chemistry/*metabolism MH - *Receptors, G-Protein-Coupled MH - Research Support, Non-U.S. Gov't MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction MH - Time Factors MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - Up-Regulation EDAT- 2001/11/29 10:00 MHDA- 2002/03/22 10:01 PHST- 2001/11/27 [aheadofprint] AID - 10.1074/jbc.M103898200 [doi] AID - M103898200 [pii] PST - ppublish SO - J Biol Chem 2002 Feb 15;277(7):5667-74. Epub 2001 Nov 27. PR -------------------------------------------------------------------------------- 95: Scassa ME et al. Phosphatidylinositol 3-kinase...[PMID: 11716532] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11716532 OWN - NLM STAT- MEDLINE DA - 20011121 DCOM- 20020111 LR - 20050111 PUBM- Print IS - 0014-4827 VI - 271 IP - 2 DP - 2001 Dec 10 TI - Phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase signaling pathways are required for the regulation of 5-aminolevulinate synthase gene expression by insulin. PG - 201-13 AB - Insulin regulates the expression of several hepatic genes. Although the general definition of insulin signaling has progressed dramatically, the elucidation of the complete signaling pathway from insulin receptor to transcription factors involved in the regulation of a specific gene remains to be established. In fact, recent works suggest that multiple divergent insulin signaling pathways regulate the expression of distinct genes. 5-Aminolevulinate synthase (ALAS) is a mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. It has been reported that insulin caused the rapid inhibition of housekeeping ALAS transcription, but the mechanism involved in this repression has not been explored. The present study investigates the role of phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein kinase pathways in insulin signaling relevant to ALAS inhibition. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in rat hepatocytes and HepG2 cells. Wortmannin and LY294002, PI3-kinase inhibitors, as well as lovastatin and PD152440, Ras farnesylation inhibitors, and MEK inhibitor PD98059 abolished the insulin repression of ALAS transcription. The inhibitor of mTOR/p70(S6K) rapamycin had no effect whatsoever upon hormone action. The overexpression of vectors encoding constitutively active Ras, MEK, or p90(RSK) mimicked the inhibitory action of insulin. Conversely, negative mutants of PKB, Ras, or MEK impaired insulin inhibition of ALAS promoter activity. Furthermore, inhibition of one of the pathways blocks the inhibitory effect produced by the activation of the other. Our findings suggest that factors involved in two signaling pathways that are often considered to be functionally separate during insulin action, the Ras/ERK/p90(RSK) pathway and the PI3K/PKB pathway, are jointly required for insulin-mediated inhibition of ALAS gene expression in rat hepatocytes and human hepatoma cells. AD - Laboratorio de Biologia Molecular, Departamento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellon II Piso 4 Ciudad Universitaria, Buenos Aires, 1428, Argentina. FAU - Scassa, M E AU - Scassa ME FAU - Guberman, A S AU - Guberman AS FAU - Varone, C L AU - Varone CL FAU - Canepa, E T AU - Canepa ET LA - eng PT - Journal Article PL - United States TA - Exp Cell Res JID - 0373226 RN - 0 (Androstadienes) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Genetic Vectors) RN - 0 (MAP Kinase Signaling System) RN - 0 (Morpholines) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Messenger) RN - 0 (Tubulin) RN - 11061-68-0 (Insulin) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 19545-26-7 (wortmannin) RN - EC 2.3.1.37 (5-Aminolevulinate Synthetase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) RN - EC 3.6.1.- (ras Proteins) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/*metabolism MH - 5-Aminolevulinate Synthetase/*genetics MH - Androstadienes/pharmacology MH - Animals MH - Carcinoma, Hepatocellular MH - Cells, Cultured MH - Chromones/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Gene Expression Regulation, Enzymologic/*physiology MH - Genetic Vectors MH - Hepatocytes/drug effects/*enzymology MH - Humans MH - Insulin/*metabolism/pharmacology MH - Liver/drug effects/*enzymology MH - MAP Kinase Signaling System/*genetics MH - Male MH - Morpholines/pharmacology MH - Promoter Regions (Genetics)/physiology MH - Protein Isoprenylation/drug effects/physiology MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/genetics MH - RNA, Messenger/drug effects/metabolism MH - Rats MH - Rats, Inbred Strains MH - Research Support, Non-U.S. Gov't MH - Ribosomal Protein S6 Kinases/genetics MH - Transcription, Genetic/drug effects/physiology MH - Tubulin/genetics MH - Tumor Cells, Cultured MH - ras Proteins/metabolism EDAT- 2001/11/22 10:00 MHDA- 2002/01/12 10:01 AID - 10.1006/excr.2001.5386 [doi] AID - S0014482701953868 [pii] PST - ppublish SO - Exp Cell Res 2001 Dec 10;271(2):201-13. PR -------------------------------------------------------------------------------- 96: Jackson JG et al. Regulation of breast cancer c...[PMID: 11704861] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11704861 OWN - NLM STAT- MEDLINE DA - 20011112 DCOM- 20011213 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 20 IP - 50 DP - 2001 Nov 1 TI - Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. PG - 7318-25 AB - Insulin-like growth factors (IGFs) regulate breast cancer cell proliferation, protect cells from apoptosis, and enhance metastasis. In this study, we examined the IGF signaling pathway in two breast cancer cell lines selected for metastatic behavior. LCC6 was selected for growth as an ascites tumor in athymic mice from parental MDA-MB-435 cells (435P). The MDA-231BO cell line was derived from osseous metastases that formed after intracardiac injection of the MDA-MB-231 cell line in athymic mice. Compared to the parental cell lines, IGF-I treatment enhanced IRS-2 phosphorylation over IRS-1 in the metastatic variants. IGF-I stimulated cell migration in the variant cells, but not in the parental cells. To determine the role for IRS-2 in IGF-mediated motility, we transfected MDA-231BO cells with an anti-sense IRS-2 construct. Transfected cells had decreased levels of IRS-2 with diminished IGF-mediated motility and anchorage independent growth when compared to control cells. However, adherence to fibronectin was enhanced in the transfected cells compared to MDA-231BO cells. Our data show that breast cancer cells selected for metastatic behavior in vivo have increased IRS-2 activation and signaling. In these cells, IGF-I enhances cell adhesion and motility suggesting that IRS-2 may mediate these aspects of the malignant phenotype. AD - Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, TX 78229, USA. FAU - Jackson, J G AU - Jackson JG FAU - Zhang, X AU - Zhang X FAU - Yoneda, T AU - Yoneda T FAU - Yee, D AU - Yee D LA - eng GR - P30CA54174/CA/NCI GR - R01CA74285/CA/NCI PT - Journal Article PL - England TA - Oncogene JID - 8711562 RN - 0 (DNA, Antisense) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (insulin receptor substrate-2 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - Apoptosis MH - Bone Neoplasms/pathology/secondary MH - Breast Neoplasms/*pathology MH - Cell Adhesion MH - Cell Division MH - Cell Movement/physiology MH - DNA, Antisense/genetics MH - Female MH - Humans MH - Insulin-Like Growth Factor I/pharmacology MH - Mice MH - Mice, Nude MH - Neoplasm Metastasis/*pathology MH - Neoplasm Proteins/genetics/*physiology MH - Phosphoproteins/genetics/*physiology MH - Phosphorylation/drug effects MH - Protein Processing, Post-Translational/drug effects MH - Protein-Tyrosine Kinase/metabolism MH - Receptor, IGF Type 1/drug effects/physiology MH - Recombinant Fusion Proteins/physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Selection (Genetics) MH - Signal Transduction MH - Transfection MH - Tumor Cells, Cultured/cytology EDAT- 2001/11/13 10:00 MHDA- 2002/01/05 10:01 PHST- 2001/01/17 [received] PHST- 2001/08/08 [revised] PHST- 2001/08/14 [accepted] AID - 10.1038/sj/onc/1204920 [doi] PST - ppublish SO - Oncogene 2001 Nov 1;20(50):7318-25. NR -------------------------------------------------------------------------------- 97: Kellerer M et al. Insulin inhibits leptin recep...[PMID: 11596667] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11596667 OWN - NLM STAT- MEDLINE DA - 20011012 DCOM- 20020220 LR - 20050317 PUBM- Print IS - 0012-186X VI - 44 IP - 9 DP - 2001 Sep TI - Insulin inhibits leptin receptor signalling in HEK293 cells at the level of janus kinase-2: a potential mechanism for hyperinsulinaemia-associated leptin resistance. PG - 1125-32 AB - AIMS/HYPOTHESIS: Leptin resistance in obese humans seems to be predominantly caused by signalling abnormalities at the post receptor level. Leptin resistance in obese individuals is frequently associated with insulin resistance and pronounced hyperinsulinaemia indicating a negative crosstalk of the insulin and leptin signalling chain. METHODS: This hypothesis was tested using a cell model of peripheral leptin signalling, i. e. insulin-secreting cell lines (RINr1046-38). Mechanisms for a crosstalk between the insulin and leptin signalling pathway were also studied in rat-1 and HEK293 cells overexpressing elements of the insulin and leptin signalling chain. RESULTS: The effects of leptin on insulin secretion are completely cancelled by a 4-h preincubation with 1 nmol/l insulin, supporting the hypothesis of a negative crosstalk of insulin and leptin signalling. We investigated the potential molecular mechanisms in more detail in HEK293 cells and Rat-1 fibroblasts that overexpressed proteins of the insulin and leptin signalling chain. Leptin (60 ng/ml) stimulated autophosphorylation of JAK-2 in HEK 293 cells. This leptin effect could be inhibited by simultaneous treatment of cells with insulin. Furthermore, overexpression of the insulin receptor in HEK 293 cells clearly reduced JAK-2 phosphorylation and led further downstream to a diminished phosphatidylinositol 3-kinase activity. The inhibitory effect of the insulin signal could be partially prevented by transfection of the cells with an inactive mutant of the tyrosine phosphatase SHP-1. CONCLUSION/INTERPRETATION: In summary, our data suggest that the insulin receptor signalling pathway interferes with leptin signalling at the level of JAK-2. Inhibition of JAK-2 phosphorylation might occur through SHP-1-dependent pathways, indicating that hyperinsulinaemia contributes to the pathogenesis of leptin resistance. AD - Eberhard-Karls University of Tubingen, Internal Medicine IV, Germany. FAU - Kellerer, M AU - Kellerer M FAU - Lammers, R AU - Lammers R FAU - Fritsche, A AU - Fritsche A FAU - Strack, V AU - Strack V FAU - Machicao, F AU - Machicao F FAU - Borboni, P AU - Borboni P FAU - Ullrich, A AU - Ullrich A FAU - Haring, H U AU - Haring HU LA - eng PT - Journal Article PL - Germany TA - Diabetologia JID - 0006777 RN - 0 (Carrier Proteins) RN - 0 (Leptin) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Cell Surface) RN - 0 (leptin receptor) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Animals MH - Carrier Proteins/*physiology MH - Cell Line MH - *Drug Resistance MH - Electrophoresis, Polyacrylamide Gel MH - Embryo MH - Gene Expression MH - Humans MH - Hyperinsulinism/*physiopathology MH - Insulin/*pharmacology MH - Insulinoma MH - Kidney MH - Leptin/*pharmacology MH - Pancreatic Neoplasms MH - Phosphorylation MH - Protein-Tyrosine Kinase/genetics/*metabolism MH - Protein-Tyrosine-Phosphatase/genetics/metabolism MH - *Proto-Oncogene Proteins MH - Rats MH - Receptor, Insulin/genetics MH - *Receptors, Cell Surface MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Transfection MH - Tumor Cells, Cultured EDAT- 2001/10/13 10:00 MHDA- 2002/02/21 10:01 PST - ppublish SO - Diabetologia 2001 Sep;44(9):1125-32. PR -------------------------------------------------------------------------------- 98: Bartucci M et al. Differential insulin-like gro...[PMID: 11559546] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11559546 OWN - NLM STAT- MEDLINE DA - 20010917 DCOM- 20011011 LR - 20050111 PUBM- Print IS - 0008-5472 VI - 61 IP - 18 DP - 2001 Sep 15 TI - Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. PG - 6747-54 AB - The insulin-like growth factor I receptor (IGF-IR) is a ubiquitous and multifunctional tyrosine kinase that has been implicated in breast cancer development. In estrogen receptor (ER)-positive breast tumors, the levels of the IGF-IR and its substrate, insulin-receptor substrate 1 (IRS-1), are often elevated, and these characteristics have been linked with increased radioresistance and cancer recurrence. In vitro, activation of the IGF-IR/IRS-1 pathway in ER-positive cells improves growth and counteracts apoptosis induced by anticancer treatments. The function of the IGF-IR in hormone-independent breast cancer is not clear. ER-negative breast cancer cells often express low levels of the IGF-IR and fail to respond to IGF-I with mitogenesis. On the other hand, anti-IGF-IR strategies effectively reduced metastatic potential of different ER-negative cell lines, suggesting a role of this receptor in late stages of the disease. Here we examined IGF-IR signaling and function in ER-negative MDA-MB-231 breast cancer cells and their IGF-IR-overexpressing derivatives. We demonstrated that IGF-I acts as a chemoattractant for these cells. The extent of IGF-I-induced migration reflected IGF-IR levels and required the activation of phosphatidylinositol 3-kinase (PI-3K) and p38 kinases. The same pathways promoted IGF-I-dependent motility in ER-positive MCF-7 cells. In contrast with the positive effects on cell migration, IGF-I was unable to stimulate growth or improve survival in MDA-MB-231 cells, whereas it induced mitogenic and antiapoptotic effects in MCF-7 cells. Moreover, IGF-I partially restored growth in ER-positive cells treated with PI-3K and ERK1/ERK2 inhibitors, whereas it had no protective effects in ER-negative cells. The impaired IGF-I growth response of ER-negative cells was not caused by a low IGF-IR expression, defective IGF-IR tyrosine phosphorylation, or improper tyrosine phosphorylation of IRS-1. Also, the acute (15-min) IGF-I activation of PI-3 and Akt kinases was similar in ER-negative and ER-positive cells. However, a chronic (2-day) IGF-I exposure induced the PI-3K/Akt pathway only in MCF-7 cells. The reactivation of this pathway in ER-negative cells by overexpression of constitutively active Akt mutants was not sufficient to significantly improve proliferation or survival (with or without IGF-I), which indicated that other pathways are also required to support these functions. Our results suggest that in breast cancer cells, IGF-IR can control nonmitogenic processes regardless of the ER status, whereas IGF-IR growth-related functions may depend on ER expression. AD - Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Bartucci, M AU - Bartucci M FAU - Morelli, C AU - Morelli C FAU - Mauro, L AU - Mauro L FAU - Ando', S AU - Ando' S FAU - Surmacz, E AU - Surmacz E LA - eng PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (MAP Kinase Signaling System) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Estrogen) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism MH - Breast Neoplasms/enzymology/genetics/*pathology MH - Cell Division/drug effects/physiology MH - Cell Movement/drug effects/physiology MH - Cell Survival/drug effects/physiology MH - Enzyme Activation MH - Humans MH - Insulin-Like Growth Factor I/pharmacology MH - MAP Kinase Signaling System/drug effects/physiology MH - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/genetics/metabolism MH - Receptor, IGF Type 1/biosynthesis/genetics/*physiology MH - Receptors, Estrogen/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Signal Transduction/drug effects/physiology MH - Transfection MH - Tumor Cells, Cultured MH - p38 Mitogen-Activated Protein Kinases EDAT- 2001/09/18 10:00 MHDA- 2001/10/12 10:01 PST - ppublish SO - Cancer Res 2001 Sep 15;61(18):6747-54. NR -------------------------------------------------------------------------------- 99: Rui L et al. Regulation of insulin/insulin...[PMID: 11546773] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11546773 OWN - NLM STAT- MEDLINE DA - 20011022 DCOM- 20011207 LR - 20050111 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 43 DP - 2001 Oct 26 TI - Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. PG - 40362-7 AB - Insulin and insulin-like growth factor-1 (IGF-1) regulate metabolism and body growth through homologous receptor tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins. IRS-2 is an important IRS protein, as it mediates peripheral insulin action and beta-cell survival. In this study, we show that insulin, IGF-1, or osmotic stress promoted ubiquitin/proteasome-mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts. MG132 or lactacystin, specific inhibitors of 26S proteasome, blocked insulin/IGF-1-induced degradation of IRS-2 and enhanced the detection of ubiquitinated IRS-2. Insulin/IGF1-induced ubiquitination and degradation of IRS-2 was blocked by inhibitors of phosphatidylinositol 3-kinase (wortmannin or LY294002) or mTOR (rapamycin). Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2, which was reversed by lactacystin pretreatment. By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin/IGF-1 stimulation in IRS-2-deficient mouse embryo fibroblasts. Thus, we identified a novel negative feedback mechanism by which the ubiquitin/proteasome-mediated degradation of IRS-2 limits the magnitude and duration of the response to insulin or IGF-1. AD - Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA. FAU - Rui, L AU - Rui L FAU - Fisher, T L AU - Fisher TL FAU - Thomas, J AU - Thomas J FAU - White, M F AU - White MF LA - eng GR - DK 43808/DK/NIDDK PT - Journal Article DEP - 20010823 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Ubiquitin) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.- (mTOR protein) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) RN - EC 3.4.- (Peptide Hydrolases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - EC 3.4.99.- (ATP dependent 26S protease) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Adipocytes/metabolism MH - Animals MH - Carcinoma, Hepatocellular/metabolism MH - Diabetes Mellitus, Type 2/etiology MH - Down-Regulation MH - Feedback MH - Fibroblasts/metabolism MH - Humans MH - Insulin/*metabolism MH - Insulin-Like Growth Factor I/*metabolism MH - Liver Neoplasms, Experimental/metabolism MH - Mice MH - Mitogen-Activated Protein Kinases/metabolism MH - Osmotic Pressure MH - Peptide Hydrolases/drug effects/*metabolism MH - Phosphoproteins/*metabolism MH - *Proteasome Endopeptidase Complex MH - Protein Kinases/metabolism MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - Receptor, Insulin/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Tumor Cells, Cultured MH - Ubiquitin EDAT- 2001/09/08 10:00 MHDA- 2002/01/05 10:01 PHST- 2001/08/23 [aheadofprint] AID - 10.1074/jbc.M105332200 [doi] AID - M105332200 [pii] PST - ppublish SO - J Biol Chem 2001 Oct 26;276(43):40362-7. Epub 2001 Aug 23. PR -------------------------------------------------------------------------------- 100: Moriki T et al. Activation of preformed EGF r...[PMID: 11531336] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11531336 OWN - NLM STAT- MEDLINE DA - 20010904 DCOM- 20010927 LR - 20041117 PUBM- Print IS - 0022-2836 VI - 311 IP - 5 DP - 2001 Aug 31 TI - Activation of preformed EGF receptor dimers by ligand-induced rotation of the transmembrane domain. PG - 1011-26 AB - The epidermal growth factor receptor plays crucial roles throughout the development of multicellular organisms, and inappropriate activation of the receptor is associated with neoplastic transformation of many cell types. The receptor is thought to be activated by ligand-induced homodimerisation. Here, however, we show by chemical cross-linking and sucrose density-gradient centrifugation that in the absence of bound ligand the receptor has an ability to form a dimer and exists as a preformed dimer on the cell surface. We also analysed the receptor dimerisation by inserting cysteine residues at strategic positions about the putative alpha-helix axis of the extracellular juxtamembrane region. The mutant receptors spontaneously formed disulphide bridges and transformed NIH3T3 cells in the absence of ligand, depending upon the positions of the cysteine residue inserted. Kinetic analyses of the disulphide bonding indicate that EGF binding induces flexible rotation or twist of the juxtamembrane region of the receptor in the plane parallel with the lipid bilayer. The binding of an ATP competitor to the intracellular domain also induced similar flexible rotation of the juxtamembrane region. All the disulphide-bonded dimers had flexible ligand-binding domains with the same biphasic affinities for EGF as the wild-type. These results demonstrate that ligand binding to the flexible extracellular domains of the receptor dimer induce rotation or twist of the juxtamembrane regions, hence the transmembrane domains, and dissociate the dimeric, inactive form of the intracellular domains. The flexible rotation of the intracellular domains may be necessary for the intrinsic catalytic kinase to become accessible to the multiple tyrosine residues present in the regulatory domain and various substrates, and may be a common property of many cell-surface receptors, such as the insulin receptor. CI - Copyright 2001 Academic Press. AD - Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. FAU - Moriki, T AU - Moriki T FAU - Maruyama, H AU - Maruyama H FAU - Maruyama, I N AU - Maruyama IN LA - eng PT - Journal Article PL - England TA - J Mol Biol JID - 2985088R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Disulfides) RN - 0 (Ligands) RN - 0 (Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 52-90-4 (Cysteine) RN - 56-65-5 (Adenosine Triphosphate) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Adenosine Triphosphate/metabolism MH - Amino Acid Sequence MH - Animals MH - Binding Sites MH - Cell Line, Transformed MH - Cell Transformation, Neoplastic MH - Cysteine/genetics/metabolism MH - Dimerization MH - Disulfides/metabolism MH - Enzyme Activation MH - Humans MH - Kinetics MH - Ligands MH - Mice MH - Models, Biological MH - Models, Molecular MH - Molecular Sequence Data MH - Mutation/genetics MH - Phosphorylation MH - Pliability MH - Protein Structure, Tertiary MH - Proteins/metabolism MH - Receptor, Epidermal Growth Factor/*chemistry/genetics/*metabolism MH - Research Support, Non-U.S. Gov't MH - *Rotation MH - Thermodynamics EDAT- 2001/09/05 10:00 MHDA- 2001/09/28 10:01 AID - 10.1006/jmbi.2001.4923 [doi] AID - S002228360194923X [pii] PST - ppublish SO - J Mol Biol 2001 Aug 31;311(5):1011-26. NR -------------------------------------------------------------------------------- 101: Scalia P et al. Regulation of the Akt/Glycoge...[PMID: 11500939] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11500939 OWN - NLM STAT- MEDLINE DA - 20010813 DCOM- 20011011 LR - 20050111 PUBM- Print IS - 0730-2312 VI - 82 IP - 4 DP - 2001 TI - Regulation of the Akt/Glycogen synthase kinase-3 axis by insulin-like growth factor-II via activation of the human insulin receptor isoform-A. PG - 610-8 AB - Insulin-like growth factor II (IGF-II) plays a key role in mitogenesis during development and tumorigenesis and is believed to exert its mitogenic functions mainly through the IGF-I receptor. Recently, we identified the insulin receptor isoform A (IR(A)) as an additional high affinity receptor for IGF-II in both fetal and cancer cells. Here we investigated the mitogenic signaling of IGF-II via the Akt/Glycogen synthase kinase 3 (Gsk3) axis employing R-IR(A) cells that are IGF-I receptor null mouse embryonic fibroblasts expressing the human IR(A). IGF-II induced activation of the proto-oncogenic serine kinase Akt, reaching maximal at 5-10 min. IGF-II also caused the rapid and sustained deactivation of glycogen synthase kinase 3-beta (Gsk3beta), reaching maximal at 1-3 min, shortly preceding, therefore, maximal activation of Akt. Under our conditions, IGF-II and insulin induced 70-80% inhibition of Gsk3betaactivity. In these cells IGF-II also deactivated Gsk3alpha although less effectively than Gsk3beta. In parallel experiments, we found that IGF-II induced transient activation of extracellular-signal-regulated kinases (Erk) reaching maximal at 5-10 min and decreasing thereafter. Time courses and potencies of regulation of both mitogenic pathways (Akt/Gsk3beta and Erk) by IGF-II via IR(A) were similar to those of insulin. Furthermore, IGF-II like insulin effectively stimulated cell cycle progression from the G0/G1 to the S and G2/M phases. Interestingly, AP-1-mediated gene expression, that was reported to be negatively regulated by Gsk3beta was only weakly increased after IGF-II stimulation. Our present data suggest that the coordinated activation or deactivation of Akt, Gsk3beta, and Erk may account for IGF-II mitogenic effects and support an active role for IR(A) in IGF-II action. CI - Copyright 2001 Wiley-Liss, Inc. AD - Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA. plscalia@hsc.usc.edu FAU - Scalia, P AU - Scalia P FAU - Heart, E AU - Heart E FAU - Comai, L AU - Comai L FAU - Vigneri, R AU - Vigneri R FAU - Sung, C K AU - Sung CK LA - eng GR - DK51015/DK/NIDDK PT - Journal Article PL - United States TA - J Cell Biochem JID - 8205768 RN - 0 (INSR protein, human) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Transcription Factor AP-1) RN - 11061-68-0 (Insulin) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.37 (Glycogen Synthase Kinase 3) RN - EC 2.7.1.37 (Glycogen Synthase Kinases) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/*metabolism MH - Cell Cycle MH - Cell Line MH - Glycogen Synthase Kinase 3 MH - Glycogen Synthase Kinases MH - Humans MH - Insulin/pharmacology MH - Insulin-Like Growth Factor II/*pharmacology MH - Kinetics MH - Mice MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/metabolism MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/*metabolism MH - Receptor, Insulin/genetics/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Trans-Activation (Genetics) MH - Transcription Factor AP-1/metabolism MH - Transfection EDAT- 2001/08/14 10:00 MHDA- 2001/10/12 10:01 AID - 10.1002/jcb.1196 [pii] PST - ppublish SO - J Cell Biochem 2001;82(4):610-8. -------------------------------------------------------------------------------- 102: Oesterreich S et al. Re-expression of estrogen rec...[PMID: 11479214] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11479214 OWN - NLM STAT- MEDLINE DA - 20010731 DCOM- 20010816 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 61 IP - 15 DP - 2001 Aug 1 TI - Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. PG - 5771-7 AB - Estrogen can increase insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) expression, two key components of IGF-I-mediated signaling. The result is sensitization of breast cancer cells to IGF-I and synergistic growth in the presence of estrogen and IGF-I. We hypothesized that loss of estrogen receptor alpha (ERalpha) would result in reduced IGF-mediated signaling and growth. To test this hypothesis, we examined IGF-I effects in MCF-7 breast cancer cell sublines that have been selected for loss of ERalpha (C4 and C4-12 cells are ERalpha-negative) by long-term estrogen withdrawal. C4 and C4-12 cells had reduced IGF-IR and IRS-1 mRNA and protein expression (compared with MCF-7 cells) that was not inducible by estrogen. Furthermore, C4 and C4-12 cells showed reduced IGF-I signaling and failed to show any growth response to either estrogen or IGF-I. To prove that loss of IGF and estrogen-mediated signaling and growth was a consequence of loss of ERalpha, we re-expressed ERalpha in C4-12 cells by stable transfection with HA-tagged ERalpha. Three independent C4-12 ERalpha-HA clones expressed a functional ERalpha that (a) was down-regulated by estrogen, (b) conferred estrogen-induction of cyclin D1 expression, and (c) caused estrogen-mediated increase in the number of cells in S phase. All of the effects were completely blocked by antiestrogens. Interestingly, ERalpha-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ERalpha-positive C4-12 cells now exhibited estrogen-induction of IGF-IR and IRS-1 levels and responded mitogenically to both estrogen and IGF-I. These data show that ERalpha is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ERalpha expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line. AD - Breast Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Oesterreich, S AU - Oesterreich S FAU - Zhang, P AU - Zhang P FAU - Guler, R L AU - Guler RL FAU - Sun, X AU - Sun X FAU - Curran, E M AU - Curran EM FAU - Welshons, W V AU - Welshons WV FAU - Osborne, C K AU - Osborne CK FAU - Lee, A V AU - Lee AV LA - eng GR - CA50354/CA/NCI GR - P50 CA58183/CA/NCI PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Estrogen Receptor alpha) RN - 0 (Hemagglutinins) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Estrogen) RN - 0 (insulin receptor substrate-1 protein) RN - 136601-57-5 (Cyclin D1) RN - 50-28-2 (Estradiol) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Breast Neoplasms/*metabolism/pathology MH - Cell Division/physiology MH - Cyclin D1/biosynthesis MH - Estradiol/*pharmacology MH - Estrogen Receptor alpha MH - Hemagglutinins/genetics MH - Humans MH - Insulin-Like Growth Factor I/*pharmacology MH - Phosphoproteins/biosynthesis/metabolism/*physiology MH - Phosphorylation/drug effects MH - Receptor, IGF Type 1/biosynthesis/*physiology MH - Receptors, Estrogen/biosynthesis/genetics/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*physiology MH - Transfection MH - Tumor Cells, Cultured EDAT- 2001/08/02 10:00 MHDA- 2001/08/17 10:01 PST - ppublish SO - Cancer Res 2001 Aug 1;61(15):5771-7. -------------------------------------------------------------------------------- 103: Kim JJ et al. Mitogenic and metabolic effec...[PMID: 11459778] Related Articles, Books, LinkOut PMID- 11459778 OWN - NLM STAT- MEDLINE DA - 20010718 DCOM- 20010816 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 142 IP - 8 DP - 2001 Aug TI - Mitogenic and metabolic effects of type I IGF receptor overexpression in insulin receptor-deficient hepatocytes. PG - 3354-60 AB - We have previously shown that hepatocytes lacking insulin receptors (Ir-/-) fail to mediate metabolic responses, such as stimulation of glycogen synthesis, while retaining the ability to proliferate in response to IGFs. In this study we have asked whether overexpression of type I IGF receptors would rescue the metabolic response of Ir-/- hepatocytes. After IGF-I stimulation, insulin receptor substrate-1 and -2 phosphorylation and PI3K activity were restored to levels similar to or greater than those seen in wild-type cells. Rates of cell proliferation in response to IGF-I increased approximately 2-fold, whereas glycogen synthesis was restored to wild-type levels, but was comparatively smaller than that elicited by overexpression of insulin receptors. In summary, overexpression of IGF-I receptors in Ir-/- hepatocytes normalized insulin receptor substrate-2 phosphorylation and glycogen synthesis to wild-type levels, whereas it increased cell proliferation above wild-type levels. Moreover, stimulation of glycogen synthesis was submaximal compared with the effect of insulin receptor overexpression. We conclude that IGF-I receptors are more efficiently coupled to cell proliferation than insulin receptors, but are less potent than insulin receptors in stimulating glycogen synthesis. The data are consistent with the possibility that there exist intrinsic signaling differences between insulin and IGF-I receptors. AD - Naomi Berrie Diabetes Center and Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. FAU - Kim, J J AU - Kim JJ FAU - Park, B C AU - Park BC FAU - Kido, Y AU - Kido Y FAU - Accili, D AU - Accili D LA - eng GR - DK-57539/DK/NIDDK GR - DK-58282/DK/NIDDK PT - Journal Article PL - United States TA - Endocrinology JID - 0375040 RN - 0 (Phosphoproteins) RN - 0 (Somatomedins) RN - 0 (insulin receptor substrate-2 protein) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Glycogen Synthase Kinase 3) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cell Division/physiology MH - Cell Transformation, Viral MH - Cells, Cultured MH - Glycogen Synthase Kinase 3 MH - Hepatocytes/*cytology/*metabolism/virology MH - Mice MH - Mice, Knockout/genetics MH - Mitosis/*physiology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/*deficiency/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Simian virus 40/physiology MH - Somatomedins/physiology EDAT- 2001/07/19 10:00 MHDA- 2001/08/17 10:01 PST - ppublish SO - Endocrinology 2001 Aug;142(8):3354-60. -------------------------------------------------------------------------------- 104: Schmid C et al. Effects of IGF-I and -II, IGF...[PMID: 11454519] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11454519 OWN - NLM STAT- MEDLINE DA - 20010716 DCOM- 20010906 LR - 20041117 PUBM- Print IS - 0804-4643 VI - 145 IP - 2 DP - 2001 Aug TI - Effects of IGF-I and -II, IGF binding protein-3 (IGFBP-3), and transforming growth factor-beta (TGF-beta) on growth and apoptosis of human osteosarcoma Saos-2/B-10 cells: lack of IGF-independent IGFBP-3 effects. PG - 213-21 AB - OBJECTIVE: Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits cell growth. Previous reports have suggested the existence of plasma membrane IGFBP-3 receptors that could mediate direct, IGF-independent effects. Thus far, however, the only well-defined putative IGFBP-3 receptor is the type V transforming growth factor-beta (TGF-beta) receptor, a membrane glycoprotein that mediates TGF-beta-induced growth inhibition in selected cells. The aim of the study was to test whether IGFBP-3 and TGF-beta exert short-term effects in an osteosarcoma cell line that produces no IGF but contains type 1 IGF receptors. DESIGN: DNA synthesis and apoptosis in Saos-2/B-10 cells were measured in response to IGF-I, IGF-II, IGFBP-3 and TGF-beta2, and to type 1 IGF receptor ligands with poor affinity for IGFBP-3 ([QAYL]-IGF-I and insulin). RESULTS: IGF-I and IGF-II stimulated thymidine incorporation into DNA and suppressed apoptosis in a dose-dependent manner with maximal effects at 1 and 3 nM respectively. TGF-beta2 slightly increased thymidine incorporation into DNA but had no effect on apoptosis. IGFBP-3 had no effect by itself. Whereas it blocked the above effects of 1 nmol/l IGF-I, it did not block those of 1 nmol/l [QAYL]-IGF-I or 100 nmol/l insulin. CONCLUSIONS: IGFBP-3 does not affect DNA synthesis or apoptosis in an IGF-independent manner in IGF-responsive osteosarcoma cells. It therefore appears to act essentially by sequestration of IGF. AD - Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, 8091 Zurich, Switzerland. ndozaj@usz.unizh.ch FAU - Schmid, C AU - Schmid C FAU - Ghirlanda-Keller, C AU - Ghirlanda-Keller C FAU - Zapf, J AU - Zapf J LA - eng PT - Journal Article PL - England TA - Eur J Endocrinol JID - 9423848 RN - 0 (DNA, Neoplasm) RN - 0 (Growth Inhibitors) RN - 0 (Insulin-Like Growth Factor Binding Protein 3) RN - 0 (Somatomedins) RN - 0 (Transforming Growth Factor beta) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Apoptosis/*drug effects MH - Blotting, Western MH - Cell Division/drug effects MH - DNA Fragmentation/drug effects MH - DNA, Neoplasm/biosynthesis MH - Enzyme-Linked Immunosorbent Assay MH - Growth Inhibitors/pharmacology MH - Humans MH - Insulin-Like Growth Factor Binding Protein 3/biosynthesis/isolation & purification/*pharmacology MH - Insulin-Like Growth Factor I/*pharmacology MH - Insulin-Like Growth Factor II/*pharmacology MH - Osteosarcoma/metabolism/*pathology MH - Receptor, IGF Type 1/physiology MH - Receptor, Insulin/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Somatomedins/biosynthesis MH - Transforming Growth Factor beta/*pharmacology MH - Tumor Cells, Cultured/drug effects EDAT- 2001/07/17 10:00 MHDA- 2001/09/08 10:01 AID - 1450213 [pii] PST - ppublish SO - Eur J Endocrinol 2001 Aug;145(2):213-21. -------------------------------------------------------------------------------- 105: Ligensa T et al. A PDZ domain protein interact...[PMID: 11445579] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 11445579 OWN - NLM STAT- MEDLINE DA - 20010904 DCOM- 20011011 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 36 DP - 2001 Sep 7 TI - A PDZ domain protein interacts with the C-terminal tail of the insulin-like growth factor-1 receptor but not with the insulin receptor. PG - 33419-27 AB - In this study, we report on the isolation of a PDZ domain protein, here designated as IIP-1, insulin-like growth factor-1 (IGF-1) receptor-interacting protein-1, which binds to the IGF-1 receptor, but not to the related insulin receptor, and which is involved in the regulation of cell motility. The interaction between the IGF-1 receptor and IIP-1 as well as a splice variant IIP-1/p26 was demonstrated in the yeast two-hybrid system. Using co-precipitation experiments, we confirmed the interaction in transfected cells as well as in vitro. Analysis of deletion mutants indicates that the PDZ domain of IIP-1 mediates interaction with the C-terminal tail of the IGF-1 receptor (serine-threonine-cysteine). This finding demonstrates that the C terminus of the IGF-1 receptor acts as novel PDZ domain binding site. Immunofluorescence analysis revealed an overlapping localization of IIP-1 and the IGF-1 receptor in the breast cancer cell line MCF-7. A functional connection between IIP-1 and the IGF-1 receptor is further supported by the finding that the level of expression of IIP-1 and the IGF-1 receptor strongly correlates in different normal and cancer cells. Furthermore, overexpression of IIP-1 resulted in an attenuation of migration of MCF-7 cells, which is one of the biological activities mediated by the IGF-1 signaling system. AD - Roche Diagnostics GmbH, Pharma Research, Nonnenwald 2, Penzberg 82372, Germany. FAU - Ligensa, T AU - Ligensa T FAU - Krauss, S AU - Krauss S FAU - Demuth, D AU - Demuth D FAU - Schumacher, R AU - Schumacher R FAU - Camonis, J AU - Camonis J FAU - Jaques, G AU - Jaques G FAU - Weidner, K M AU - Weidner KM LA - eng PT - Journal Article DEP - 20010709 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Carrier Proteins) RN - 0 (DNA, Complementary) RN - 52-90-4 (Cysteine) RN - 56-45-1 (Serine) RN - 72-19-5 (Threonine) RN - EC 2.5.1.18 (Glutathione Transferase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - 3T3 Cells MH - Alternative Splicing MH - Amino Acid Sequence MH - Animals MH - Binding Sites MH - Carrier Proteins/*chemistry/metabolism MH - Cell Division MH - Cell Movement MH - Cloning, Molecular MH - Cysteine/chemistry MH - DNA, Complementary/metabolism MH - Gene Deletion MH - Gene Library MH - Glutathione Transferase/metabolism MH - Humans MH - Immunoblotting MH - Jurkat Cells MH - Mice MH - Microscopy, Fluorescence MH - Molecular Sequence Data MH - Mutagenesis MH - Phosphorylation MH - Precipitin Tests MH - Protein Binding MH - Protein Structure, Tertiary MH - Receptor, IGF Type 1/*chemistry MH - Receptor, Insulin/*chemistry MH - Serine/chemistry MH - Signal Transduction MH - Threonine/chemistry MH - Transfection MH - Tumor Cells, Cultured MH - Two-Hybrid System Techniques EDAT- 2001/07/11 10:00 MHDA- 2001/10/12 10:01 PHST- 2001/07/09 [aheadofprint] AID - 10.1074/jbc.M104509200 [doi] AID - M104509200 [pii] PST - ppublish SO - J Biol Chem 2001 Sep 7;276(36):33419-27. Epub 2001 Jul 9. -------------------------------------------------------------------------------- 106: Poretsky L et al. Phosphatidyl-inositol-3 kinas...[PMID: 11443175] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11443175 OWN - NLM STAT- MEDLINE DA - 20010709 DCOM- 20010802 LR - 20041117 PUBM- Print IS - 0021-972X VI - 86 IP - 7 DP - 2001 Jul TI - Phosphatidyl-inositol-3 kinase-independent insulin action pathway(s) in the human ovary. PG - 3115-9 AB - Hyperandrogenism observed in women with a variety of insulin-resistant states is thought to be due to a stimulatory effect of insulin on ovarian steroid hormone production. However, it is not known what mechanisms could allow the ovary to remain sensitive to insulin while classical target organs for insulin action (liver, fat, and muscle) exhibit insulin resistance. One hypothesis proposed to explain this paradox suggests that a postbinding divergence of insulin receptor signaling occurs in the ovary and that signaling pathways for steroid hormone synthesis and other ovarian effects of insulin may be distinct from classical glucose signaling pathways. We now report that activation of phosphatidyl-inositol-3 (PI-3) kinase, which is crucial for glucose transport, is not necessary for the insulin-induced stimulation of progesterone production or for the insulin-induced inhibition of insulin-like growth factor binding protein 1 (IGFBP-1) production in cultured human ovarian cells. Human granulosa cells obtained during in vitro fertilization procedures were cultured with 10, 10(2), 10(3), or 10(4) ng/mL insulin with or without preincubation with 100 nM wortmannin, a specific irreversible inhibitor of PI-3 kinase. IGFBP-1 concentration in the conditioned medium was measured using immunoradiometric assay or by Western blot analysis. Progesterone concentration was measured using RIA. Additional studies were carried out in cultures of human ovarian cells prepared from homogenized whole ovarian tissue of a woman with a family history of breast cancer and a mutation of BRCA-1 gene who underwent bilateral oophorectomy. These cells were cultured with 10(3) ng/mL insulin with or without preincubation with 100 nM wortmannin. Two-way ANOVA was used to compare mean values of IGFBP-1 and progesterone according to insulin dose and the use of wortmannin. In cultured granulosa cell medium, progesterone production was stimulated by insulin in a dose-related manner up to 175% of control (P < 0.0001). In tissue culture medium from ovarian cells obtained from a patient with BRCA-gene mutation, concentration of progesterone in the tissue culture medium increased from 2.5 +/- 0.2 ng/mL for control to 5.4 +/- 0.3 ng/mL for cells incubated with insulin (P < 0.001). IGFBP-1 production in tissue culture medium from human granulosa cells was inhibited by insulin to the nadir of 45% of control (P < 0.0001). Preincubation with wortmannin, despite complete inhibition of PI-3 kinase in both cell systems confirmed by Western blot analysis, failed to significantly alter these results. We conclude that inhibition of PI-3 kinase by wortmannin fails to abolish stimulatory effect of insulin on progesterone production or inhibitory effect of insulin on IGFBP-1 production in cultured human ovarian cells. These findings suggest that activation of PI-3 kinase, an enzyme crucial for insulin-stimulated glucose transport, is not necessary for the above effects of insulin in the ovary. These data provide evidence for the presence of PI-3 kinase-independent insulin signaling pathway(s) in human ovarian cells. AD - Division of Endocrinology, Beth Israel Medical Center and Albert Einstein College of Medicine, New York, New York 10003, USA. Lporetsk@bethisraelny.org FAU - Poretsky, L AU - Poretsky L FAU - Seto-Young, D AU - Seto-Young D FAU - Shrestha, A AU - Shrestha A FAU - Dhillon, S AU - Dhillon S FAU - Mirjany, M AU - Mirjany M FAU - Liu, H C AU - Liu HC FAU - Yih, M C AU - Yih MC FAU - Rosenwaks, Z AU - Rosenwaks Z LA - eng GR - M01-RR00047/RR/NCRR GR - RO3-HD5618/HD/NICHD PT - Journal Article PL - United States TA - J Clin Endocrinol Metab JID - 0375362 RN - 0 (Androstadienes) RN - 0 (Culture Media, Conditioned) RN - 0 (Enzyme Inhibitors) RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 11061-68-0 (Insulin) RN - 19545-26-7 (wortmannin) RN - 57-83-0 (Progesterone) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism MH - Androstadienes/pharmacology MH - Breast Neoplasms/genetics/metabolism MH - Cells, Cultured MH - Culture Media, Conditioned MH - Enzyme Activation/drug effects MH - Enzyme Inhibitors/pharmacology MH - Female MH - Fertilization in Vitro MH - Genes, BRCA1/genetics MH - Granulosa Cells/drug effects/metabolism MH - Humans MH - Insulin/*pharmacology MH - Insulin Resistance MH - Insulin-Like Growth Factor Binding Protein 1/analysis/biosynthesis MH - Mutation MH - Ovary/*drug effects MH - Progesterone/analysis/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction EDAT- 2001/07/10 10:00 MHDA- 2001/08/03 10:01 PST - ppublish SO - J Clin Endocrinol Metab 2001 Jul;86(7):3115-9. -------------------------------------------------------------------------------- 107: Dunaif A et al. Defects in insulin receptor s...[PMID: 11440917] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11440917 OWN - NLM STAT- MEDLINE DA - 20010706 DCOM- 20010809 LR - 20041117 PUBM- Print IS - 0193-1849 VI - 281 IP - 2 DP - 2001 Aug TI - Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). PG - E392-9 AB - Women with polycystic ovary syndrome (PCOS) are insulin resistant secondary to a postbinding defect in insulin signaling. Sequential euglycemic glucose clamp studies at 40 and 400 mU. m(-2). min(-1) insulin doses with serial skeletal muscle biopsies were performed in PCOS and age-, weight-, and ethnicity-matched control women. Steady-state insulin levels did not differ, but insulin-mediated glucose disposal was significantly decreased in PCOS women (P < 0.05). Insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI 3K) activity was significantly decreased in PCOS (n = 12) compared with control skeletal muscle (n = 8; P < 0.05). There was no significant difference in the abundance of IR, IRS-1, or the p85 regulatory subunit of PI 3K in PCOS (n = 14) compared with control (n = 12) muscle. The abundance of IRS-2 was significantly increased (P < 0.05) in PCOS skeletal muscle, suggesting a compensatory change. We conclude that there is a physiologically relevant defect in insulin receptor signaling in PCOS that is independent of obesity and type 2 diabetes mellitus. AD - Division of Women's Health, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. FAU - Dunaif, A AU - Dunaif A FAU - Wu, X AU - Wu X FAU - Lee, A AU - Lee A FAU - Diamanti-Kandarakis, E AU - Diamanti-Kandarakis E LA - eng PT - Clinical Trial PT - Controlled Clinical Trial PT - Journal Article PL - United States TA - Am J Physiol Endocrinol Metab JID - 100901226 RN - 0 (Blood Glucose) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 50-99-7 (Glucose) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Adult MH - Biopsy MH - Blood Glucose/metabolism MH - Body Mass Index MH - Chromatography, Thin Layer MH - Female MH - Glucose/pharmacokinetics MH - Glucose Clamp Technique MH - Humans MH - Insulin/blood/pharmacology MH - Insulin Resistance MH - Muscle, Skeletal/metabolism/pathology MH - Phosphoproteins/genetics/metabolism MH - Polycystic Ovary Syndrome/*metabolism/pathology MH - RNA, Messenger/metabolism MH - Receptor, Insulin/*metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - *Signal Transduction EDAT- 2001/07/07 10:00 MHDA- 2001/08/10 10:01 PST - ppublish SO - Am J Physiol Endocrinol Metab 2001 Aug;281(2):E392-9. -------------------------------------------------------------------------------- 108: Shaw LM. Identification of insulin rec...[PMID: 11438664] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 11438664 OWN - NLM STAT- MEDLINE DA - 20010704 DCOM- 20010816 LR - 20041117 PUBM- Print IS - 0270-7306 VI - 21 IP - 15 DP - 2001 Aug TI - Identification of insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the alpha6beta4 integrin-dependent activation of phosphoinositide 3-OH kinase and promotion of invasion. PG - 5082-93 AB - Expression of the alpha6beta4 integrin increases the invasive potential of carcinoma cells by a mechanism that involves activation of phosphoinositide 3-OH kinase (PI3K). In the present study, we investigated the signaling pathway by which the alpha6beta4 integrin activates PI3K. Neither the alpha6 nor the beta4 cytoplasmic domain contains the consensus binding motif for PI3K, pYMXM, indicating that additional proteins are likely to be involved in the activation of this lipid kinase by the alpha6beta4 integrin. We identified insulin receptor substrate 1 (IRS-1) and IRS-2 as signaling intermediates in the activation of PI3K by the alpha6beta4 integrin. IRS-1 and IRS-2 are cytoplasmic adapter proteins that do not contain intrinsic kinase activity but rather function by recruiting proteins to surface receptors, where they organize signaling complexes. Ligation of the alpha6beta4 receptor promotes tyrosine phosphorylation of IRS-1 and IRS-2 and increases their association with PI3K, as determined by coimmunoprecipitation. Moreover, we identified a tyrosine residue in the cytoplasmic domain of the beta4 subunit, Y1494, that is required for alpha6beta4-dependent phosphorylation of IRS-2 and activation of PI3K in response to receptor ligation. Most importantly, Y1494 is essential for the ability of the alpha6beta4 integrin to promote carcinoma invasion. Taken together, these results imply a key role for the IRS proteins in the alpha6beta4-dependent promotion of carcinoma invasion. AD - Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. lshaw@caregroup.harvard.edu FAU - Shaw, L M AU - Shaw LM LA - eng GR - CA81325/CA/NCI PT - Journal Article PL - United States TA - Mol Cell Biol JID - 8109087 RN - 0 (Antigens, Surface) RN - 0 (DNA, Complementary) RN - 0 (Integrin alpha6beta4) RN - 0 (Integrins) RN - 0 (Laminin) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 0 (laminin 1) RN - 55520-40-6 (Tyrosine) RN - 9007-34-5 (Collagen) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/*metabolism MH - Amino Acid Motifs MH - Antigens, Surface/*metabolism MH - Cell Adhesion MH - Collagen/metabolism MH - Cytoplasm/metabolism MH - DNA, Complementary/metabolism MH - Enzyme Activation MH - Humans MH - Immunoblotting MH - Integrin alpha6beta4 MH - Integrins/*metabolism MH - Laminin/metabolism MH - Mutagenesis, Site-Directed MH - Neoplasm Invasiveness MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Polymerase Chain Reaction MH - Precipitin Tests MH - Protein Binding MH - Protein Structure, Tertiary MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction MH - Transfection MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2001/07/05 10:00 MHDA- 2001/08/17 10:01 AID - 10.1128/MCB.21.15.5082-5093.2001 [doi] PST - ppublish SO - Mol Cell Biol 2001 Aug;21(15):5082-93. -------------------------------------------------------------------------------- 109: Banfi C et al. Transcriptional regulation of...[PMID: 11423472] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11423472 OWN - NLM STAT- MEDLINE DA - 20010625 DCOM- 20010719 LR - 20041117 PUBM- Print IS - 0012-1797 VI - 50 IP - 7 DP - 2001 Jul TI - Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: insights into the signaling pathway. PG - 1522-30 AB - Impairment of the fibrinolytic system, caused primarily by increases in the plasma levels of plasminogen activator inhibitor (PAI) type 1, are frequently found in diabetes and the insulin-resistance syndrome. Among the factors responsible for the increases of PAI-1, insulin has recently attracted attention. In this study, we analyzed the effects of insulin on PAI-1 biosynthesis in HepG2 cells, paying particular attention to the signaling network evoked by this hormone. Experiments performed in CHO cells overexpressing the insulin receptor indicate that insulin increases PAI-1 gene transcription through interaction with its receptor. By using inhibitors of the different signaling pathways evoked by insulin-receptor binding, it has been shown that the biosynthesis of PAI-1 is due to phosphatidylinositol (PI) 3-kinase activation, followed by protein kinase C and ultimately by mitogen-activated protein (MAP) kinase activation and extracellular signal-regulated kinase 2 phosphorylation. We also showed that this pathway is Ras-independent. Transfection of HepG2 cells with several truncations of the PAI-1 promoter coupled to a CAT gene allowed us to recognize two major response elements located in the regions between -804 and -708 and between -211 and -54. Electrophoretic mobility shift assay identified three binding sites for insulin-induced factors, all colocalized with putative Sp1 binding sites. Using supershifting antibodies, the binding of Sp1 could only be confirmed at the binding site located just upstream from the transcription start site of the PAI-1 promoter. A construct comprising four tandem repeat copies of the -93/-62 region of the PAI-1 promoter linked to CAT was transcriptionally activated in HepG2 cells by insulin. These results outline the central role of MAP kinase activation in the regulation of PAI-1 induced by insulin. AD - Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. FAU - Banfi, C AU - Banfi C FAU - Eriksson, P AU - Eriksson P FAU - Giandomenico, G AU - Giandomenico G FAU - Mussoni, L AU - Mussoni L FAU - Sironi, L AU - Sironi L FAU - Hamsten, A AU - Hamsten A FAU - Tremoli, E AU - Tremoli E LA - eng PT - Journal Article PL - United States TA - Diabetes JID - 0372763 RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 0 (Plasminogen Activator Inhibitor 1) RN - 11061-68-0 (Insulin) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2.7.1.37 (Protein Kinase C) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) RN - EC 3.6.1.- (ras Proteins) SB - AIM SB - IM MH - Base Sequence MH - Carcinoma, Hepatocellular/metabolism MH - Chromones/pharmacology MH - Chromosome Mapping MH - Enzyme Inhibitors/pharmacology MH - Humans MH - Insulin/*physiology MH - Liver Neoplasms/metabolism MH - Molecular Sequence Data MH - Morpholines/pharmacology MH - Plasminogen Activator Inhibitor 1/biosynthesis/*genetics MH - Promoter Regions (Genetics) MH - Protein Kinase C/metabolism MH - Research Support, Non-U.S. Gov't MH - Ribosomal Protein S6 Kinases/metabolism MH - *Signal Transduction MH - *Transcription, Genetic MH - Tumor Cells, Cultured MH - ras Proteins/physiology EDAT- 2001/06/26 10:00 MHDA- 2001/07/20 10:01 PST - ppublish SO - Diabetes 2001 Jul;50(7):1522-30. -------------------------------------------------------------------------------- 110: Lin YL et al. Complexes formation between i...[PMID: 11409918] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 11409918 OWN - NLM STAT- MEDLINE DA - 20010618 DCOM- 20010823 LR - 20041117 PUBM- Print IS - 1522-4724 VI - 4 IP - 4 DP - 2000 Oct TI - Complexes formation between insulin receptor and extracellular signal-regulated kinases ERKs. PG - 234-8 AB - A property of signal transduction pathways that might explain their efficiency and specificity is the formation of signaling complexes. The recent demonstration that adaptor proteins can interact with many components of the extracellular signal-regulated kinases (ERKs) signaling cascade leads us to investigate whether such complexes may include the transmembrane receptor. The present work shows that in human hepatoma Hep3B cells, insulin receptor (IR) can be coimmunoprecipitated with other components of the ERKs cascade: insulin receptor substrate (IRS), Raf-1, and ERKs. Furthermore, these complexes formed near the cytoplasmic membrane even prior to insulin stimulation. CI - Copyright 2001 Academic Press. AD - Institut de Genetique Humaine, Centre National de la Recherche Scientifique, 141 rue de la Cardonille, Montpellier Cedex 5, 34396, France FAU - Lin, Y L AU - Lin YL FAU - Mettling, C AU - Mettling C FAU - Chou, C K AU - Chou CK LA - eng PT - Journal Article PL - United States TA - Mol Cell Biol Res Commun JID - 100889076 RN - 0 (Macromolecular Substances) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Proto-Oncogene Proteins c-raf) SB - IM MH - Blotting, Western MH - Carcinoma, Hepatocellular/chemistry/metabolism MH - Humans MH - Macromolecular Substances MH - Mitogen-Activated Protein Kinase 1/analysis/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/analysis/*metabolism MH - Phosphorylation MH - Precipitin Tests MH - Proto-Oncogene Proteins c-raf/analysis/metabolism MH - Receptor, Insulin/analysis/*metabolism MH - Signal Transduction/physiology MH - Tumor Cells, Cultured EDAT- 2001/06/21 10:00 MHDA- 2001/08/24 10:01 AID - 10.1006/mcbr.2001.0286 [doi] AID - S1522472401902867 [pii] PST - ppublish SO - Mol Cell Biol Res Commun 2000 Oct;4(4):234-8. -------------------------------------------------------------------------------- 111: Murata M et al. Dual action of eicosapentaeno...[PMID: 11390373] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11390373 OWN - NLM STAT- MEDLINE DA - 20010813 DCOM- 20010906 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 33 DP - 2001 Aug 17 TI - Dual action of eicosapentaenoic acid in hepatoma cells: up-regulation of metabolic action of insulin and inhibition of cell proliferation. PG - 31422-8 AB - Exogenous administration of eicosapentaenoic acid (EPA) improves insulin sensitivity, but its precise mechanism remains unknown. Here we show that EPA stimulates the intracellular insulin signaling pathway in hepatoma cells. Exposure of these cells to EPA caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor substrate-1, insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, and its downstream target Akt kinase activity as well as down-regulation of gluconeogenesis. In contrast, EPA decreased mitogen-activated protein kinase activity and inhibited cell proliferation. These findings raise the possibility that EPA up-regulates metabolic action of insulin and inhibits cell growth in humans. AD - Third Division, Department of Medicine, and Department of Basic Allied Medicine, Kobe University School of Medicine, Kobe, 650-0017, Japan. muratam@med.kobe-u.ac.jp FAU - Murata, M AU - Murata M FAU - Kaji, H AU - Kaji H FAU - Iida, K AU - Iida K FAU - Okimura, Y AU - Okimura Y FAU - Chihara, K AU - Chihara K LA - eng PT - Journal Article DEP - 20010604 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 0 (Transcription Factors) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 1553-41-9 (Eicosapentaenoic Acid) RN - 3416-24-8 (Glucosamine) RN - 50-99-7 (Glucose) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/physiology MH - *Adaptor Proteins, Signal Transducing MH - Carcinoma, Hepatocellular/pathology MH - Cell Division MH - Eicosapentaenoic Acid/*pharmacology MH - Glucosamine/metabolism MH - Glucose/metabolism MH - Humans MH - Insulin/*pharmacology MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/physiology MH - Phosphorylation MH - Proteins/physiology MH - Receptors, Cytoplasmic and Nuclear/physiology MH - Transcription Factors/physiology MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - Up-Regulation EDAT- 2001/06/08 10:00 MHDA- 2001/09/08 10:01 PHST- 2001/06/04 [aheadofprint] AID - 10.1074/jbc.M010497200 [doi] AID - M010497200 [pii] PST - ppublish SO - J Biol Chem 2001 Aug 17;276(33):31422-8. Epub 2001 Jun 4. -------------------------------------------------------------------------------- 112: Gingras S et al. Multiple signal transduction ...[PMID: 11384880] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11384880 OWN - NLM STAT- MEDLINE DA - 20010531 DCOM- 20010712 LR - 20041117 PUBM- Print IS - 0960-0760 VI - 76 IP - 1-5 DP - 2001 Jan-Mar TI - Multiple signal transduction pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase in normal and tumoral target tissues. PG - 213-25 AB - The 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in several human cancer cell lines and in normal human mammary and prostatic epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the Stat6-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. As a matter of fact, we have shown that IL-4-activated Stat6 in all cell lines studied, where IL-4 induced 3beta-HSD type 1 expression but not in those cell lines that failed to respond to IL-4. The mechanism of the induction of 3beta-HSD type 1 gene expression was further characterized in ZR-75-1 human breast cancer cells. We have also found that IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in these cell lines. Moreover, insulin-like growth factor (IGF)-1 and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2 domain-containing proteins, leading to the activation of multiple pathways, such as the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein (MAP) pathways. The inhibition of IL-4-induced 3beta-HSD expression by PI 3-kinase inhibitors (wortmannin and LY294002) as well as an inhibitor of MAP kinase activation (PD98059), indicates the involvement of those pathways in this response to IL-4. Wortmannin also blocked MAP kinase activation by IL-4, insulin and IGF-1 suggesting that the MAP kinase cascade acts as a downstream effector of PI 3-kinases. Furthermore, we showed that the PKC activator phorbol-12-myristate-13-acetate (PMA) also potentiated the IL-4-induced 3beta-HSD activity, thus suggesting that one signaling molecule that is involved in the signal transduction of the IL-4 action on 3beta-HSD type 1 expression is also a substrate for PKC. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involve in the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAP kinase-dependent signaling pathway. However, the inability of IGF-1, insulin and PMA to stimulate 3beta-HSD type 1 expression by themselves in the absence of IL-4 indicates that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with an IL-4-specific signaling molecule, such as the transcription factor Stat6. It is also of interest to note that there also appear to be differences between the regulation of the 3beta-HSD type 1 and type 2 promoters. AD - Laboratory of Hereditary Cancers, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, 2705 Laurier Blvd, Quebec, G1V 4G2, Quebec City, Canada. FAU - Gingras, S AU - Gingras S FAU - Cote, S AU - Cote S FAU - Simard, J AU - Simard J LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - J Steroid Biochem Mol Biol JID - 9015483 RN - 0 (3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase) RN - 0 (Interleukin-13) RN - 0 (Multienzyme Complexes) RN - 207137-56-2 (Interleukin-4) RN - EC 1.1.1.145 (Progesterone Reductase) RN - EC 5.3.3.- (Steroid Isomerases) SB - IM MH - Base Sequence MH - Breast/cytology/enzymology MH - Comparative Study MH - Enzyme Induction MH - Female MH - Gene Expression Regulation, Enzymologic/drug effects MH - Humans MH - Interleukin-13/pharmacology MH - Interleukin-4/*pharmacology MH - Male MH - Molecular Sequence Data MH - Multienzyme Complexes/*biosynthesis/genetics MH - Progesterone Reductase/*biosynthesis/genetics MH - Promoter Regions (Genetics) MH - Prostate/cytology/enzymology MH - Sequence Homology, Nucleic Acid MH - *Signal Transduction MH - Steroid Isomerases/*biosynthesis/genetics MH - Tumor Cells, Cultured RF - 58 EDAT- 2001/06/01 10:00 MHDA- 2001/07/13 10:01 AID - S0960076000001485 [pii] PST - ppublish SO - J Steroid Biochem Mol Biol 2001 Jan-Mar;76(1-5):213-25. -------------------------------------------------------------------------------- 113: Dupont J et al. Insulin-like growth factor 1 ...[PMID: 11376126] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11376126 OWN - NLM STAT- MEDLINE DA - 20010528 DCOM- 20010719 LR - 20041211 PUBM- Print IS - 1366-8714 VI - 54 IP - 3 DP - 2001 Jun TI - Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects. PG - 149-54 AB - In MCF-7 breast cancer cells, the insulin-like growth factor 1 receptor (IGF-1R) and the oestrogen receptor (ER) are coexpressed and the two signalling systems are engaged in a crosstalk that results in synergistic growth. However, coupling between the signalling cascades is poorly understood. Oestradiol enhances IGF-1R signalling by inducing the expression of insulin receptor substrate 1 (IRS-1), a substrate of the IGF-1R. Oestradiol induced expression of IRS-1 results in enhanced tyrosine phosphorylation of IRS-1 after IGF-1 stimulation, followed by enhanced mitogen activated protein kinase, phosphoinositide 3' kinase, and Akt activation. Oestradiol can also potentiate the effect of IGF-1 on the expression of cyclin D1 and cyclin E, and on the phosphorylation of the retinoblastoma protein (RB). These effects are greatly diminished in SX13 cells, which exhibit a 50% reduction in IGF-1R expression but few functional IGF-1Rs at the surface. Oestradiol and IGF-1 regulate the expression of two cyclin dependent kinase inhibitors, p21 and p27, differently. Whereas IGF-1 increases p21 expression and reduces p27 expression, oestradiol has no effect on p21. In summary, in MCF-7 cells, oestrogen potentiates the effect of IGF-1 on IGF-1R signalling and its effects on certain cell cycle components. AD - Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda MD 20892-1758, USA. FAU - Dupont, J AU - Dupont J FAU - Le Roith, D AU - Le Roith D LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Mol Pathol JID - 9706282 RN - 0 (Cyclin E) RN - 0 (Cyclins) RN - 0 (Microfilament Proteins) RN - 0 (Muscle Proteins) RN - 0 (Retinoblastoma Protein) RN - 0 (Tagln protein, mouse) RN - 0 (cyclin-dependent kinase Inhibitor p21) RN - 136601-57-5 (Cyclin D1) RN - 50-28-2 (Estradiol) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/physiology MH - Breast Neoplasms/*metabolism MH - Cell Division/physiology MH - Cyclin D1/metabolism MH - Cyclin E/metabolism MH - Cyclins/metabolism MH - Estradiol/*physiology MH - Female MH - Humans MH - Insulin-Like Growth Factor I/*physiology MH - Microfilament Proteins/metabolism MH - Mitogen-Activated Protein Kinases/physiology MH - *Muscle Proteins MH - Phosphorylation MH - Receptor, IGF Type 1/physiology MH - Retinoblastoma Protein/metabolism MH - Signal Transduction/physiology MH - Tumor Cells, Cultured MH - Tyrosine/physiology RF - 43 EDAT- 2001/05/29 10:00 MHDA- 2001/07/20 10:01 PST - ppublish SO - Mol Pathol 2001 Jun;54(3):149-54. -------------------------------------------------------------------------------- 114: Scharf JG et al. The IGF axis and hepatocarcin...[PMID: 11376124] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11376124 OWN - NLM STAT- MEDLINE DA - 20010528 DCOM- 20010719 LR - 20041117 PUBM- Print IS - 1366-8714 VI - 54 IP - 3 DP - 2001 Jun TI - The IGF axis and hepatocarcinogenesis. PG - 138-44 AB - Deregulation of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and the expression of the IGF receptors, has been identified in the development of hepatocellular carcinoma (HCC). Characteristic alterations detected in HCC and hepatoma cell lines comprise the increased expression of IGF-II and the IGF-I receptor (IGF-IR), which have emerged as crucial events in malignant transformation and the growth of tumours. Alterations of IGFBP production and the proteolytic degradation of IGFBPs resulting in an excess of bioactive IGFs, as well as the defective function of the IGF degrading IGF-II/mannose 6-phosphate receptor (IGF-II/M6PR), may further potentiate the mitogenic effects of IGFs in the development of HCC. AD - Department of Medicine, Division of Gastroenterology and Endocrinology, Georg-August-Universitat, D-37075 Gottingen, Germany. jscharf@med.uni-goettingen.de FAU - Scharf, J G AU - Scharf JG FAU - Dombrowski, F AU - Dombrowski F FAU - Ramadori, G AU - Ramadori G LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Mol Pathol JID - 9706282 RN - 0 (Insulin-Like Growth Factor Binding Proteins) RN - 0 (Receptor, IGF Type 2) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.4.- (Endopeptidases) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/*metabolism MH - Cell Transformation, Neoplastic/metabolism MH - Chickens MH - Endopeptidases/metabolism MH - Humans MH - Insulin-Like Growth Factor Binding Proteins/metabolism MH - Insulin-Like Growth Factor I/*metabolism MH - Insulin-Like Growth Factor II/*metabolism MH - Liver Neoplasms/*metabolism MH - Mice MH - Rats MH - Receptor, IGF Type 1/metabolism MH - Receptor, IGF Type 2/metabolism MH - Receptor, Insulin/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/physiology MH - Tumor Cells, Cultured RF - 99 EDAT- 2001/05/29 10:00 MHDA- 2001/07/20 10:01 PST - ppublish SO - Mol Pathol 2001 Jun;54(3):138-44. -------------------------------------------------------------------------------- 115: Valentinis B et al. IGF-I receptor signalling in ...[PMID: 11376123] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11376123 OWN - NLM STAT- MEDLINE DA - 20010528 DCOM- 20010719 LR - 20041117 PUBM- Print IS - 1366-8714 VI - 54 IP - 3 DP - 2001 Jun TI - IGF-I receptor signalling in transformation and differentiation. PG - 133-7 AB - The type 1 insulin-like growth factor receptor (IGF-IR) sends several signals, some of which are contradictory. When the concentrations of insulin receptor substrate 1 (IRS-1), a major substrate of the IGF-IR, are high, the signal is mitogenic, anti-apoptotic, and can even cause malignant transformation. However, in the absence of IRS-1, the IGF-IR sends a differentiation signal, which leads to granulocytic differentiation in haemopoietic cells. The mitogenic signal of the IGF-IR/IRS-1 combination depends largely, but not exclusively, on the activation of the phosphatidylinositol-3 kinase (PI3K). AD - Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th Street, 624 BLSB, Philadelphia, PA 19107, USA. FAU - Valentinis, B AU - Valentinis B FAU - Baserga, R AU - Baserga R LA - eng GR - CA 78890/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Mol Pathol JID - 9706282 RN - 0 (Biological Markers) RN - EC 1.11.1.7 (Peroxidase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/physiology MH - Animals MH - Apoptosis/physiology MH - Biological Markers/analysis MH - Cell Differentiation/*physiology MH - *Cell Transformation, Neoplastic MH - Down-Regulation/physiology MH - Humans MH - Mice MH - Peroxidase/analysis MH - Receptor, IGF Type 1/*physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*physiology RF - 51 EDAT- 2001/05/29 10:00 MHDA- 2001/07/20 10:01 PST - ppublish SO - Mol Pathol 2001 Jun;54(3):133-7. -------------------------------------------------------------------------------- 116: Vella V et al. The IGF system in thyroid can...[PMID: 11376121] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11376121 OWN - NLM STAT- MEDLINE DA - 20010528 DCOM- 20010719 LR - 20041117 PUBM- Print IS - 1366-8714 VI - 54 IP - 3 DP - 2001 Jun TI - The IGF system in thyroid cancer: new concepts. PG - 121-4 AB - In recent years, the activation of the insulin-like growth factor (IGF) system in cancer has emerged as a key factor for tumour progression and resistance to apoptosis. Therefore, a variety of strategies have been developed to block the type I IGF receptor (IGF-I-R), which is thought to mediate the biological effects of both IGF-I and IGF-II. However, recent data suggest that the IGF signalling system is complex and that other receptors are involved. To unravel the complexity of the IGF system in thyroid cancer, IGF-I and IGF-II production, and the expression and function of their cognate receptors were studied. Both IGFs were found to be locally produced in thyroid cancer: IGF-I by stromal cells and IGF-II by malignant thyrocytes. Values were significantly higher in malignant tissue than in normal tissue. IGF-I-Rs were overexpressed in differentiated papillary carcinomas but not in poorly differentiated or undifferentiated tumours, whereas insulin receptors (IRs) were greatly overexpressed in all tumour hystotypes, with a trend for higher values in dedifferentiated tumours. As a consequence of IR overexpression, high amounts of IR/IGF-I-R hybrids (which bind IGF-I with high affinity) were present in all thyroid cancer histotypes. Because of recent evidence that isoform A of IR (IR-A) is a physiological receptor for IGF-II in fetal life, the relative abundance of IR-A in thyroid cancer was measured. Preliminary data indicate that overexpressed IRs mainly occur as IR-A in thyroid cancer. These data indicate that both IR/IGF-I-R hybrids and IR-A play an important role in the overactivation of the IGF system in thyroid cancer and in IGF-I mitogenic signalling in these tumours. J Clin PATHOL: Mol Pathol AD - Cattedra di Endocrinologia, Istituto di Medicina Interna, Malattie Endocrine e del Metabolismo, University of Catania, Ospedale Garibaldi, Catania, Italy. FAU - Vella, V AU - Vella V FAU - Sciacca, L AU - Sciacca L FAU - Pandini, G AU - Pandini G FAU - Mineo, R AU - Mineo R FAU - Squatrito, S AU - Squatrito S FAU - Vigneri, R AU - Vigneri R FAU - Belfiore, A AU - Belfiore A LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Mol Pathol JID - 9706282 RN - 0 (Protein Isoforms) RN - 0 (Receptor, IGF Type 2) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Carcinoma, Papillary/metabolism MH - Case-Control Studies MH - Enzyme-Linked Immunosorbent Assay MH - Humans MH - Insulin-Like Growth Factor I/*metabolism MH - Insulin-Like Growth Factor II/*metabolism MH - Protein Isoforms/metabolism MH - Receptor, IGF Type 1/*metabolism MH - Receptor, IGF Type 2/*metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Stromal Cells/metabolism MH - Thyroid Gland/pathology MH - Thyroid Neoplasms/*metabolism MH - Tumor Cells, Cultured RF - 31 EDAT- 2001/05/29 10:00 MHDA- 2001/07/20 10:01 PST - ppublish SO - Mol Pathol 2001 Jun;54(3):121-4. -------------------------------------------------------------------------------- 117: Lin WH et al. Cloning, mapping, and charact...[PMID: 11374898] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11374898 OWN - NLM STAT- MEDLINE DA - 20010525 DCOM- 20010823 LR - 20041117 PUBM- Print IS - 0888-7543 VI - 74 IP - 1 DP - 2001 May 15 TI - Cloning, mapping, and characterization of the human sorbin and SH3 domain containing 1 (SORBS1) gene: a protein associated with c-Abl during insulin signaling in the hepatoma cell line Hep3B. PG - 12-20 AB - SH3P12/CAP/ponsin, a gene product with a sorbin homology domain and three consecutive SH3 domains in the carboxy-terminus, has been isolated from murine adipocytes and identified as an important adaptor during insulin signaling. Here we describe the cloning, mapping, and expression of the human homologue, termed SORBS1 (sorbin and SH3 domain containing 1). Multiple transcripts of this gene with different mRNA isoforms were observed among different tissues. Here we report 13 alternatively spliced exons, which were ascertained from the full-length cDNA cloned in adipose, liver, and skeletal muscle tissues. Among the major isoforms, the shortest, 2223-bp, open reading frame (ORF) encodes a protein with a predicted molecular weight of 81.5 kDa, while the longest, 3879-bp, ORF encodes a protein of about 142.2 kDa. This gene was mapped to human chromosome 10q23.3-q24.1, which is a candidate region for insulin resistance found in Pima Indians. In human hepatoma Hep3B cells, SORBS1 was partly dissociated from the insulin receptor complex and bound to c-Abl protein upon insulin stimulation. This interaction with c-Abl was through the third SH3 domain and a possible conformational change of SORBS1 induced by insulin. Our data suggest that c-Abl oncoprotein via SORBS1 might play a role in the insulin signaling pathway. CI - Copyright 2001 Academic Press. AD - Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. FAU - Lin, W H AU - Lin WH FAU - Huang, C J AU - Huang CJ FAU - Liu, M W AU - Liu MW FAU - Chang, H M AU - Chang HM FAU - Chen, Y J AU - Chen YJ FAU - Tai, T Y AU - Tai TY FAU - Chuang, L M AU - Chuang LM LA - eng SI - GENBANK/AF136380 SI - GENBANK/AF356525 SI - GENBANK/AF356526 SI - GENBANK/AF356527 PT - Journal Article PL - United States TA - Genomics JID - 8800135 RN - 0 (DNA, Complementary) RN - 0 (Microfilament Proteins) RN - 0 (Protein Isoforms) RN - 0 (RNA, Messenger) RN - 0 (SORBS1 protein, human) RN - EC 2.7.1.112 (Proto-Oncogene Proteins c-abl) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Amino Acid Sequence MH - Carcinoma, Hepatocellular/genetics/pathology MH - Chromosome Banding MH - Chromosome Mapping MH - Chromosomes, Human, Pair 10/genetics MH - Cloning, Molecular MH - DNA, Complementary/chemistry/genetics MH - Exons MH - Female MH - Genes, Structural/*genetics MH - Humans MH - In Situ Hybridization, Fluorescence MH - Introns MH - Liver Neoplasms/genetics/pathology MH - Microfilament Proteins/*genetics/metabolism MH - Molecular Sequence Data MH - Protein Binding MH - Protein Isoforms/genetics MH - Proto-Oncogene Proteins c-abl/metabolism MH - RNA, Messenger/genetics/metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Sequence Analysis, DNA MH - Sequence Homology, Amino Acid MH - Signal Transduction MH - Tissue Distribution MH - Tumor Cells, Cultured EDAT- 2001/05/26 10:00 MHDA- 2001/08/24 10:01 AID - 10.1006/geno.2001.6541 [doi] AID - S0888754301965413 [pii] PST - ppublish SO - Genomics 2001 May 15;74(1):12-20. -------------------------------------------------------------------------------- 118: Simpson L et al. PTEN expression causes feedba...[PMID: 11359902] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 11359902 OWN - NLM STAT- MEDLINE DA - 20010521 DCOM- 20010628 LR - 20050111 PUBM- Print IS - 0270-7306 VI - 21 IP - 12 DP - 2001 Jun TI - PTEN expression causes feedback upregulation of insulin receptor substrate 2. PG - 3947-58 AB - PTEN is a tumor suppressor that antagonizes phosphatidylinositol-3 kinase (PI3K) by dephosphorylating the D3 position of phosphatidylinositol (3,4,5)-triphosphate (PtdIns-3,4,5-P3). Given the importance of PTEN in regulating PtdIns-3,4,5-P3 levels, we used Affymetrix GeneChip arrays to identify genes regulated by PTEN. PTEN expression rapidly reduced the activity of Akt, which was followed by a G(1) arrest and eventually apoptosis. The gene encoding insulin receptor substrate 2 (IRS-2), a mediator of insulin signaling, was found to be the most induced gene at all time points. A PI3K-specific inhibitor, LY294002, also upregulated IRS-2, providing evidence that it was the suppression of the PI3K pathway that was responsible for the message upregulation. In addition, PTEN, LY294002, and rapamycin, an inhibitor of mammalian target of rapamycin, caused a reduction in the molecular weight of IRS-2 and an increase in the association of IRS-2 with PI3K. Apparently, PTEN inhibits a negative regulator of IRS-2 to upregulate the IRS-2-PI3K interaction. These studies suggest that PtdIns-3,4,5-P3 levels regulate the specific activity and amount of IRS-2 available for insulin signaling. AD - Institute of Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. FAU - Simpson, L AU - Simpson L FAU - Li, J AU - Li J FAU - Liaw, D AU - Liaw D FAU - Hennessy, I AU - Hennessy I FAU - Oliner, J AU - Oliner J FAU - Christians, F AU - Christians F FAU - Parsons, R AU - Parsons R LA - eng GR - CA82783/CA/NCI GR - CCA75553/CA/NCI PT - Journal Article PL - United States TA - Mol Cell Biol JID - 8109087 RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 0 (Phosphatidylinositol Phosphates) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Tumor Suppressor Proteins) RN - 0 (insulin receptor substrate-2 protein) RN - 0 (phosphatidylinositol 3,4,5-triphosphate) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 53123-88-9 (Sirolimus) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTEN protein) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism MH - Apoptosis MH - Breast Neoplasms/genetics/metabolism/pathology MH - Cell Cycle MH - Cell Line MH - Chromones/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Feedback MH - Female MH - Genes, Tumor Suppressor MH - Humans MH - Models, Biological MH - Morpholines/pharmacology MH - Oligonucleotide Array Sequence Analysis MH - Phosphatidylinositol Phosphates/metabolism MH - Phosphoproteins/*genetics MH - Phosphoric Monoester Hydrolases/*genetics/*metabolism MH - Phosphorylation MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Sirolimus/pharmacology MH - Tumor Cells, Cultured MH - *Tumor Suppressor Proteins MH - Up-Regulation EDAT- 2001/05/22 10:00 MHDA- 2001/06/29 10:01 AID - 10.1128/MCB.21.12.3947-3958.2001 [doi] PST - ppublish SO - Mol Cell Biol 2001 Jun;21(12):3947-58. -------------------------------------------------------------------------------- 119: Mahadev K et al. Insulin-stimulated hydrogen p...[PMID: 11297536] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11297536 OWN - NLM STAT- MEDLINE DA - 20010611 DCOM- 20010719 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 24 DP - 2001 Jun 15 TI - Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. PG - 21938-42 AB - The insulin signaling pathway is activated by tyrosine phosphorylation of the insulin receptor and key post-receptor substrate proteins and balanced by the action of specific protein-tyrosine phosphatases (PTPases). PTPase activity, in turn, is highly regulated in vivo by oxidation/reduction reactions involving the cysteine thiol moiety required for catalysis. Here we show that insulin stimulation generates a burst of intracellular H(2)O(2) in insulin-sensitive hepatoma and adipose cells that is associated with reversible oxidative inhibition of up to 62% of overall cellular PTPase activity, as measured by a novel method using strictly anaerobic conditions. The specific activity of immunoprecipitated PTP1B, a PTPase homolog implicated in the regulation of insulin signaling, was also strongly inhibited by up to 88% following insulin stimulation. Catalase pretreatment abolished the insulin-stimulated production of H(2)O(2) as well as the inhibition of cellular PTPases, including PTP1B, and was associated with reduced insulin-stimulated tyrosine phosphorylation of its receptor and high M(r) insulin receptor substrate (IRS) proteins. These data provide compelling new evidence for a redox signal that enhances the early insulin-stimulated cascade of tyrosine phosphorylation by oxidative inactivation of PTP1B and possibly other tyrosine phosphatases. AD - Dorrance H. Hamilton Research Laboratories, Division of Endocrinology and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Mahadev, K AU - Mahadev K FAU - Zilbering, A AU - Zilbering A FAU - Zhu, L AU - Zhu L FAU - Goldstein, B J AU - Goldstein BJ LA - eng GR - DK43396/DK/NIDDK GR - DK53388/DK/NIDDK PT - Journal Article DEP - 20010410 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 28822-58-4 (1-Methyl-3-isobutylxanthine) RN - 50-02-2 (Dexamethasone) RN - 7722-84-1 (Hydrogen Peroxide) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.1.3.48 (protein tyrosine phosphatase 1B) SB - IM MH - 1-Methyl-3-isobutylxanthine/pharmacology MH - 3T3 Cells MH - Adipocytes/cytology/drug effects/enzymology MH - Animals MH - Carcinoma, Hepatocellular MH - Cell Differentiation MH - Dexamethasone/pharmacology MH - Humans MH - Hydrogen Peroxide/*pharmacology MH - Insulin/*metabolism/*pharmacology MH - Liver Neoplasms MH - Mice MH - Phosphoproteins/metabolism MH - Phosphotyrosine/metabolism MH - Protein-Tyrosine-Phosphatase/antagonists & inhibitors/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 2001/04/12 10:00 MHDA- 2001/07/20 10:01 PHST- 2001/04/10 [aheadofprint] AID - 10.1074/jbc.C100109200 [doi] AID - C100109200 [pii] PST - ppublish SO - J Biol Chem 2001 Jun 15;276(24):21938-42. Epub 2001 Apr 10. -------------------------------------------------------------------------------- 120: Navab R et al. Inhibition of endosomal insul...[PMID: 11278993] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11278993 OWN - NLM STAT- MEDLINE DA - 20010424 DCOM- 20010614 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 17 DP - 2001 Apr 27 TI - Inhibition of endosomal insulin-like growth factor-I processing by cysteine proteinase inhibitors blocks receptor-mediated functions. PG - 13644-9 AB - The receptor for the type 1 insulin-like growth factor (IGF-I) has been implicated in cellular transformation and the acquisition of an invasive/metastatic phenotype in various tumors. Following ligand binding, the IGF-I receptor is internalized, and the receptor.ligand complex dissociates as the ligand is degraded by endosomal proteinases. In the present study we show that the inhibition of endosomal IGF-I-degrading enzymes in human breast and murine lung carcinoma cells by the cysteine proteinase inhibitors, E-64 and CA074-methyl ester, profoundly altered receptor trafficking and signaling. In treated cells, intracellular ligand degradation was blocked, and although the receptor and two substrates, Shc and Insulin receptor substrate, were hyperphosphorylated on tyrosine, IGF-I-induced DNA synthesis, anchorage-independent growth, and matrix metalloproteinase synthesis were inhibited. The results suggest that ligand processing by endosomal proteinases is a key step in receptor signaling and function and a potential target for therapy. AD - Department of Surgery, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec H3A 1A4, Canada. FAU - Navab, R AU - Navab R FAU - Chevet, E AU - Chevet E FAU - Authier, F AU - Authier F FAU - Di Guglielmo, G M AU - Di Guglielmo GM FAU - Bergeron, J J AU - Bergeron JJ FAU - Brodt, P AU - Brodt P LA - eng PT - Journal Article DEP - 20010126 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (CA 074 methyl ester) RN - 0 (Cysteine Proteinase Inhibitors) RN - 0 (Dipeptides) RN - 0 (Ligands) RN - 0 (Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 55520-40-6 (Tyrosine) RN - 61-90-5 (Leucine) RN - 66701-25-5 (E 64) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9007-49-2 (DNA) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Animals MH - Blotting, Western MH - Cell Membrane/metabolism MH - Chromatography, High Pressure Liquid MH - Cysteine Proteinase Inhibitors/*pharmacology MH - DNA/biosynthesis MH - Dipeptides/pharmacology MH - Dose-Response Relationship, Drug MH - Endosomes/enzymology/*metabolism MH - Female MH - Flow Cytometry MH - Humans MH - Insulin-Like Growth Factor I/*antagonists & inhibitors/*metabolism MH - Kinetics MH - Leucine/*analogs & derivatives/pharmacology MH - Ligands MH - Liver/metabolism MH - Male MH - Mice MH - Models, Biological MH - Neoplasm Metastasis MH - Phosphorylation MH - Precipitin Tests MH - Protein Binding/drug effects MH - Proteins/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, IGF Type 1/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Time Factors MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2001/03/30 10:00 MHDA- 2001/06/15 10:01 PHST- 2001/01/26 [aheadofprint] AID - 10.1074/jbc.M100019200 [doi] AID - M100019200 [pii] PST - ppublish SO - J Biol Chem 2001 Apr 27;276(17):13644-9. Epub 2001 Jan 26. -------------------------------------------------------------------------------- 121: Liu YF et al. Insulin stimulates PKCzeta -m...[PMID: 11278339] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11278339 OWN - NLM STAT- MEDLINE DA - 20010424 DCOM- 20010614 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 17 DP - 2001 Apr 27 TI - Insulin stimulates PKCzeta -mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins. PG - 14459-65 AB - Incubation of rat hepatoma Fao cells with insulin leads to a transient rise in Tyr phosphorylation of insulin receptor substrate (IRS) proteins. This is followed by elevation in their P-Ser/Thr content, and their dissociation from the insulin receptor (IR). Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished the increase in the P-Ser/Thr content of IRS-1, its dissociation from the IR, and the decrease in its P-Tyr content following 60 min of insulin treatment, indicating that the Ser kinases that negatively regulate IRS-1 function are downstream effectors of PI3K. PKCzeta fulfills this criterion, being an insulin-activated downstream effector of PI3K. Overexpression of PKCzeta in Fao cells, by infection of the cells with adenovirus-based PKCzeta construct, had no effect on its own, but it accelerated the rate of insulin-stimulated dissociation of IR.IRS-1 complexes and the rate of Tyr dephosphorylation of IRS-1. The insulin-stimulated negative regulatory role of PKCzeta was specific and could not be mimic by infecting Fao cells with adenoviral constructs encoding for PKC alpha, delta, or eta. Because the reduction in P-Tyr content of IRS-1 was accompanied by a reduced association of IRS-1 with p85, the regulatory subunit of PI3K, it suggests that this negative regulatory process induced by PKCzeta, has a built-in attenuation signal. Hence, insulin triggers a sequential cascade in which PI3K-mediated activation of PKCzeta inhibits IRS-1 functions, reduces complex formation between IRS-1 and PI3K, and inhibits further activation of PKCzeta itself. These findings implicate PKCzeta as a key element in a multistep negative feedback control mechanism of IRS-1 functions. AD - Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. FAU - Liu, Y F AU - Liu YF FAU - Paz, K AU - Paz K FAU - Herschkovitz, A AU - Herschkovitz A FAU - Alt, A AU - Alt A FAU - Tennenbaum, T AU - Tennenbaum T FAU - Sampson, S R AU - Sampson SR FAU - Ohba, M AU - Ohba M FAU - Kuroki, T AU - Kuroki T FAU - LeRoith, D AU - LeRoith D FAU - Zick, Y AU - Zick Y LA - eng PT - Journal Article DEP - 20010129 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Androstadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (Protein Isoforms) RN - 0 (Recombinant Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 19545-26-7 (wortmannin) RN - 55520-40-6 (Tyrosine) RN - 56-45-1 (Serine) RN - 72-19-5 (Threonine) RN - EC 2.7.1.- (protein kinase C zeta) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors MH - Adenoviridae/genetics/metabolism MH - Androstadienes/pharmacology MH - Animals MH - Carcinoma, Hepatocellular/metabolism MH - Cell Line MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/pharmacology MH - *Gene Expression Regulation MH - Humans MH - Insulin/*metabolism/physiology MH - Liver Neoplasms/metabolism MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Precipitin Tests MH - Protein Isoforms MH - Protein Kinase C/*metabolism MH - Rats MH - Receptor, Insulin/metabolism MH - Recombinant Proteins/metabolism MH - Serine/chemistry MH - Threonine/chemistry MH - Time Factors MH - Tumor Necrosis Factor-alpha/metabolism MH - Tyrosine/metabolism EDAT- 2001/03/30 10:00 MHDA- 2001/06/15 10:01 PHST- 2001/01/29 [aheadofprint] AID - 10.1074/jbc.M007281200 [doi] AID - M007281200 [pii] PST - ppublish SO - J Biol Chem 2001 Apr 27;276(17):14459-65. Epub 2001 Jan 29. -------------------------------------------------------------------------------- 122: Osipo C et al. Loss of insulin-like growth f...[PMID: 11262195] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11262195 OWN - NLM STAT- MEDLINE DA - 20010323 DCOM- 20010607 LR - 20041117 PUBM- Print IS - 0014-4827 VI - 264 IP - 2 DP - 2001 Apr 1 TI - Loss of insulin-like growth factor II receptor expression promotes growth in cancer by increasing intracellular signaling from both IGF-I and insulin receptors. PG - 388-96 AB - The insulin-like growth factor-II receptor (IGF-IIR) is frequently mutated or deleted in some malignant human tumors, suggesting that the IGF-IIR is a tumor suppressor. However, the exact mechanism by which IGF-IIR suppresses growth in tumors has not been definitively established. We demonstrate that IGF-IIR-deficient murine L cells (D9) have higher growth rates than IGF-IIR-positive L cells (Cc2) in response to IGF-II. IGF-II levels are higher in growth-conditioned medium from D9 versus Cc2 cells. Receptor neutralization studies and measurements of insulin receptor substrate 1 phosphorylation confirm that the enhanced growth of D9 cells is due to increased stimulation of the IGF-I and insulin receptors by IGF-II. In contrast, the levels of secreted latent and active transforming growth factor beta (TGF-beta) are similar for both D9 and Cc2 cells, indicating that the slower growth of Cc2 cells is not due to activation of latent TGF-beta by IGF-IIR and growth inhibition. The results directly demonstrate that down regulation of the IGF-IIR promotes the growth of transformed D9 cells by sustaining IGF-II, which binds to and activates IGF-IR and insulin receptor to increase intracellular growth signals. CI - Copyright 2001 Academic Press. AD - Division of Molecular and Cellular Biochemistry, Loyola University Medical Center, Maywood, Illinois 60153, USA. FAU - Osipo, C AU - Osipo C FAU - Dorman, S AU - Dorman S FAU - Frankfater, A AU - Frankfater A LA - eng PT - Journal Article PL - United States TA - Exp Cell Res JID - 0373226 RN - 0 (Culture Media, Conditioned) RN - 0 (Phosphoproteins) RN - 0 (Receptor, IGF Type 2) RN - 0 (Transforming Growth Factor beta) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Cattle MH - Cell Division MH - Culture Media, Conditioned MH - Humans MH - Insulin-Like Growth Factor II/*biosynthesis/pharmacology MH - Intracellular Fluid MH - L Cells (Cell Line) MH - Mice MH - Phosphoproteins/*metabolism MH - Receptor, IGF Type 1/*metabolism MH - Receptor, IGF Type 2/genetics/*metabolism MH - Receptor, Insulin/*metabolism MH - Signal Transduction/*physiology MH - Transforming Growth Factor beta/metabolism EDAT- 2001/03/23 10:00 MHDA- 2001/06/08 10:01 AID - 10.1006/excr.2000.5121 [doi] AID - S0014482700951218 [pii] PST - ppublish SO - Exp Cell Res 2001 Apr 1;264(2):388-96. -------------------------------------------------------------------------------- 123: Venkatesan AM et al. Insulin resistance in polycys...[PMID: 11237218] Related Articles, Books, LinkOut PMID- 11237218 OWN - NLM STAT- MEDLINE DA - 20010309 DCOM- 20010426 LR - 20041117 PUBM- Print IS - 0079-9963 VI - 56 DP - 2001 TI - Insulin resistance in polycystic ovary syndrome: progress and paradoxes. PG - 295-308 AB - Over the past 20 years, it has been clearly documented that 1) polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and 2) insulin resistance plays an important role in the pathogenesis of the reproductive abnormalities of the disorder. Women with PCOS are at significantly increased risk of developing type 2 diabetes mellitus (DM). Studies in isolated adipocytes and in cultured skin fibroblasts from PCOS women have demonstrated intrinsic postbinding defects in insulin-mediated glucose metabolism. In fibroblasts, the mitogenic pathway of insulin action is intact, consistent with a selective defect in insulin signaling. While PCOS skeletal muscle is resistant to insulin in vivo, cultured muscle cells have normal insulin sensitivity, consistent with a major role of extrinsic factors in producing insulin resistance in this tissue. Excessive serine phosphorylation of the insulin receptor or downstream signaling proteins may be involved in the pathogenesis of insulin resistance in PCOS. The putative serine kinase is extrinsic to the insulin receptor but its identity is unknown. The explanations for tissue-specific and signaling pathway-specific differences in insulin action in PCOS are unknown but may involve differential roles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal transduction. AD - The Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. FAU - Venkatesan, A M AU - Venkatesan AM FAU - Dunaif, A AU - Dunaif A FAU - Corbould, A AU - Corbould A LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - United States TA - Recent Prog Horm Res JID - 0404471 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) SB - IM MH - Adipocytes/metabolism MH - Diabetes Mellitus, Type 2/etiology MH - Dose-Response Relationship, Drug MH - Female MH - Fibroblasts/metabolism MH - Humans MH - *Insulin Resistance MH - Models, Biological MH - Muscle, Skeletal/metabolism MH - Phosphoproteins/metabolism MH - Polycystic Ovary Syndrome/*complications MH - Protein-Serine-Threonine Kinases/metabolism MH - Risk Factors MH - Signal Transduction RF - 75 EDAT- 2001/03/10 10:00 MHDA- 2001/05/01 10:01 PST - ppublish SO - Recent Prog Horm Res 2001;56:295-308. -------------------------------------------------------------------------------- 124: Weng LP et al. PTEN inhibits insulin-stimula...[PMID: 11230180] Related Articles, Substance via MeSH, OMIM, Cited in PMC, Books, LinkOut PMID- 11230180 OWN - NLM STAT- MEDLINE DA - 20010320 DCOM- 20010628 LR - 20050111 PUBM- Print IS - 0964-6906 VI - 10 IP - 6 DP - 2001 Mar 15 TI - PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. PG - 605-16 AB - The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein substrates and phosphatidylinositol-3,4,5-triphosphate. PTEN seems to play multiple roles in tumour suppression and the blockade of phosphoinositide-3-kinase signalling is important for its growth suppressive effects, although precise mechanisms are not fully understood. In this study, we show that PTEN plays a unique role in the insulin-signalling pathway in a breast cancer model. Ectopic expression of wild-type PTEN in MCF-7 epithelial breast cancer cells resulted in universal inhibition of Akt phosphorylation in response to stimulation by diverse growth factors and selective inhibition of MEK/extracellular signal-regulated kinase (ERK) phosphorylation stimulated by insulin or insulin-like growth factor 1 (IGF-1). The latter was accompanied by a decrease in the phosphorylation of insulin receptor substrate 1 (IRS-1) and the association of IRS-1 with Grb2/Sos, without affecting the phosphorylation status of the insulin receptor and Shc, nor Shc/Grb2 complex formation. The MEK inhibitor, PD980059, but not the PI3K inhibitor, wortmannin, abolished the effect of PTEN on insulin-stimulated cell growth. Without addition of insulin, wortmannin reduced PTEN-mediated growth suppression, whereas PD980059 had little effect, suggesting that PTEN suppresses insulin-stimulated cell growth by blocking the mitogen-activated protein kinase (MAPK) pathway. Furthermore, PD980059 treatment led to the downregulation of cyclin D1 and the suppression of cell cycle progression. Our data suggest that PTEN blocks MAPK phosphorylation in response to insulin stimulation by inhibiting the phosphorylation of IRS-1 and IRS-1/Grb2/Sos complex formation, which leads to downregulation of cyclin D1, inhibition of cell cycle progression and suppression of cell growth. AD - Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. FAU - Weng, L P AU - Weng LP FAU - Smith, W M AU - Smith WM FAU - Brown, J L AU - Brown JL FAU - Eng, C AU - Eng C LA - eng GR - P30CA16058/CA/NCI PT - Journal Article PL - England TA - Hum Mol Genet JID - 9208958 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (Tumor Suppressor Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTEN protein) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Breast Neoplasms/*enzymology/metabolism MH - Cell Division/drug effects MH - Drug Interactions MH - Enzyme Inhibitors/pharmacology MH - Humans MH - Insulin/*pharmacology MH - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/chemistry/*metabolism MH - Phosphoric Monoester Hydrolases/genetics/*physiology MH - Phosphorylation MH - Proteins/metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - *Tumor Suppressor Proteins EDAT- 2001/03/07 10:00 MHDA- 2001/06/29 10:01 PST - ppublish SO - Hum Mol Genet 2001 Mar 15;10(6):605-16. -------------------------------------------------------------------------------- 125: Cai DX et al. PS6K amplification characteri...[PMID: 11211609] Related Articles, Books, LinkOut PMID- 11211609 OWN - NLM STAT- MEDLINE DA - 20010209 DCOM- 20010222 LR - 20041117 PUBM- Print IS - 0002-9173 VI - 115 IP - 2 DP - 2001 Feb TI - PS6K amplification characterizes a small subset of anaplastic meningiomas. PG - 213-8 AB - PS6K, a putative oncogene mapped to chromosome 17q23, encodes a serine/threonine kinase, which phosphorylates ribosomal subunit 6 and is part of the insulin receptor signal transduction pathway involved in the regulation of messenger RNA translation, protein synthesis, cell cycle progression, and cell size. Comparative genomic hybridization studies have detected 17q23 amplifications in a subset of meningiomas, particularly those with aggressive histologic features. PS6K amplifications have been reported in breast cancer, another hormonally driven neoplasm. We assessed PS6K dosage in 94 archival paraffin-embedded meningiomas using dual-color fluorescence in situ hybridization. We found high-level PS6K amplifications in 3 of 22 anaplastic grade III meningiomas. Amplification was confirmed by differential polymerase chain reaction in 1 of these cases. In contrast, no amplifications were identified in 37 benign (grade I) and 35 atypical (grade II) meningiomas. To our knowledge, this represents the first report of gene amplification in primary human meningiomas. Given its exclusive association with anaplastic meningiomas, PS6K amplification likely occurs during the malignant progression of a small subset of anaplastic tumors. Further studies are needed to map the 17q23 amplicon to determine whether additional genes in this region are amplified in high-grade meningiomas. AD - Department of Pathology, Washington University School of Medicine, 660 S Euclid Ave, Box 8118, St Louis, MO 63110, USA. FAU - Cai, D X AU - Cai DX FAU - James, C D AU - James CD FAU - Scheithauer, B W AU - Scheithauer BW FAU - Couch, F J AU - Couch FJ FAU - Perry, A AU - Perry A LA - eng PT - Journal Article PL - United States TA - Am J Clin Pathol JID - 0370470 RN - 0 (DNA Primers) RN - 0 (DNA, Neoplasm) RN - 0 (Plant Proteins) RN - EC 2.7.1.- (PSK6 protein, Petunia x hybrida) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) SB - AIM SB - IM MH - DNA Primers/chemistry MH - DNA, Neoplasm/analysis MH - *Gene Amplification MH - Humans MH - In Situ Hybridization, Fluorescence MH - Meningeal Neoplasms/classification/genetics/*pathology MH - Meningioma/classification/genetics/*pathology MH - Neoplasm Staging MH - *Plant Proteins MH - Polymerase Chain Reaction MH - Protein-Serine-Threonine Kinases/*genetics/metabolism EDAT- 2001/02/24 12:00 MHDA- 2001/03/03 10:01 AID - 10.1309/FVNU-7UBY-DXE3-77MT [doi] PST - ppublish SO - Am J Clin Pathol 2001 Feb;115(2):213-8. -------------------------------------------------------------------------------- 126: Egawa K et al. Protein-tyrosine phosphatase-...[PMID: 11136729] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11136729 OWN - NLM STAT- MEDLINE DA - 20010327 DCOM- 20010510 LR - 20050111 PUBM- Print-Electronic IS - 0021-9258 VI - 276 IP - 13 DP - 2001 Mar 30 TI - Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in l6 myocytes and Fao hepatoma cells. PG - 10207-11 AB - Insulin signaling is regulated by tyrosine phosphorylation of the signaling molecules, such as the insulin receptor and insulin receptor substrates (IRSs). Therefore, the balance between protein-tyrosine kinases and protein-tyrosine phosphatase activities is thought to be important in the modulation of insulin signaling in insulin-resistant states. We thus employed the adenovirus-mediated gene transfer technique, and we analyzed the effect of overexpression of a wild-type protein-tyrosine phosphatase-1B (PTP1B) on insulin signaling in both L6 myocytes and Fao cells. In both cells, PTP1B overexpression blocked insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 by more than 70% and resulted in a significant inhibition of the association between IRS-1 and the p85 subunit of phosphatidylinositol 3-kinase and Akt phosphorylation as well as mitogen-activated protein kinase phosphorylation. Moreover, insulin-stimulated glycogen synthesis was also inhibited by PTP1B overexpression in both cells. These effects were specific for insulin signaling, because platelet-derived growth factor (PDGF)-stimulated PDGF receptor tyrosine phosphorylation and Akt phosphorylation were not inhibited by PTP1B overexpression. The present findings demonstrate that PTP1B negatively regulates insulin signaling in L6 and Fao cells, suggesting that PTP1B plays an important role in insulin resistance in muscle and liver. AD - Third Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan. FAU - Egawa, K AU - Egawa K FAU - Maegawa, H AU - Maegawa H FAU - Shimizu, S AU - Shimizu S FAU - Morino, K AU - Morino K FAU - Nishio, Y AU - Nishio Y FAU - Bryer-Ash, M AU - Bryer-Ash M FAU - Cheung, A T AU - Cheung AT FAU - Kolls, J K AU - Kolls JK FAU - Kikkawa, R AU - Kikkawa R FAU - Kashiwagi, A AU - Kashiwagi A LA - eng GR - RR-00211/RR/NCRR PT - Journal Article DEP - 20010102 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Phosphoproteins) RN - 0 (Platelet-Derived Growth Factor) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 9005-79-2 (Glycogen) RN - EC 2.4.1.11 (Glycogen Synthase) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Adenoviridae/genetics MH - Blotting, Western MH - Carcinoma, Hepatocellular/metabolism MH - Cell Line MH - Gene Transfer Techniques MH - Glycogen/metabolism MH - Glycogen Synthase/metabolism MH - Humans MH - Insulin/*metabolism MH - Insulin Resistance MH - Liver/metabolism MH - Liver Neoplasms/metabolism MH - Muscles/metabolism MH - Myocardium/*cytology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Platelet-Derived Growth Factor/metabolism MH - *Protein-Serine-Threonine Kinases MH - Protein-Tyrosine Kinase/metabolism MH - Protein-Tyrosine-Phosphatase/*metabolism MH - Proto-Oncogene Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction MH - Tumor Cells, Cultured EDAT- 2001/01/14 19:15 MHDA- 2001/05/22 10:01 PHST- 2001/01/02 [aheadofprint] AID - 10.1074/jbc.M009489200 [doi] AID - M009489200 [pii] PST - ppublish SO - J Biol Chem 2001 Mar 30;276(13):10207-11. Epub 2001 Jan 2. -------------------------------------------------------------------------------- 127: Hermanto U et al. Inhibition of mitogen-activat...[PMID: 11149601] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11149601 OWN - NLM STAT- MEDLINE DA - 20010108 DCOM- 20010412 LR - 20041117 PUBM- Print IS - 1044-9523 VI - 11 IP - 12 DP - 2000 Dec TI - Inhibition of mitogen-activated protein kinase kinase selectively inhibits cell proliferation in human breast cancer cells displaying enhanced insulin-like growth factor I-mediated mitogen-activated protein kinase activation. PG - 655-64 AB - Mitogen-activated protein (MAP) kinase mediates cell proliferation, cell differentiation, and cell survival by regulating signaling pathways activated by receptor protein tyrosine kinases (RPTKs), including the insulin-like growth factor 1 receptor (IGF-IR). We analyzed the upstream signaling components of the MAP kinase pathway, including RPTKs, in human breast cancer cell lines and found that some of those components were overexpressed. Importantly, signaling molecules such as IGF-IR, insulin receptor, and insulin receptor substrate 1, leading to the MAP kinase pathway, were found to be concomitantly overexpressed within certain tumor lines, i.e., MCF-7 and T-47D. When compared with the nonmalignant and other breast tumor lines examined, MCF-7 and T-47D cells displayed a more rapid, robust, and sustained MAP kinase activation in response to insulin-like growth factor I (IGF-I) stimulation. By contrast, IGF-I treatment led to a sustained down-regulation of MAP kinase in those lines overexpressing ErbB2-related RPTKs. Interestingly, blocking the MAP kinase pathway with PD098059 had the greatest antiproliferative effect on MCF-7 and T-47D among the normal and tumor lines tested. Furthermore, addition of an IGF-IR blocking antibody to growth medium attenuated the ability of PD098059 to suppress the growth of MCF-7 and T-47D cells. Thus, our study suggests that concomitant overexpression of multiple signaling components of the IGF-IR pathway leads to the amplification of IGF-I-mediated MAP kinase signaling and resultant sensitization to PD098059. The enhanced sensitivity to PD098059 implies an increased requirement for the MAP kinase pathway in those breast cancer cells, making this pathway a potential target in the treatment of selected breast malignancies. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029-6574, USA. FAU - Hermanto, U AU - Hermanto U FAU - Zong, C S AU - Zong CS FAU - Wang, L H AU - Wang LH LA - eng GR - CA29339/CA/NCI GR - CA55054/CA/NCI GR - T32GM07280/GM/NIGMS PT - Journal Article PL - United States TA - Cell Growth Differ JID - 9100024 RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (MAP Kinase Signaling System) RN - 0 (PD 98059) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Breast Neoplasms/*drug therapy/metabolism MH - Cell Differentiation MH - Cell Division MH - Cell Line MH - Cell Survival MH - Down-Regulation MH - Electrophoresis, Polyacrylamide Gel MH - Enzyme Inhibitors/pharmacology MH - Female MH - Flavonoids/pharmacology MH - Humans MH - Immunoblotting MH - Insulin-Like Growth Factor I/*metabolism MH - *MAP Kinase Signaling System MH - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors MH - Phosphorylation MH - Precipitin Tests MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Time Factors MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - Up-Regulation EDAT- 2001/01/10 11:00 MHDA- 2001/04/17 10:01 PST - ppublish SO - Cell Growth Differ 2000 Dec;11(12):655-64. -------------------------------------------------------------------------------- 128: Ricort JM et al. Insulin-like growth factor (I...[PMID: 11145572] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11145572 OWN - NLM STAT- MEDLINE DA - 20010126 DCOM- 20010301 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 142 IP - 1 DP - 2001 Jan TI - Insulin-like growth factor (IGF) binding protein-3 inhibits type 1 IGF receptor activation independently of its IGF binding affinity. PG - 108-13 AB - Insulin-like growth factor binding proteins (IGFBPs) regulate the cellular actions of the IGFs owing to their strong affinities, which are equal to or stronger than the affinity of the type 1 IGF receptor (IGF-IR), the mediator of IGF signal transduction. We recently found that IGFBP-3 modulates IGF-I binding to its receptor via a different mechanism possibly involving conformational alteration of the receptor. We have now investigated the effects of IGFBP-3 on the initial steps in the IGF signaling pathway. MCF-7 breast carcinoma cells were preincubated with increasing concentrations of IGFBP-3 and then stimulated with IGF-I, des(1-3)IGF-I, or [Q(3)A(4)Y(15)L(16)]-IGF-I, the latter two being IGF-I analogs with intact affinity for the type 1 IGF receptor, but weak or virtually no affinity for IGFBPs. Stimulation of autophosphorylation of the receptor and its tyrosine kinase activity was dose-dependently depressed. At 2.5 nM, IGFBP-3 provoked more than 50% inhibition of the stimulation induced by 3 nM des(1-3)IGF-1 and, at 10 nM, more than 80% inhibition. Similar results were obtained with [Q(3)A(4)Y(15)L(16)]-IGF-I. Cross-linking experiments using iodinated or unlabeled IGFBP-3 and anti-IGF-IR antibodies indicated that the inhibitory effects do not involve direct interaction between IGFBP-3 and IGF-IR. The inhibition appeared to be specific to IGFBP-3, because IGFBP-1 and IGFBP-5 at 10 nM had no significant effect. Also, inhibition was restricted to the IGF receptor, because IGFBP-3 failed to inhibit the tyrosine kinase activity of the insulin receptor stimulated by physiological concentrations of insulin. Our results provide the first demonstration that IGFBP-3 can specifically modulate the IGF-I signaling pathway independently of its IGF-I-binding ability. They also reveal a regulatory mechanism specific to the type 1 IGF receptor, with no effect on insulin receptor activation. AD - Institut National de la Sante et de la Recherche Medicale, Unite 515, Croissance, Differenciation et Processus tumoraux, Hopital Saint-Antoine, Paris, France. FAU - Ricort, J M AU - Ricort JM FAU - Binoux, M AU - Binoux M LA - eng PT - Journal Article PL - United States TA - Endocrinology JID - 0375040 RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 0 (Insulin-Like Growth Factor Binding Protein 3) RN - 0 (Insulin-Like Growth Factor Binding Protein 5) RN - 0 (Recombinant Proteins) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - AIM SB - IM MH - Breast Neoplasms MH - Female MH - Humans MH - Insulin-Like Growth Factor Binding Protein 1/pharmacology MH - Insulin-Like Growth Factor Binding Protein 3/*pharmacology MH - Insulin-Like Growth Factor Binding Protein 5/pharmacology MH - Insulin-Like Growth Factor I/analogs & derivatives/*pharmacology MH - Phosphorylation MH - Protein-Tyrosine Kinase/metabolism MH - Receptor, IGF Type 1/drug effects/*metabolism MH - Recombinant Proteins/pharmacology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured EDAT- 2001/01/06 11:00 MHDA- 2001/03/07 10:01 PST - ppublish SO - Endocrinology 2001 Jan;142(1):108-13. -------------------------------------------------------------------------------- 129: Lingohr MK et al. Effects of dichloroacetate (D...[PMID: 11134557] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11134557 OWN - NLM STAT- MEDLINE DA - 20010126 DCOM- 20010222 LR - 20050111 PUBM- Print IS - 1096-6080 VI - 59 IP - 1 DP - 2001 Jan TI - Effects of dichloroacetate (DCA) on serum insulin levels and insulin-controlled signaling proteins in livers of male B6C3F1 mice. PG - 178-84 AB - DCA is hepatocarcinogenic in rodents. At carcinogenic doses, DCA causes a large accumulation of liver glycogen. Thus, we studied the effects of DCA treatment on insulin levels and expression of insulin-controlled signaling proteins in the liver. DCA treatment (0.2-2.0 g/l in drinking water for 2 weeks) reduced serum insulin levels. The decrease persisted for at least 8 weeks. In livers of mice treated with DCA for 2-, 10-, and 52-week periods, insulin receptor (IR) protein levels were significantly depressed. Additionally, protein kinase B (PKBalpha) expression decreased significantly with DCA treatment. In normal liver, glycogen levels were increased as early as at 1 week, and this effect preceded changes in insulin and IR and PKBalpha. In contrast to normal liver, IR protein was elevated in DCA-induced liver tumors relative to that in liver tissue of untreated animals and to an even greater extent when compared to adjacent normal liver in the treated animal. Mitogen-activated protein kinase (MAP kinase) phosphorylation was also increased in tumor tissue relative to normal liver tissue and tissue from untreated controls. These data suggest that normal hepatocytes down-regulate insulin-signaling proteins in response to the accumulation of liver glycogen caused by DCA. Furthermore, these results suggest that the initiated cell population, which does not accumulate glycogen and is promoted by DCA treatment, responds differently from normal hepatocytes to the insulin-like effects of this chemical. The differential sensitivity of the 2 cell populations may contribute to the tumorigenic effects of DCA in the liver. AD - Washington State University, Pullman, Washington 99164-6510, USA. FAU - Lingohr, M K AU - Lingohr MK FAU - Thrall, B D AU - Thrall BD FAU - Bull, R J AU - Bull RJ LA - eng PT - Journal Article PL - United States TA - Toxicol Sci JID - 9805461 RN - 0 (Carcinogens) RN - 0 (Proto-Oncogene Proteins) RN - 11061-68-0 (Insulin) RN - 13425-80-4 (Dichloroacetate) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - Animals MH - Blotting, Western MH - Carcinogens/*toxicity MH - Dichloroacetate/*toxicity MH - Hepatocytes/drug effects/metabolism MH - Insulin/*blood MH - Liver/*drug effects/metabolism MH - Liver Neoplasms/chemically induced/metabolism MH - Male MH - Mice MH - Mice, Inbred Strains MH - Mitogen-Activated Protein Kinases/metabolism MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - Receptor, Insulin/metabolism MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Signal Transduction EDAT- 2001/01/03 11:00 MHDA- 2001/03/03 10:01 PST - ppublish SO - Toxicol Sci 2001 Jan;59(1):178-84. -------------------------------------------------------------------------------- 130: Nguyen KT et al. Differential requirements of ...[PMID: 11103940] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11103940 OWN - NLM STAT- MEDLINE DA - 20001204 DCOM- 20010125 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 19 IP - 47 DP - 2000 Nov 9 TI - Differential requirements of the MAP kinase and PI3 kinase signaling pathways in Src- versus insulin and IGF-1 receptors-induced growth and transformation of rat intestinal epithelial cells. PG - 5385-97 AB - There have been few studies on the specific signaling pathways involved in the transformation of epithelial cells by oncogenic protein tyrosine kinases. Here we investigate the requirement of MAP (MAPK) and phosphatidylinositol 3- (PI3K) kinases in the transformation of rat intestinal epithelial (RIE) cells by oncogenic forms of insulin receptor (gag-IR), insulin-like growth factor-1 receptor (gag-IGFR), and v-Src. MAPK is not significantly activated in cells transformed by gag-IR and gag-IGFR but is activated in v-Src transformed cells. Treatment with PD98059, a MEK inhibitor, at concentrations where MAPK activity was reduced below the basal level showed that MAPK is partially required for the monolayer growth of parental and transformed RIE cells. However, MAPK is not essential for the focus forming ability of the three oncogene-transformed cells. It is also not necessary for the colony forming ability of gag-IR- and gag-IGFR-, but is partially required for v-Src-transformed cells. PI3K is significantly activated in all three oncogene transformed RIE cells. LY294002, a PI3K inhibitor, potently inhibited monolayer growth of all three oncogene-transformed cells. However, at concentrations of LY294002 where activated forms of Akt, a downstream component of the PI3K pathway, were undetectable, colony and focus forming abilities of the v-Src-RIE cells were only slightly affected whereas those of gag-IR/IGFR-RIE cells were greatly inhibited. These results were confirmed using a different pharmacological inhibitor, wortmannin, and a dominant negative form of PI3K, Ap85. Similarly, rapamycin, known to inhibit p70S6 kinase, a downstream component of the PI3K-Akt pathway, also inhibited gag-IR/IGFR-induced, but not v-Src-induced, focus and colony formation. We conclude that the MAPK and PI3K signaling pathways are differentially required for transformation of RIE cells by oncogenic IR and IGFR versus Src and the pattern of requirements is different from that of fibroblast transformation. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029, USA. FAU - Nguyen, K T AU - Nguyen KT FAU - Wang, W J AU - Wang WJ FAU - Chan, J L AU - Chan JL FAU - Wang, L H AU - Wang LH LA - eng GR - CA55054/CA/NCI PT - Journal Article PL - ENGLAND TA - Oncogene JID - 8711562 RN - 0 (Androstadienes) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Morpholines) RN - 0 (PD 98059) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 19545-26-7 (wortmannin) RN - 53123-88-9 (Sirolimus) RN - EC 2.7.1.112 (Oncogene Protein pp60(v-src)) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism MH - Androstadienes/pharmacology MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/antagonists & inhibitors MH - Cell Division/drug effects MH - Cell Line, Transformed MH - *Cell Transformation, Neoplastic MH - Chromones/pharmacology MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Epithelial Cells/cytology MH - Flavonoids/pharmacology MH - Intestinal Mucosa/cytology MH - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism MH - Morpholines/pharmacology MH - Oncogene Protein pp60(v-src)/*genetics MH - Rats MH - Receptor, IGF Type 1/*genetics MH - Receptor, Insulin/*genetics MH - Research Support, U.S. Gov't, P.H.S. MH - Ribosomal Protein S6 Kinases/antagonists & inhibitors MH - *Signal Transduction MH - Sirolimus/pharmacology EDAT- 2000/12/05 11:00 MHDA- 2001/02/28 10:01 AID - 10.1038/sj.onc.1203911 [doi] PST - ppublish SO - Oncogene 2000 Nov 9;19(47):5385-97. -------------------------------------------------------------------------------- 131: Schnarr B et al. Down-regulation of insulin-li...[PMID: 11102895] Related Articles, Cited in PMC, Books, LinkOut PMID- 11102895 OWN - NLM STAT- MEDLINE DA - 20001213 DCOM- 20001222 LR - 20041117 PUBM- Print IS - 0020-7136 VI - 89 IP - 6 DP - 2000 Nov 20 TI - Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. PG - 506-13 AB - The ligands, receptors and related signaling proteins of the insulin-like growth factor family are involved in the regulation of breast-cancer cell growth. We investigated the expression pattern of insulin-like growth factor-I receptor (IGF-IR), insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), a core downstream signaling protein, in 69 primary breast-cancer specimens of different grades and in 21 control tissues by immunohistochemistry. In addition, cell proliferation (percentage of Ki67(+) nuclei) and estrogen receptor (ER) expression were determined. IGF-IR, IRS-1 and IR were expressed mainly in epithelial cells. IRS-1 and IGF-IR were expressed at high levels in control tissues and in well and moderately differentiated carcinomas but at low levels in poorly differentiated breast cancers. IR expression did not show a significant correlation with the differentiation grade of the tissues investigated. Statistical analysis (ROC analysis for tumor grade) demonstrated that down-regulation of IGF-IR and IRS-1 correlated better with tumor progression than reduction of ER expression or increase in cell proliferation, IGF-IR showing the best correlation, followed by IRS-1 and, less significant, ER and Ki67. Our findings clearly show that progression of breast cancer is accompanied by a reduction of IGF-IR/IRS-1 expression and that IGF-IR/IRS-1 expression inversely correlates with high proliferation rate in dedifferentiated breast cancers. The strong correlation of IGF-IR and IRS-1 down-regulation with tumor progression suggests the use of IGF-IR and IRS-1 as a novel set of marker proteins for tumor grading. CI - Copyright 2000 Wiley-Liss, Inc. AD - Hormones and Signal Transduction Research Group, Deutsches Krebsforschungszentrum, Heidelberg, Germany. FAU - Schnarr, B AU - Schnarr B FAU - Strunz, K AU - Strunz K FAU - Ohsam, J AU - Ohsam J FAU - Benner, A AU - Benner A FAU - Wacker, J AU - Wacker J FAU - Mayer, D AU - Mayer D LA - eng PT - Journal Article PL - UNITED STATES TA - Int J Cancer JID - 0042124 RN - 0 (Phosphoproteins) RN - 0 (Receptors, Estrogen) RN - 0 (Tumor Markers, Biological) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Blotting, Western MH - Breast Neoplasms/*genetics/metabolism/pathology MH - Carcinoma, Ductal, Breast/genetics/metabolism/pathology MH - Carcinoma, Lobular/genetics/metabolism/pathology MH - Cell Division/physiology MH - Down-Regulation MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Middle Aged MH - Phosphoproteins/*biosynthesis/genetics MH - Receptor, IGF Type 1/*biosynthesis/genetics MH - Receptor, Insulin/biosynthesis/genetics MH - Receptors, Estrogen/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Tumor Markers, Biological/biosynthesis/genetics EDAT- 2000/12/05 11:00 MHDA- 2001/02/28 10:01 AID - 10.1002/1097-0215(20001120)89:6<506::AID-IJC7>3.0.CO;2-F [pii] PST - ppublish SO - Int J Cancer 2000 Nov 20;89(6):506-13. -------------------------------------------------------------------------------- 132: Zeng L et al. Vav3 mediates receptor protei...[PMID: 11094073] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 11094073 OWN - NLM STAT- MEDLINE DA - 20001213 DCOM- 20010111 LR - 20050223 PUBM- Print IS - 0270-7306 VI - 20 IP - 24 DP - 2000 Dec TI - Vav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformation. PG - 9212-24 AB - A recently reported new member of the Vav family proteins, Vav3 has been identified as a Ros receptor protein tyrosine kinase (RPTK) interacting protein by yeast two-hybrid screening. Northern analysis shows that Vav3 has a broad tissue expression profile that is distinct from those of Vav and Vav2. Two species of Vav3 transcripts, 3.4 and 5.4 kb, were detected with a differential expression pattern in various tissues. Transient expression of Vav in 293T and NIH 3T3 cells demonstrated that ligand stimulation of several RPTKs (epidermal growth factor receptor [EGFR], Ros, insulin receptor [IR], and insulin-like growth factor I receptor [IGFR]) led to tyrosine phosphorylation of Vav3 and its association with the receptors as well as their downstream signaling molecules, including Shc, Grb2, phospholipase C (PLC-gamma), and phosphatidylinositol 3 kinase. In vitro binding assays using glutathione S-transferase-fusion polypeptides containing the GTPase-binding domains of Rok-alpha, Pak, or Ack revealed that overexpression of Vav3 in NIH 3T3 cells resulted in the activation of Rac-1 and Cdc42 whereas a deletion mutant lacking the N-terminal calponin homology and acidic region domains activated RhoA and Rac-1 but lost the ability to activate Cdc42. Vav3 induced marked membrane ruffles and microspikes in NIH 3T3 cells, while the N-terminal truncation mutants of Vav3 significantly enhanced membrane ruffle formation but had a reduced ability to induce microspikes. Activation of IR further enhanced the ability of Vav3 to induce membrane ruffles, but IGFR activation specifically promoted Vav3-mediated microspike formation. N-terminal truncation of Vav3 activated its transforming potential, as measured by focus-formation assays. We conclude that Vav3 mediates RPTK signaling and regulates GTPase activity, its native and mutant forms are able to modulate cell morphology, and it has the potential to induce cell transformation. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. FAU - Zeng, L AU - Zeng L FAU - Sachdev, P AU - Sachdev P FAU - Yan, L AU - Yan L FAU - Chan, J L AU - Chan JL FAU - Trenkle, T AU - Trenkle T FAU - McClelland, M AU - McClelland M FAU - Welsh, J AU - Welsh J FAU - Wang, L H AU - Wang LH LA - eng GR - CA29339/CA/NCI GR - CA55054/CA/NCI PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Cell Cycle Proteins) RN - 0 (Culture Media, Serum-Free) RN - 0 (Plasmids) RN - 0 (Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Somatomedin) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (proto-oncogene protein c-vav) RN - EC 2.7.1.112 (ROS1 protein, human) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Ros1 protein, mouse) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.4.3 (Phospholipase C) RN - EC 3.6.1.- (rho GTP-Binding Proteins) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - 3T3 Cells MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Animals MH - Blotting, Northern MH - Blotting, Western MH - *Cell Cycle Proteins MH - Cell Line MH - *Cell Size MH - *Cell Transformation, Neoplastic MH - Culture Media, Serum-Free MH - Humans MH - Kidney/embryology MH - Mice MH - Phospholipase C/metabolism MH - Phosphorylation MH - Plasmids/genetics/metabolism MH - Precipitin Tests MH - Proteins/metabolism MH - Proto-Oncogene Proteins/genetics/*metabolism MH - Receptor Protein-Tyrosine Kinases/*metabolism MH - Receptors, Somatomedin/metabolism MH - Recombinant Fusion Proteins/genetics/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Two-Hybrid System Techniques MH - rho GTP-Binding Proteins/*metabolism EDAT- 2000/11/30 11:00 MHDA- 2001/02/28 10:01 PST - ppublish SO - Mol Cell Biol 2000 Dec;20(24):9212-24. -------------------------------------------------------------------------------- 133: De La Vega LA et al. Regulation of the insulin and...[PMID: 11078721] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11078721 OWN - NLM STAT- MEDLINE DA - 20001201 DCOM- 20010104 LR - 20041117 PUBM- Print IS - 0363-6143 VI - 279 IP - 6 DP - 2000 Dec TI - Regulation of the insulin and asialoglycoprotein receptors via cGMP-dependent protein kinase. PG - C2037-42 AB - Biotin regulation of asialoglycoprotein receptor expression and insulin receptor activity has been established in two human hepatoblastoma cell lines, Hep G2 and HuH-7. Second messenger cGMP mimics the effect of biotin on asialoglycoprotein receptor expression at the translational level. Metabolic labeling and subsequent immunoprecipitation indicate that the loss of insulin receptor activity during biotin deprivation was due to suppression of receptor synthesis. Evidence for posttranscriptional regulation of insulin receptor synthesis was provided by rapid biotin induction of receptor synthesis without an increase in gene transcript number. Addition of a cGMP-dependent protein kinase (cGK) inhibitor prevented biotin induction of the insulin and asialoglycoprotein receptors, suggesting that protein phosphorylation propagates the cGMP signal transduction cascade. Coatomer protein COPI was recently identified as the trans-acting factor that regulates in vitro translation of the asialoglycoprotein receptor. Biotin repletion of the culture medium resulted in the hyperphosphorylation of alpha-COP, which was prevented by simultaneous addition of the cGK inhibitor. These findings suggest that the end point of this cGMP signal cascade is modulated by cGK and that a phosphorylation reaction governs the expression of both receptor proteins. AD - Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. FAU - De La Vega, L A AU - De La Vega LA FAU - Stockert, R J AU - Stockert RJ LA - eng GR - DK-17702/DK/NIDDK GR - DK-32972/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Am J Physiol Cell Physiol JID - 100901225 RN - 0 (Asialoglycoprotein Receptor) RN - 0 (Coatomer Protein) RN - 0 (Receptors, Cell Surface) RN - 58-85-5 (Biotin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Cyclic GMP-Dependent Protein Kinases) SB - IM MH - Asialoglycoprotein Receptor MH - Biotin/pharmacology MH - Coatomer Protein/metabolism MH - Cyclic GMP-Dependent Protein Kinases/*metabolism MH - Gene Expression Regulation/drug effects/physiology MH - Hepatoblastoma MH - Humans MH - Liver Neoplasms MH - Phosphorylation MH - Protein Biosynthesis/drug effects/physiology MH - Receptor, Insulin/*genetics MH - Receptors, Cell Surface/*genetics MH - Research Support, U.S. Gov't, P.H.S. MH - Second Messenger Systems/drug effects/physiology MH - Signal Transduction/drug effects/physiology MH - Tumor Cells, Cultured EDAT- 2000/11/18 11:00 MHDA- 2001/02/28 10:01 PST - ppublish SO - Am J Physiol Cell Physiol 2000 Dec;279(6):C2037-42. -------------------------------------------------------------------------------- 134: Dey BR et al. Suppressor of cytokine signal...[PMID: 11071852] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11071852 OWN - NLM STAT- MEDLINE DA - 20001204 DCOM- 20010104 LR - 20041117 PUBM- Print IS - 0006-291X VI - 278 IP - 1 DP - 2000 Nov 11 TI - Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor. PG - 38-43 AB - SOCS proteins are a class of proteins that are negative regulators of cytokine receptor signaling via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. In a yeast two-hybrid screen of a human fetal brain library, we have previously identified SOCS-2 as a binding partner of the activated IGF-I receptor (IGFIR). To test whether or not SOCS-3 also binds to the IGFIR, we cloned human SOCS-3 by reverse transcription-polymerase chain reaction from human skeletal muscle mRNA. SOCS-3 mRNA was expressed in many human fetal and adult tissues and in some human cancer cell lines (Hela, A549 pulmonary adenocarcinoma and G361 human melanoma). We found that human SOCS-3 protein interacts directly with the cytoplasmic domains of the activated IGFIR and the insulin receptor (IR) in the yeast two-hybrid assay. In GST-SOCS-3 pull-down experiments using IGFIR from mammalian cells and in immunoprecipitation experiments in which IGFIR and FLAG-SOCS-3 were transiently expressed in human embryonic kidney 293 cells, we found that SOCS-3 interacts constitutively with IGFIR in vitro and in intact cells. Unlike SOCS-2, hSOCS-3 was phosphorylated on tyrosines in response to IGF-I addition to 293 cells. We conclude that SOCS-3 binds to the IGFIR and may be a direct substrate for the receptor tyrosine kinase. CI - Copyright 2000 Academic Press. AD - Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. FAU - Dey, B R AU - Dey BR FAU - Furlanetto, R W AU - Furlanetto RW FAU - Nissley, P AU - Nissley P LA - eng PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (DNA, Complementary) RN - 0 (Ligands) RN - 0 (Plasmids) RN - 0 (Proteins) RN - 0 (RNA, Messenger) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Repressor Proteins) RN - 0 (SOCS3 protein, human) RN - 0 (Transcription Factors) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.5.1.18 (Glutathione Transferase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Blotting, Northern MH - Brain/embryology/metabolism MH - Cell Line MH - Cloning, Molecular MH - Cytoplasm/metabolism MH - DNA, Complementary/metabolism MH - Electrophoresis, Polyacrylamide Gel MH - Gene Library MH - Glutathione Transferase/metabolism MH - Hela Cells MH - Humans MH - Insulin-Like Growth Factor I/pharmacology MH - Jurkat Cells MH - Ligands MH - Muscle, Skeletal/metabolism MH - Phosphorylation MH - Plasmids/metabolism MH - Precipitin Tests MH - Protein Binding MH - Protein Structure, Tertiary MH - Proteins/*genetics/*metabolism MH - RNA, Messenger/metabolism MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/metabolism MH - Recombinant Fusion Proteins/metabolism MH - *Repressor Proteins MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction MH - Tissue Distribution MH - *Transcription Factors MH - Tumor Cells, Cultured MH - Two-Hybrid System Techniques MH - Tyrosine/metabolism EDAT- 2000/11/10 11:00 MHDA- 2001/02/28 10:01 AID - 10.1006/bbrc.2000.3762 [doi] AID - S0006291X00937628 [pii] PST - ppublish SO - Biochem Biophys Res Commun 2000 Nov 11;278(1):38-43. -------------------------------------------------------------------------------- 135: Zhao YL et al. Differentially expressed gene...[PMID: 11062161] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11062161 OWN - NLM STAT- MEDLINE DA - 20001206 DCOM- 20001214 LR - 20041117 PUBM- Print IS - 0143-3334 VI - 21 IP - 11 DP - 2000 Nov TI - Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism. PG - 2005-10 AB - Although exposure to asbestos fibers is associated with the development of lung cancer, the underlying mechanism(s) remains unclear. Using human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells, we previously showed that UICC chrysotiles can malignantly transform these cells in a stepwise fashion before they become tumorigenic in nude mice. In the present study we used cDNA expression arrays to screen differentially expressed genes among the tumorigenic cells. A total of 15 genes were identified, 11 of which were further confirmed by northern blot. Expression levels of these genes were then determined among transformed BEP2D cells at different stages of the neoplastic process, including non-tumorigenic cells that were resistant to serum-induced terminal differentiation, early and late passage transformed BEP2D cells, five representative tumor cell lines and fused tumorigenic-control cell lines which were no longer tumorigenic. A consistent 2- to 3-fold down-regulation of the DCC (deleted in colon cancer), Ku70 and heat shock protein 27 genes were detected in all the independently generated tumor cell lines while expression levels in early transformants as well as in the fusion cell lines remained normal. In contrast, all the tumor cell lines examined demonstrated 2- to 4-fold overexpression of the insulin receptor and its signal transduction genes. Differential expression of these genes was completely restored in the fusion cell lines examined. No alteration in c-jun or EGF receptor expression was found in any of the cell lines. Our data suggest that activation of the insulin receptor pathway and inactivation of DCC and Ku70 may cooperate in malignant transformation of BEP2D cells induced by asbestos. AD - Center for Radiological Research, College of Physicians & Surgeons of Columbia University, VC11-218, 630 West 168th Street, New York, NY 10032, USA. FAU - Zhao, Y L AU - Zhao YL FAU - Piao, C Q AU - Piao CQ FAU - Wu, L J AU - Wu LJ FAU - Suzuki, M AU - Suzuki M FAU - Hei, T K AU - Hei TK LA - eng GR - ES 05786/ES/NIEHS GR - ES 07890/ES/NIEHS PT - Journal Article PL - ENGLAND TA - Carcinogenesis JID - 8008055 RN - 0 (Antigens, Nuclear) RN - 0 (Asbestos, Serpentine) RN - 0 (Cell Adhesion Molecules) RN - 0 (DNA-Binding Proteins) RN - 0 (Ku autoantigen) RN - 0 (Nuclear Proteins) RN - 0 (Saccharomyces cerevisiae Proteins) RN - 0 (Tumor Suppressor Proteins) RN - 0 (XRCC5 protein, human) RN - 0 (deleted in colorectal carcinoma protein) RN - 0 (high affinity DNA-binding factor, S cerevisiae) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (DNA-activated protein kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 5.99.- (DNA Helicases) SB - IM MH - Animals MH - *Antigens, Nuclear MH - Asbestos, Serpentine/*adverse effects MH - Blotting, Northern MH - Bronchi/drug effects/pathology/virology MH - Cell Adhesion Molecules/biosynthesis/genetics MH - Cell Fusion MH - Cell Line, Transformed MH - Cell Transformation, Neoplastic/drug effects/*genetics/metabolism MH - *DNA Helicases MH - DNA-Binding Proteins/biosynthesis/genetics MH - Down-Regulation MH - Epithelial Cells/drug effects/pathology/virology MH - *Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/*etiology/*genetics/metabolism MH - Male MH - Mice MH - Mice, Nude MH - Nuclear Proteins/biosynthesis/genetics MH - Oligonucleotide Array Sequence Analysis MH - Papillomavirus, Human MH - Phenotype MH - Protein-Serine-Threonine Kinases/biosynthesis/genetics MH - Receptor, Insulin/biosynthesis/genetics MH - Research Support, U.S. Gov't, P.H.S. MH - *Saccharomyces cerevisiae Proteins MH - *Tumor Suppressor Proteins EDAT- 2000/11/04 11:00 MHDA- 2001/02/28 10:01 PST - ppublish SO - Carcinogenesis 2000 Nov;21(11):2005-10. -------------------------------------------------------------------------------- 136: Zi X et al. Silibinin up-regulates insuli...[PMID: 11059749] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11059749 OWN - NLM STAT- MEDLINE DA - 20001102 DCOM- 20001108 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 60 IP - 20 DP - 2000 Oct 15 TI - Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. PG - 5617-20 AB - Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention. AD - Lady Davis Research Institute of Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec, Canada. FAU - Zi, X AU - Zi X FAU - Zhang, J AU - Zhang J FAU - Agarwal, R AU - Agarwal R FAU - Pollak, M AU - Pollak M LA - eng PT - Journal Article PL - UNITED STATES TA - Cancer Res JID - 2984705R RN - 0 (Androgens) RN - 0 (Antineoplastic Agents) RN - 0 (Growth Inhibitors) RN - 0 (Insulin-Like Growth Factor Binding Protein 3) RN - 0 (Phosphoproteins) RN - 0 (Silymarin) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Androgens/physiology MH - Antineoplastic Agents/*pharmacology MH - Blotting, Western MH - Cell Division/drug effects MH - Comparative Study MH - Gene Expression Regulation, Neoplastic/drug effects MH - Growth Inhibitors/pharmacology MH - Humans MH - Insulin-Like Growth Factor Binding Protein 3/*biosynthesis/genetics/secretion MH - Insulin-Like Growth Factor I/antagonists & inhibitors/physiology MH - Male MH - Neoplasms, Hormone-Dependent/genetics/metabolism/pathology MH - Phosphoproteins/metabolism MH - Phosphorylation/drug effects MH - Prostatic Neoplasms/genetics/*metabolism/*pathology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/drug effects/physiology MH - Silymarin/*pharmacology MH - Tumor Cells, Cultured MH - Up-Regulation/drug effects EDAT- 2000/11/04 11:00 MHDA- 2001/02/28 10:01 PST - ppublish SO - Cancer Res 2000 Oct 15;60(20):5617-20. -------------------------------------------------------------------------------- 137: Schutt M et al. The HIV-1 protease inhibitor ...[PMID: 11043860] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11043860 OWN - NLM STAT- MEDLINE DA - 20010202 DCOM- 20010202 LR - 20041117 PUBM- Print IS - 0012-186X VI - 43 IP - 9 DP - 2000 Sep TI - The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells. PG - 1145-8 AB - AIMS/HYPOTHESIS: Patients treated with human immunodeficiency virus-1 protease inhibitors often develop impaired glucose tolerance or diabetes, most likely due to an induction of insulin resistance. We therefore investigated whether the protease inhibitor indinavir alters insulin signalling. METHODS: We incubated HepG2 cells for 48 h without or with indinavir (100 micromol/l). Subsequently 125I-insulin binding to the cells and the effects of insulin stimulation on insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-Thr308-phosphorylation were measured. RESULTS: In cells not exposed to indinavir, insulin (100 nmol/l) led to rapid increases of insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-phosphorylation during the first 75 s, followed by subsequent decreases. In indinavir-treated cells, these insulin-stimulated increases during the first 75 s were reduced by 30-60% and this was not associated with alterations in cell number or viability, insulin binding to the cells or cellular insulin-receptor substrate-1-content. CONCLUSION/INTERPRETATION: Effects of indinavir on initial insulin signalling could cause, or contribute to, the metabolic effects of human immunodeficiency virus-1 protease inhibitors. AD - Department of Internal Medicine I, Medical University of Lubeck, Germany. FAU - Schutt, M AU - Schutt M FAU - Meier, M AU - Meier M FAU - Meyer, M AU - Meyer M FAU - Klein, J AU - Klein J FAU - Aries, S P AU - Aries SP FAU - Klein, H H AU - Klein HH LA - eng PT - Journal Article PL - GERMANY TA - Diabetologia JID - 0006777 RN - 0 (HIV Protease Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin, iodo-) RN - 11061-68-0 (Insulin) RN - 150378-17-9 (Indinavir) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.4.23.- (HIV Protease) SB - IM MH - Carcinoma, Hepatocellular MH - Cell Survival/drug effects MH - HIV Protease/metabolism MH - HIV Protease Inhibitors/*pharmacology MH - Humans MH - Indinavir/*pharmacology MH - Insulin/analogs & derivatives/pharmacokinetics/*physiology MH - Kinetics MH - Liver Neoplasms MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Receptor, Insulin/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects/physiology MH - Tumor Cells, Cultured EDAT- 2000/10/24 11:00 MHDA- 2001/03/03 10:01 PST - ppublish SO - Diabetologia 2000 Sep;43(9):1145-8. -------------------------------------------------------------------------------- 138: Engelman JA et al. Tumor necrosis factor alpha-m...[PMID: 11043572] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11043572 OWN - NLM STAT- MEDLINE DA - 20010124 DCOM- 20010208 LR - 20041118 PUBM- Print IS - 0888-8809 VI - 14 IP - 10 DP - 2000 Oct TI - Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. PG - 1557-69 AB - Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. AD - Department of Molecular Pharmacology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA. FAU - Engelman, J A AU - Engelman JA FAU - Berg, A H AU - Berg AH FAU - Lewis, R Y AU - Lewis RY FAU - Lisanti, M P AU - Lisanti MP FAU - Scherer, P E AU - Scherer PE LA - eng GR - 1R01-DK55758/DK/NIDDK GR - T32-GM07288/GM/NIGMS GR - T32-GM07491/GM/NIGMS GR - etc. PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (PD 98059) RN - 0 (Phosphoproteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 17885-08-4 (Phosphoserine) RN - 21820-51-9 (Phosphotyrosine) RN - 22862-76-6 (Anisomycin) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.1.- (MAP Kinase Kinase 1) RN - EC 2.7.1.- (MAP Kinase Kinase 2) RN - EC 2.7.1.- (Map2k1 protein, mouse) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) SB - IM MH - 3T3 Cells MH - Adipocytes/cytology/*drug effects MH - Animals MH - Anisomycin/pharmacology MH - Cell Differentiation/*drug effects MH - Enzyme Inhibitors/*pharmacology MH - Epidermal Growth Factor/pharmacology MH - Flavonoids/pharmacology MH - Insulin/pharmacology MH - *Insulin Resistance MH - Kinetics MH - MAP Kinase Kinase 1 MH - MAP Kinase Kinase 2 MH - Mice MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/metabolism MH - Phosphoserine/metabolism MH - Phosphotyrosine/metabolism MH - Protein-Serine-Threonine Kinases/antagonists & inhibitors MH - Protein-Tyrosine Kinase/antagonists & inhibitors MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Tumor Necrosis Factor-alpha/*pharmacology EDAT- 2000/10/24 11:00 MHDA- 2001/03/03 10:01 PST - ppublish SO - Mol Endocrinol 2000 Oct;14(10):1557-69. -------------------------------------------------------------------------------- 139: Playford MP et al. Insulin-like growth factor 1 ...[PMID: 11035789] Related Articles, Gene, Substance via MeSH, UniGene, Nucleotide, Protein, OMIM, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 11035789 OWN - NLM STAT- MEDLINE DA - 20001128 DCOM- 20001128 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 97 IP - 22 DP - 2000 Oct 24 TI - Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. PG - 12103-8 AB - The insulin-like growth factor (IGF) type 1 receptor is required for growth, transformation, and protection from apoptosis. IGFs can enhance cell migration, which is known to be influenced via regulation of the E-cadherin/beta-catenin complex. We sought to investigate whether IGF-1 modulated the interaction between E-cadherin and beta-catenin in human colorectal cancer cells. We used the C10 cell line, which we established and have previously shown to lack adenomatous polyposis coli, E-cadherin, or beta-catenin mutations. We found that IGF-1 stimulation enhanced tyrosine phosphorylation of two proteins, beta-catenin and insulin-receptor substrate 1, which formed a complex with E-cadherin. Tyrosine phosphorylation of beta-catenin was accompanied by rapid (<1 min) dissociation from E-cadherin at the plasma membrane, followed by relocation to the cellular cytoplasm. IGF-1 also enhanced the stability of beta-catenin protein. Despite this, we observed no enhancement of transcriptional activity in complex with T-cell factor 4 (Tcf-4) in human embryonic kidney 293 cells treated with IGF-1 or insulin alone. IGF-1 did, however, enhance transcriptional activity in combination with lithium chloride, an inhibitor of glycogen synthase kinase 3 beta, which also stabilizes beta-catenin. In conclusion, we have shown that IGF-1 causes tyrosine phosphorylation and stabilization of beta-catenin. These effects may contribute to transformation, cell migration, and a propensity for metastasis in vivo. AD - IGF Group, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom. FAU - Playford, M P AU - Playford MP FAU - Bicknell, D AU - Bicknell D FAU - Bodmer, W F AU - Bodmer WF FAU - Macaulay, V M AU - Macaulay VM LA - eng PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Cytoskeletal Proteins) RN - 0 (Receptors, Somatomedin) RN - 0 (Trans-Activators) RN - 146409-33-8 (beta catenin) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Cell Line MH - Colorectal Neoplasms/metabolism MH - Cytoskeletal Proteins/*physiology MH - Humans MH - Insulin-Like Growth Factor I/metabolism/*physiology MH - Receptors, Somatomedin/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - *Trans-Activators MH - Transcription, Genetic/*physiology MH - Tumor Cells, Cultured EDAT- 2000/10/18 11:00 MHDA- 2001/02/28 10:01 AID - 10.1073/pnas.210394297 [doi] AID - 210394297 [pii] PST - ppublish SO - Proc Natl Acad Sci U S A 2000 Oct 24;97(22):12103-8. -------------------------------------------------------------------------------- 140: Ge NL et al. Insulin-like growth factor I ...[PMID: 11023522] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11023522 OWN - NLM STAT- MEDLINE DA - 20001109 DCOM- 20001109 LR - 20050111 PUBM- Print IS - 0006-4971 VI - 96 IP - 8 DP - 2000 Oct 15 TI - Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. PG - 2856-61 AB - Multiple myeloma (MM) is an invariably fatal disease that accounts for approximately 1% to 2% of all human cancers. Surprisingly little is known about the cellular pathways contributing to growth of these tumors. Although the cytokine interleukin-6 has been suggested to be the major stimulus for myeloma cell growth, the role of a second potential growth factor, insulin-like growth factor I (IGF-I), has been less clearly defined. The IGF-I signaling cascade in 8 MM cell lines was examined. In 7 of these, the IGF-I receptor (IGF-IR) was expressed and autophosphorylated in response to ligand. Downstream of IGF-IR, insulin receptor substrate 1 was phosphorylated, leading to the activation of phosphatidylinositol-3'-kinase (PI-3K). PI-3K, in turn, regulated 2 distinct pathways. The first included Akt and Bad, leading to an inhibition of apoptosis; the second included the mitogen-activated protein kinase (MAPK), resulting in proliferation. Biologic relevance of this pathway was demonstrated because in vitro IGF-I induced both an antiapoptotic and a proliferative effect. Importantly, in vivo administration of IGF-I in SCID mice inoculated with the OPM-2 line led to approximately twice the growth rate of tumor cells as in controls. These results suggest that IGF-I activates at least 2 pathways effecting myeloma cell growth and contributes significantly to expansion of these cells in vivo. (Blood. 2000;96:2856-2861) AD - Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. FAU - Ge, N L AU - Ge NL FAU - Rudikoff, S AU - Rudikoff S LA - eng PT - Journal Article PL - UNITED STATES TA - Blood JID - 7603509 RN - 0 (Bad protein) RN - 0 (Carrier Proteins) RN - 0 (Interleukin-6) RN - 0 (MAP Kinase Signaling System) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/physiology MH - Animals MH - Apoptosis/drug effects MH - Carrier Proteins/physiology MH - Enzyme Activation/drug effects MH - Humans MH - Insulin-Like Growth Factor I/*physiology MH - Interleukin-6/physiology MH - MAP Kinase Signaling System/drug effects MH - Mice MH - Mice, SCID MH - Multiple Myeloma/pathology/*physiopathology MH - Neoplasm Proteins/*physiology MH - Neoplasm Transplantation MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Processing, Post-Translational MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/physiology MH - Receptor, IGF Type 1/*physiology MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured/transplantation EDAT- 2000/10/07 11:00 MHDA- 2001/02/28 10:01 PST - ppublish SO - Blood 2000 Oct 15;96(8):2856-61. -------------------------------------------------------------------------------- 141: Wu X et al. Expression of insulin-recepto...[PMID: 10973656] Related Articles, Books, LinkOut PMID- 10973656 OWN - NLM STAT- MEDLINE DA - 20001010 DCOM- 20001010 LR - 20041117 PUBM- Print IS - 0015-0282 VI - 74 IP - 3 DP - 2000 Sep TI - Expression of insulin-receptor substrate-1 and -2 in ovaries from women with insulin resistance and from controls. PG - 564-72 AB - OBJECTIVE: To evaluate the role of insulin-receptor substrate (IRS)-1 and -2 in ovary dysfunction in women with insulin resistance. DESIGN: Immunoblotting and immunohistochemical analyses of the localization and staining intensity of IRS-1 and IRS-2 in the ovaries of women with the polycystic ovary syndrome (PCOS) and gestational diabetes mellitus. SETTING: Department of Obstetrics and Gynecology, Turku University Central Hospital. PATIENT(S): Sections of ovary were obtained at the time of cesarean section from five volunteers without medical complications and three patients with gestational diabetes mellitus. Paraffin-embedded ovary sections were selected from those on file from the department of pathology; four were from women with a histologic diagnosis of PCOS and seven were from women with endometriosis (controls). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Protein expression of IRS in human ovary samples. RESULT(S): Immunoblotting with specific monoclonal and polyclonal antibodies showed the presence of 165-kDa and 183-kDa proteins that corresponded to the size of IRS-1 and IRS-2, respectively, in normal pregnant ovaries and human cultured follicles. Immunohistochemical staining showed that positive IRS-2 expression in antral follicles was restricted to theca internal cells in ovulatory ovaries but was distributed widely in all compartments of follicles in different stages in polycystic ovaries. Compared with follicles at a similar stage of development in ovulatory ovaries, follicles in polycystic ovaries showed decreased staining for IRS-1 in granulosa cells but increased staining for IRS-2 in theca internal cells. These features of IRS-1 and -2 expression were also noted in preantral and atretic follicles from patients with gestational diabetes mellitus compared with those who had uncomplicated pregnancy. CONCLUSION(S): This study highlights a shift of the follicular insulin signal protein from IRS-1 to IRS-2 in insulin-resistant states and suggests an association between this change and ovarian abnormality in PCOS and gestational diabetes mellitus. AD - Department of Obstetrics and Gynecology, University Central Hospital of Turku, Turku, Finland. xiaoke.wu@utu.fi FAU - Wu, X AU - Wu X FAU - Sallinen, K AU - Sallinen K FAU - Anttila, L AU - Anttila L FAU - Makinen, M AU - Makinen M FAU - Luo, C AU - Luo C FAU - Pollanen, P AU - Pollanen P FAU - Erkkola, R AU - Erkkola R LA - eng PT - Journal Article PL - UNITED STATES TA - Fertil Steril JID - 0372772 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) SB - IM CIN - Fertil Steril. 2001 Oct;76(4):855-6. PMID: 11680438 MH - Adult MH - Cells, Cultured MH - Diabetes, Gestational/metabolism MH - Electrophoresis, Polyacrylamide Gel MH - Female MH - Humans MH - *Insulin Resistance MH - Molecular Weight MH - Oligomenorrhea/complications/metabolism MH - Ovary/*metabolism/pathology MH - Phosphoproteins/*biosynthesis MH - Polycystic Ovary Syndrome/complications/metabolism MH - Pregnancy EDAT- 2000/09/26 11:00 MHDA- 2000/10/14 11:01 AID - S0015028200006889 [pii] PST - ppublish SO - Fertil Steril 2000 Sep;74(3):564-72. -------------------------------------------------------------------------------- 142: Hennige AM et al. Ret oncogene signal transduct...[PMID: 11000521] Related Articles, Books, LinkOut PMID- 11000521 OWN - NLM STAT- MEDLINE DA - 20001102 DCOM- 20001115 LR - 20050119 PUBM- Print IS - 0303-7207 VI - 167 IP - 1-2 DP - 2000 Sep 25 TI - Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cells. PG - 69-76 AB - Multiple endocrine neoplasia 2A (MEN 2A) is an inherited disease caused by mutations of the Ret proto-oncogene. Although many different Ret mutations have been described, little is known about the signaling pathways triggered by the Ret oncogene. In this study, we have determined the signaling properties of a Ret-9bp duplication encoding amino acids 634-636, which was recently identified in a patient with all clinical features of the MEN 2A syndrome. The Ret-9bp duplication leads to constitutive activation of the Ret tyrosine kinase. Furthermore, Ret-9bp increased mitogenic and transforming activity demonstrated by thymidine incorporation as well as colony formation in soft agar. Studying intracellular signaling pathways, which may be involved in malignant transformation of Ret-9bp expressing NIH3T3 cells, we could demonstrate Ret-9bp dependent phosphorylation of insulin receptor substrate-2 (IRS-2) with consecutive activation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (PKB/AKT). Moreover, Ret-9bp induces phosphorylation of SHC resulting in growth factor receptor binding protein-2 (Grb-2) binding and activation of the mitogen activating protein (MAP) kinase pathway. In addition to these postreceptor cytoplasmic signaling events, we have studied nuclear signal by Ret-9bp and found activation of c-jun and jun-D, two members of the jun/AP-1 family of transcription factors. In summary, an oncogenic 9bp duplication of Ret causes Ret dimer formation and ligand independent activation of the tyrosine kinase. Besides the signaling steps leading to MAPK activation, we could demonstrate that Ret-9bp induced constitutive activation of a signaling pathway involving IRS-2, PI 3-kinase and PKB/AKT which could transduce the oncogenic Ret signal to increased gene transcription via activation of the jun/AP-1 transcription factor family. AD - Medizinische Klinik und Poliklinik, Universitat Tubingen, Abt. Innere 4, Otfried-Muller-Str. 10, D-72076, Tubingen, Germany. FAU - Hennige, A M AU - Hennige AM FAU - Lammers, R AU - Lammers R FAU - Arlt, D AU - Arlt D FAU - Hoppner, W AU - Hoppner W FAU - Strack, V AU - Strack V FAU - Niederfellner, G AU - Niederfellner G FAU - Seif, F J AU - Seif FJ FAU - Haring, H U AU - Haring HU FAU - Kellerer, M AU - Kellerer M LA - eng PT - Journal Article PL - IRELAND TA - Mol Cell Endocrinol JID - 7500844 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Drosophila Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Proto-Oncogene Proteins c-jun) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-2 protein) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Ret oncogene protein, Drosophila) RN - EC 2.7.1.112 (proto-oncogene protein c-ret) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/*metabolism MH - 3T3 Cells MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Amino Acid Motifs MH - Animals MH - Blotting, Western MH - Cell Transformation, Neoplastic MH - *Drosophila Proteins MH - Enzyme Induction MH - Humans MH - Mice MH - Multiple Endocrine Neoplasia Type 2a/genetics MH - Mutation MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Protein-Serine-Threonine Kinases/metabolism MH - Proteins/*metabolism MH - Proto-Oncogene Proteins/biosynthesis/*genetics/*metabolism MH - Proto-Oncogene Proteins c-jun/metabolism MH - Receptor Protein-Tyrosine Kinases/biosynthesis/*genetics/metabolism MH - Receptor, Epidermal Growth Factor/metabolism MH - *Signal Transduction MH - Transfection MH - src Homology Domains EDAT- 2000/09/23 11:00 MHDA- 2001/02/28 10:01 AID - S0303720700002835 [pii] PST - ppublish SO - Mol Cell Endocrinol 2000 Sep 25;167(1-2):69-76. -------------------------------------------------------------------------------- 143: Jaffiol C et al. [Insulin resistance: from cli...[PMID: 10987057] Related Articles, Books, LinkOut PMID- 10987057 OWN - NLM STAT- MEDLINE DA - 20000928 DCOM- 20000928 LR - 20041117 PUBM- Print IS - 0001-4079 VI - 183 IP - 9 DP - 1999 TI - [Insulin resistance: from clinical diagnosis to molecular genetics. Implications in diabetes mellitus] PG - 1761-75; discussion 1775-7 AB - Insulin resistance is observed in several diseases such as non insulin dependent diabetes mellitus (NIDDM) or polycystic ovarian syndrome (PCOS). To understand genetic determinism of this abnormality we have developed a multidisciplinary approach including selection of phenotypes with insulin resistance confirmed in vivo by minimal model of Bergman and characterization of cellular defects in insulin action on circulating erythrocytes and monocytes. Exploration of variability in candidate genes by direct sequencing in some genetic syndromes of severe insulin resistance and acanthosis nigricans (mainly the Type A syndrome) revealed mutations of the insulin receptor gene associated with major defects in insulin binding or kinase activity. In other rare genetic syndromes or patients affected by NIDDM or PCOS defects appear to be located at post-receptor level, where IRS (insulin receptor substrate) genes are the most attractive candidates. Prevalence of some allelic variants suggested a potential role of IRS genes in insulin resistance, although their involvement in the pathogenesis of NIDDM remains controversial. Genotype-phenotype correlations in first degree relatives of an index case caring the Type A syndrome, suggested that association of allelic variants of IRS-1 and IRS-2 with insulin receptor mutations contribute, by synergistic effects, to phenotypic expression of defects in signal transduction. These mechanisms through genetic epistasis, involving several genes in insulin action, fit better with the polygenic nature of current forms of NIDDM and represent a good model in the study of pathogenesis of insulin resistance. AD - Laboratoire d'Endocrinologie Moleculaire, Institut Universitaire de Recherche Clinique (IURC), Montpellier, France. FAU - Jaffiol, C AU - Jaffiol C FAU - Rouard, M AU - Rouard M FAU - Macari, F AU - Macari F FAU - Lautier, C AU - Lautier C FAU - Ait el Mkadem, S AU - Ait el Mkadem S FAU - Mechaly, I AU - Mechaly I FAU - Brun, J F AU - Brun JF FAU - Renard, E AU - Renard E FAU - Cros, G AU - Cros G FAU - Bringer, J AU - Bringer J FAU - Grigorescu, F AU - Grigorescu F LA - fre PT - Journal Article PT - Review PT - Review, Tutorial TT - La resistance a l'insuline: du diagnostic clinique a la genetique moleculaire. Implications dans le diabete sucre. PL - FRANCE TA - Bull Acad Natl Med JID - 7503383 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Acanthosis Nigricans/genetics MH - Amino Acid Substitution MH - Animals MH - Diabetes Mellitus, Type 2/*genetics/*metabolism MH - English Abstract MH - Epistasis, Genetic MH - Female MH - Humans MH - Insulin Resistance/*genetics/physiology MH - Models, Genetic MH - Phosphoproteins/genetics/metabolism MH - Point Mutation MH - Polycystic Ovary Syndrome/genetics MH - Receptor, Insulin/*genetics/metabolism RF - 38 EDAT- 2000/09/15 11:00 MHDA- 2000/09/30 11:01 PST - ppublish SO - Bull Acad Natl Med 1999;183(9):1761-75; discussion 1775-7. -------------------------------------------------------------------------------- 144: Li W et al. Activation of insulin-like gr...[PMID: 10919668] Related Articles, Books, LinkOut PMID- 10919668 OWN - NLM STAT- MEDLINE DA - 20000824 DCOM- 20000824 LR - 20031114 PUBM- Print IS - 0008-5472 VI - 60 IP - 14 DP - 2000 Jul 15 TI - Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth. PG - 3909-15 AB - Plasma cell neoplasia in humans generally occurs as multiple myeloma, an incurable form of cancer. Tumors with marked similarity can be induced in mice by a variety of agents, including chemicals, silicone, and oncogene-containing retroviruses, suggesting the use of murine tumors as an informative model to study plasma cell disease. Herein, we have focused on the role of insulin-like growth factor I receptor (IGF-IR) signaling in the development of plasma cell disease. The insulin receptor substrate 2/phosphatidylinositol 3'-kinase/p70S6K pathway was found to be either constitutively or IGF-I-dependently activated in all plasma cell tumors. Biological relevance was demonstrated in that plasma cell lines with up-regulated IGF-IR expression levels exhibited mitogenic responses to IGF-I. More importantly, expression of a dominant-negative mutant of IGF-IR in these lines strongly suppressed tumorigenesis in vivo. Taken together, these results demonstrate that up-regulation and activation of IGF-IR and the downstream signaling pathway involving insulin receptor substrate 2, phosphatidylinositol 3'-kinase, and p70S6K may play an important role in the development of a broad spectrum of plasma cell tumors. AD - Department of Oncology/Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA. wwl@gunet.georgetown.edu FAU - Li, W AU - Li W FAU - Hyun, T AU - Hyun T FAU - Heller, M AU - Heller M FAU - Yam, A AU - Yam A FAU - Flechner, L AU - Flechner L FAU - Pierce, J H AU - Pierce JH FAU - Rudikoff, S AU - Rudikoff S LA - eng PT - Journal Article PL - UNITED STATES TA - Cancer Res JID - 2984705R RN - 0 (Culture Media, Serum-Free) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (insulin receptor substrate-2 protein) RN - EC 2.7.1.112 (Proto-Oncogene Proteins c-abl) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Proto-Oncogene Proteins c-raf) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Animals MH - Culture Media, Serum-Free MH - Enzyme Activation MH - Female MH - Immunoblotting MH - Lymphoma, B-Cell/metabolism MH - Mice MH - Mice, Inbred BALB C MH - Neoplasm Transplantation MH - Neoplasms, Experimental/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Plasmacytoma/chemically induced/*metabolism MH - Precipitin Tests MH - Proto-Oncogene Proteins c-abl/metabolism MH - Proto-Oncogene Proteins c-myc/metabolism MH - Proto-Oncogene Proteins c-raf/metabolism MH - Receptor, IGF Type 1/*metabolism/*physiology MH - Ribosomal Protein S6 Kinases/metabolism MH - Signal Transduction MH - Time Factors MH - Transfection MH - Tumor Cells, Cultured MH - Up-Regulation EDAT- 2000/08/05 11:00 MHDA- 2000/08/29 11:01 PST - ppublish SO - Cancer Res 2000 Jul 15;60(14):3909-15. -------------------------------------------------------------------------------- 145: Jiang H et al. IL-4/IL-13 signaling beyond J...[PMID: 10856136] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10856136 OWN - NLM STAT- MEDLINE DA - 20000808 DCOM- 20000808 LR - 20050126 PUBM- Print IS - 0091-6749 VI - 105 IP - 6 Pt 1 DP - 2000 Jun TI - IL-4/IL-13 signaling beyond JAK/STAT. PG - 1063-70 AB - In the past several years, extensive studies on the mechanisms underlying IL-4 and IL-13 signaling have enabled us to gain insight into how these cytokines regulate immune responses. Because both IL-4 and IL-13 use the IL-4Ralpha as a receptor component, these cytokines activate many common signaling pathways. Both of these cytokines use Janus kinases (JAKs) to initiate signaling and activate signal transducer and activator of transcription-6 (STAT6), which is a transcription factor required for many of their biologic functions. In addition to JAK/STAT, these cytokines also activate a variety of other signaling molecules that are important in regulating IL-4-induced proliferation and protection from apoptosis. Suppressor of cytokine signaling-1 (SOCS-1) is a molecule that can inhibit the activation of IL-4 signaling through the inhibition of JAKs. The Fes tyrosine kinase is activated by IL-4 and appears to be important in regulating IL-4-induced proliferation through the phosphorylation of insulin receptor substrate (IRS) molecules. IRS molecules are essential for IL-4-induced proliferation through their ability to recruit phosphoinositol-3 kinase to the activated IL-4 receptor kinase. In addition, IL-4 can activate a number of phosphatases including SH2-containing inositol phosphatase (SHIP), SHP-1, and SHP-2. Finally, B-cell lymphoma gene-6 (BCL-6) appears to regulate a subset of IL-4-induced genes. Thus the biologic responses induced by IL-4/IL-13 require a complex interaction of signaling pathways and regulators. AD - Department of Medicine and Microbiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. FAU - Jiang, H AU - Jiang H FAU - Harris, M B AU - Harris MB FAU - Rothman, P AU - Rothman P LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - J Allergy Clin Immunol JID - 1275002 RN - 0 (Carrier Proteins) RN - 0 (Interleukin-13) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Receptors, Interleukin) RN - 0 (Receptors, Interleukin-4) RN - 0 (Repressor Proteins) RN - 0 (SOCS1 protein, human) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (interleukin-13 receptor) RN - 207137-56-2 (Interleukin-4) RN - EC 2.7.1.112 (Janus kinase 3) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) SB - AIM SB - IM MH - Carrier Proteins/pharmacology MH - Gene Expression Regulation/drug effects MH - Humans MH - Interleukin-13/*physiology MH - Interleukin-4/*physiology MH - *Intracellular Signaling Peptides and Proteins MH - Lymphoma, B-Cell/genetics MH - Phosphoric Monoester Hydrolases/pharmacology MH - Protein-Tyrosine Kinase/*physiology MH - Receptors, Interleukin/physiology MH - Receptors, Interleukin-4/physiology MH - *Repressor Proteins MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/genetics MH - Trans-Activators/*physiology RF - 89 EDAT- 2000/06/16 09:00 MHDA- 2000/08/12 11:00 AID - S0091674900452255 [pii] PST - ppublish SO - J Allergy Clin Immunol 2000 Jun;105(6 Pt 1):1063-70. -------------------------------------------------------------------------------- 146: Sanchez-Margalet V et al. Characterization of pancreast...[PMID: 10844119] Related Articles, Books, LinkOut PMID- 10844119 OWN - NLM STAT- MEDLINE DA - 20000815 DCOM- 20000815 LR - 20041117 PUBM- Print IS - 0014-2999 VI - 397 IP - 2-3 DP - 2000 Jun 2 TI - Characterization of pancreastatin receptor and signaling in rat HTC hepatoma cells. PG - 229-35 AB - Pancreastatin, a chromogranin A-derived peptide widely distributed throughout the neuroendocrine system, has a general inhibitory effect on endocrine secretion and a counterregulatory effect on insulin action. We have recently described the cross-talk of pancreastatin with insulin signaling in rat hepatoma cells (HTC), where it inhibits insulin action and signaling through the serine phosphorylation of the insulin receptor, thereby impairing tyrosine kinase activity. Here, we have characterized pancreastatin receptors and signaling in HTC cells. The pancreastatin effector systems were studied by determining phospholipase C activity in HTC membranes and mitogen-activated protein kinase (MAPK) phosphorylation activity in HTC cells. Binding studies with radiolabeled pancreastatin showed a population of high affinity binding sites, with a B(max) of 8 fmol/mg protein and a K(d) of 0.6 nM. Moreover, we assessed the coupling of the receptor with a G protein system by inhibiting the binding with guanine nucleotide and by measuring the GTP binding to HTC membranes. We found that pancreastatin receptor was coupled with a G alpha(q/11) protein which activates phospholipase C-beta(1) and phospholipase C-beta(3), in addition to MAPK via both beta gamma and alpha(q/11). AD - Departamento de Bioquimica Medica y Biologia Molecular, Facultad de Medicina, Unidad de Investigacion, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Av. Sanchez Pizjuan 4, 41009, Sevilla, Spain. vsanchez@cica.es FAU - Sanchez-Margalet, V AU - Sanchez-Margalet V FAU - Gonzalez-Yanes, C AU - Gonzalez-Yanes C FAU - Santos-Alvarez, J AU - Santos-Alvarez J FAU - Najib, S AU - Najib S LA - eng PT - Journal Article PL - NETHERLANDS TA - Eur J Pharmacol JID - 1254354 RN - 0 (MAP Kinase Signaling System) RN - 0 (Pancreatic Hormones) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (pancreatic polypeptide receptor) RN - 106477-83-2 (pancreastatin) RN - EC 3.1.4.3 (Phospholipase C) RN - EC 3.6.1.- (GTP-Binding Proteins) SB - IM MH - Animals MH - Binding, Competitive MH - Carcinoma, Hepatocellular/metabolism/pathology/*physiopathology MH - Cell Membrane/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Activation/drug effects MH - GTP-Binding Proteins/drug effects/metabolism MH - MAP Kinase Signaling System/drug effects MH - Pancreatic Hormones/metabolism/pharmacology MH - Phospholipase C/drug effects/metabolism MH - Protein Binding MH - Rats MH - Receptors, Gastrointestinal Hormone/metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Tumor Cells, Cultured EDAT- 2000/06/14 09:00 MHDA- 2000/08/19 11:00 AID - S0014299900002533 [pii] PST - ppublish SO - Eur J Pharmacol 2000 Jun 2;397(2-3):229-35. -------------------------------------------------------------------------------- 147: Valentinis B et al. Insulin receptor substrate-1,...[PMID: 10846175] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10846175 OWN - NLM STAT- MEDLINE DA - 20000921 DCOM- 20000921 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 275 IP - 33 DP - 2000 Aug 18 TI - Insulin receptor substrate-1, p70S6K, and cell size in transformation and differentiation of hemopoietic cells. PG - 25451-9 AB - After an initial burst of cell proliferation, the type 1 insulin-like growth factor receptor (IGF-IR) induces granulocytic differentiation of 32D IGF-IR cells, an interleukin-3-dependent murine hemopoietic cell line devoid of insulin receptor substrate-1 (IRS-1). The combined expression of the IGF-IR and IRS-1 (32D IGF-IR/IRS-1 cells) inhibits IGF-I-mediated differentiation, and causes malignant transformation of 32D cells. Because of the role of IRS-1 in changing the fate of 32D IGF-IR cells from differentiation (and subsequent cell death) to malignant transformation, we have looked for differences in IGF-IR signaling between 32D IGF-IR and 32D IGF-IR/IRS-1 cells. In this report, we have focused on p70(S6K), which is activated by the IRS-1 pathway. We find that the ectopic expression of IRS-1 and the inhibition of differentiation correlated with a sustained activation of p70(S6K) and an increase in cell size. Phosphorylation in vivo of threonine 389 and, to a lesser extent, of threonine 421/serine 424 of p70(S6K) seemed to be a requirement for inhibition of differentiation. A role of IRS-1 and p70(S6K) in the alternative between transformation or differentiation of 32D IGF-IR cells was confirmed by findings that inhibition of p70(S6K) activation or IRS-1 signaling, by rapamycin or okadaic acid, induced differentiation of 32D IGF-IR/IRS-1 cells. We have also found that the expression of myeloperoxidase mRNA (a marker of differentiation, which sharply increases in 32D IGF-IR cells), does not increase in 32D IGF-IR/IRS-1 cells, suggesting that the expression of IRS-1 in 32D IGF-IR cells causes the extinction of the differentiation program initiated by the IGF-IR, while leaving intact its proliferation program. AD - Kimmel Cancer Center and the Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Valentinis, B AU - Valentinis B FAU - Navarro, M AU - Navarro M FAU - Zanocco-Marani, T AU - Zanocco-Marani T FAU - Edmonds, P AU - Edmonds P FAU - McCormick, J AU - McCormick J FAU - Morrione, A AU - Morrione A FAU - Sacchi, A AU - Sacchi A FAU - Romano, G AU - Romano G FAU - Reiss, K AU - Reiss K FAU - Baserga, R AU - Baserga R LA - eng GR - CA 78890/CA/NCI GR - GM 33694/GM/NIGMS PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Culture Media, Serum-Free) RN - 0 (Enzyme Inhibitors) RN - 0 (Interleukin-3) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-1 protein) RN - 53123-88-9 (Sirolimus) RN - 72-19-5 (Threonine) RN - 78111-17-8 (Okadaic Acid) RN - EC 1.11.1.7 (Peroxidase) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) SB - IM MH - Animals MH - Antibiotics, Antineoplastic/pharmacology MH - Cell Cycle MH - Cell Differentiation MH - Cell Division MH - Cell Size MH - *Cell Transformation, Neoplastic MH - Culture Media, Serum-Free MH - Enzyme Activation/drug effects MH - Enzyme Inhibitors/pharmacology MH - Hematopoietic Stem Cells/*cytology MH - Humans MH - Interleukin-3/metabolism MH - Liver/pathology MH - Mice MH - Mice, Nude MH - Neoplasm Transplantation MH - Neoplasms, Experimental MH - Okadaic Acid/pharmacology MH - Peroxidase/metabolism MH - Phenotype MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - RNA, Messenger/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Ribosomal Protein S6 Kinases/*metabolism/physiology MH - Sirolimus/pharmacology MH - Spleen/pathology MH - Threonine/chemistry MH - Time Factors MH - Transfection MH - Tumor Cells, Cultured EDAT- 2000/06/10 09:00 MHDA- 2000/09/23 11:01 AID - 10.1074/jbc.M002271200 [doi] AID - M002271200 [pii] PST - ppublish SO - J Biol Chem 2000 Aug 18;275(33):25451-9. -------------------------------------------------------------------------------- 148: Sawka-Verhelle D et al. Stat 5B, activated by insulin...[PMID: 10830280] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10830280 OWN - NLM STAT- MEDLINE DA - 20000615 DCOM- 20000615 LR - 20041217 PUBM- Print IS - 0013-7227 VI - 141 IP - 6 DP - 2000 Jun TI - Stat 5B, activated by insulin in a Jak-independent fashion, plays a role in glucokinase gene transcription. PG - 1977-88 AB - Stat proteins are SH2 domain-containing transcription factors that are activated by various cytokines and growth factors. In a previous work, we have identified Stat 5B as a substrate of the insulin receptor based on yeast two-hybrid and mammalian cell transfection studies. In the present study, we have approached the biological relevance of the interaction between the insulin receptor and the transcription factor Stat 5B. Firstly, we show that both insulin and insulin-like growth factor I lead to tyrosine phosphorylation of Stat 5B, and this promotes binding of the transcription factor to the beta-casein promoter containing a Stat 5 binding site. Further, we demonstrate that insulin stimulates the transcriptional activity of Stat 5B. Activation of Stat 5B by insulin appears to be Jak2-independent, whereas Jak2 is required for GH-induced Stat 5B activation. Hence the pathway by which Stat 5B is activated by insulin is different from that used by GH. In addition, by using Jak1- and Tyk2-deficient cells we exclude the involvement of both Jak1 and Tyk2 in Stat 5B activation by insulin. Taken together, our results strengthen the notion that insulin receptor can directly activate Stat 5B. More importantly, we have identified a Stat 5 binding site in the human hepatic glucokinase promoter, and we show that insulin leads to a Stat 5B-dependent increase in transcription of a reporter gene carrying this promoter. These observations favor the idea that Stat 5B plays a role in mediating the expression of the glucokinase gene induced by insulin. As a whole, our results provide evidence for the occurrence of a newly identified circuit in insulin signaling in which the cell surface receptor is directly linked to nuclear events through a transcription factor. Further, we have revealed an insulin target gene whose expression is, at least in part, dependent on Stat 5B activation and/or binding. AD - Institut National de la Sante et de la Recherche Medicale U145, Nice, France. FAU - Sawka-Verhelle, D AU - Sawka-Verhelle D FAU - Tartare-Deckert, S AU - Tartare-Deckert S FAU - Decaux, J F AU - Decaux JF FAU - Girard, J AU - Girard J FAU - Van Obberghen, E AU - Van Obberghen E LA - eng PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (DNA-Binding Proteins) RN - 0 (Milk Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Stat5 protein) RN - 0 (Trans-Activators) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9007-49-2 (DNA) RN - EC 2.7.1.112 (Janus kinase 1) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.2 (Glucokinase) SB - AIM SB - IM MH - 3T3 Cells MH - Animals MH - Carcinoma, Hepatocellular/metabolism MH - DNA/metabolism MH - DNA-Binding Proteins/*physiology MH - Glucokinase/*genetics MH - Humans MH - Insulin/*pharmacology MH - Insulin-Like Growth Factor I/pharmacology MH - Liver/enzymology MH - Liver Neoplasms/metabolism MH - Mice MH - *Milk Proteins MH - Mutagenesis, Site-Directed MH - Phosphotyrosine/metabolism MH - Promoter Regions (Genetics) MH - Protein-Tyrosine Kinase/*physiology MH - *Proto-Oncogene Proteins MH - Research Support, Non-U.S. Gov't MH - Trans-Activators/*physiology MH - *Transcription, Genetic MH - Transfection MH - Tumor Cells, Cultured EDAT- 2000/06/01 09:00 MHDA- 2000/06/17 09:00 PST - ppublish SO - Endocrinology 2000 Jun;141(6):1977-88. -------------------------------------------------------------------------------- 149: Paz K et al. The juxtamembrane but not the...[PMID: 10828835] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10828835 OWN - NLM STAT- MEDLINE DA - 20000712 DCOM- 20000712 LR - 20050111 PUBM- Print IS - 0952-5041 VI - 24 IP - 3 DP - 2000 Jun TI - The juxtamembrane but not the carboxyl-terminal domain of the insulin receptor mediates insulin's metabolic functions in primary adipocytes and cultured hepatoma cells. PG - 419-32 AB - Insulin-stimulated signaling pathways are activated upon interactions between the intracellular domains of the receptor and its downstream effectors. Insulin receptor substrate proteins (IRS-1, -2, -3 and -4) are the best-studied substrates for the insulin receptor kinase (IRK). We have previously shown that IRS-1 and IRS-2 interact with the juxtamembrane (JM) but not with the carboxyl-terminal (CT) region of the insulin receptor (IR) in vitro. However, the precise role of these IR regions in mediating insulin's bioeffects is still unresolved. In the present work we made use of vaccinia virus as a vector for quantitative expression of the JM and CT domains within the cytoplasm of physiologically insulin-responsive primary rat adipocytes and rat hepatoma Fao cells. We could demonstrate that overexpression of either the JM or the CT domains did not inhibit either insulin binding or insulin-stimulated receptor autophosphorylation. In contrast, metabolic effects such as insulin-induced glucose utilization in adipocytes, and insulin-induced amino acid utilization in Fao hepatoma cells were inhibited (70-80%) in cells overexpressing the JM but not the CT domains of IR. The inhibitory effects of the overexpressed JM domain were accompanied by inhibition of insulin-stimulated IRS-1 phosphorylation, decreased IRS-1-associated PI3K activity, and decreased phosphorylation of the downstream effectors of PI3K, PKB and p70 S6K. Insulin-stimulated thymidine incorporation in Fao cells was also inhibited (40%) upon overexpression of the JM but not the CT region of IR. Our findings suggest that interactions between the JM region of IR and its downstream effectors are obligatory for insulin-stimulated metabolic functions in physiologically relevant insulin responsive cells. They also rule out the possibility that interaction of proteins, including PI3K, with the CT domain can provide an alternative pathway. AD - Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. FAU - Paz, K AU - Paz K FAU - Boura-Halfon, S AU - Boura-Halfon S FAU - Wyatt, L S AU - Wyatt LS FAU - LeRoith, D AU - LeRoith D FAU - Zick, Y AU - Zick Y LA - eng PT - Journal Article PL - ENGLAND TA - J Mol Endocrinol JID - 8902617 RN - 0 (Genetic Vectors) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 50-99-7 (Glucose) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Adipocytes/enzymology/*metabolism MH - Animals MH - Cells, Cultured MH - DNA Replication MH - Enzyme Activation MH - Genetic Vectors MH - Glucose/metabolism MH - Insulin/*metabolism MH - Liver Neoplasms, Experimental/*metabolism/pathology MH - Male MH - Phosphoproteins/metabolism MH - Phosphorylation MH - *Protein-Serine-Threonine Kinases MH - Proto-Oncogene Proteins/metabolism MH - Rats MH - Rats, Wistar MH - Receptor, Insulin/chemistry/*metabolism MH - Research Support, Non-U.S. Gov't MH - Ribosomal Protein S6 Kinases/metabolism MH - Tumor Cells, Cultured MH - Vaccinia virus/genetics EDAT- 2000/06/01 09:00 MHDA- 2000/07/15 11:00 AID - JME00870 [pii] PST - ppublish SO - J Mol Endocrinol 2000 Jun;24(3):419-32. -------------------------------------------------------------------------------- 150: Zhang H et al. Insulin-like growth factor I-...[PMID: 10811632] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10811632 OWN - NLM STAT- MEDLINE DA - 20000824 DCOM- 20000824 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 275 IP - 29 DP - 2000 Jul 21 TI - Insulin-like growth factor I-mediated degradation of insulin receptor substrate-1 is inhibited by epidermal growth factor in prostate epithelial cells. PG - 22558-62 AB - We have sought to determine whether insulin-like growth factor I (IGF-I) regulates the levels of insulin receptor substrate-1 (IRS-1) in prostate epithelial cells. Exposure of prostate epithelial cells to IGF-I in the absence of other growth factors leads to a reduction in IRS-1 levels. Ubiquitin content of IRS-1 is increased in the presence of IGF-I, and inhibitors of the proteasome prevented the reduction of IRS-1 levels seen following IGF-I exposure. These results imply that IRS-1 is targeted to the proteasome upon exposure to IGF-I. The addition of epidermal growth factor (EGF) maintained IRS-1 levels even in the presence of IGF-I and inhibits IGF-I-dependent ubiquitination of IRS-1. Thus, these two growth factors, IGF-I and EGF, had antagonistic effects on IRS-1 protein levels in prostate epithelial cells. This regulation of IRS-1 reveals a novel level of cross-talk between the IGF-I and EGF signal pathways, which may have implications in tumors that harbor activating mutations in the EGF receptor. AD - Lankenau Medical Research Center, Wynnewood, Pennsylvania 19096, USA. FAU - Zhang, H AU - Zhang H FAU - Hoff, H AU - Hoff H FAU - Sell, C AU - Sell C LA - eng GR - CA68923/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 62229-50-9 (Epidermal Growth Factor) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) SB - IM MH - Cells, Cultured MH - Epidermal Growth Factor/*metabolism/pharmacology MH - Epithelial Cells/*metabolism MH - Humans MH - Insulin-Like Growth Factor I/*metabolism MH - Male MH - Phosphoproteins/*metabolism MH - Prostate MH - Receptor Cross-Talk MH - Receptor, Epidermal Growth Factor/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects EDAT- 2000/05/16 09:00 MHDA- 2000/08/29 11:01 AID - 10.1074/jbc.M000412200 [doi] AID - M000412200 [pii] PST - ppublish SO - J Biol Chem 2000 Jul 21;275(29):22558-62. -------------------------------------------------------------------------------- 151: Sozen I et al. Hyperinsulinism and its inter...[PMID: 10804539] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10804539 OWN - NLM STAT- MEDLINE DA - 20000613 DCOM- 20000613 LR - 20041117 PUBM- Print IS - 0029-7828 VI - 55 IP - 5 DP - 2000 May TI - Hyperinsulinism and its interaction with hyperandrogenism in polycystic ovary syndrome. PG - 321-8 AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It has become increasingly evident that insulin resistance plays a significant role both as a cause and result of the syndrome. The purpose of this review is to summarize the possible mechanisms leading to insulin resistance and resultant hyperinsulinism (HI) and their interaction with hyperandrogenism (HA) in PCOS. We conducted a computerized search of MEDLINE for relevant studies in the English literature published between January 1966 and January 2000. We reviewed all studies that investigated the roles of insulin, insulin receptor, and insulin gene in insulin resistance and its interaction with hyperandrogenism in PCOS. Insulin resistance in PCOS seems to involve a postbinding defect in the insulin receptor and/or in the receptor signal transduction. Current research has focused on identifying a genetic predisposition for insulin resistance in this syndrome. The answer to the question whether HI or HA is the initiating event is still unclear inasmuch as there are clinical and molecular evidences to support both of these approaches. Our view is that whichever is the triggering insult, a vicious cycle is established where HI acts to aggravate HA and vice versa. In this model, obesity and genetic predisposition seem to be the independent factors that can give rise or contribute to HI, HA, or both simultaneously. It seems that "hyperinsulinemic hyperandrogenism" represents a significant subgroup of PCOS, which probably needs to be renamed and reclassified in the light of this new approach. AD - Owensboro Mercy Hospital, Kentucky, USA. FAU - Sozen, I AU - Sozen I FAU - Arici, A AU - Arici A LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Obstet Gynecol Surv JID - 0401007 RN - 58-22-0 (Testosterone) SB - IM MH - Animals MH - Female MH - Genetic Predisposition to Disease MH - Humans MH - Hyperandrogenism/complications/genetics/*physiopathology MH - Hyperinsulinism/complications/genetics/*physiopathology MH - Insulin Resistance/physiology MH - Obesity/complications/physiopathology MH - Polycystic Ovary Syndrome/complications/genetics/*physiopathology MH - Testosterone/physiology RF - 76 EDAT- 2000/05/11 09:00 MHDA- 2000/06/17 09:00 PST - ppublish SO - Obstet Gynecol Surv 2000 May;55(5):321-8. -------------------------------------------------------------------------------- 152: Kasus-Jacobi A et al. Evidence for an interaction b...[PMID: 10803466] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 10803466 OWN - NLM STAT- MEDLINE DA - 20000525 DCOM- 20000525 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 19 IP - 16 DP - 2000 Apr 13 TI - Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2. PG - 2052-9 AB - The molecular adapter Grb7 is likely to be implicated in the development of certain cancer types. In this study we show that Grb7 binds the insulin receptors, when they are activated and tyrosine phosphorylated. This interaction is documented by two-hybrid experiments, GST pull-down assays and in vivo coimmunoprecipitations. In addition, our results argue in favor of a preferential association between Grb7 and the insulin receptors when compared to other tyrosine kinase receptors like the EGF receptor, the FGF receptor and Ret. Interestingly, Grb7 is not a substrate of the insulin receptor tyrosine kinase activity. Grb7 binds the activated tyrosine kinase loop of the insulin receptors. Two domains of Grb7 are implicated in the insulin receptor binding: the SH2 domain and the PIR (phosphotyrosine interacting region). The role of these two domains in the interaction with the insulin receptor was already reported for Grb10 and Grb14, the other members of the Grb7 family of proteins. However, the relative importance of these domains varies, considering the receptor and the Grb protein. These differences should be a determinant of the specificity of the receptor tyrosine kinase-Grbs binding, and thus of the implication of Grb7/10/14 in signal transduction. AD - Endocrinologie Metabolisme et Developpement, CNRS, UPR 1524, Meudon, France. FAU - Kasus-Jacobi, A AU - Kasus-Jacobi A FAU - Bereziat, V AU - Bereziat V FAU - Perdereau, D AU - Perdereau D FAU - Girard, J AU - Girard J FAU - Burnol, A F AU - Burnol AF LA - eng SI - GENBANK/AF190121 PT - Journal Article PL - ENGLAND TA - Oncogene JID - 8711562 RN - 0 (Proteins) RN - 0 (Recombinant Fusion Proteins) RN - 149058-53-7 (growth factor receptor-bound protein-7) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Binding Sites MH - COS Cells/metabolism MH - Cloning, Molecular MH - Female MH - Kidney/metabolism MH - Liver/metabolism MH - Molecular Sequence Data MH - Mutation MH - Phosphorylation MH - Placenta/metabolism MH - Pregnancy MH - Proteins/*genetics/immunology/*metabolism MH - Rats MH - Receptor, Insulin/genetics/*metabolism MH - Recombinant Fusion Proteins/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Two-Hybrid System Techniques MH - Yeasts/genetics MH - src Homology Domains EDAT- 2000/05/10 09:00 MHDA- 2000/06/08 09:00 AID - 10.1038/sj.onc.1203469 [doi] PST - ppublish SO - Oncogene 2000 Apr 13;19(16):2052-9. -------------------------------------------------------------------------------- 153: Karas M et al. Lycopene interferes with cell...[PMID: 10798222] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10798222 OWN - NLM STAT- MEDLINE DA - 20000719 DCOM- 20000719 LR - 20041117 PUBM- Print IS - 0163-5581 VI - 36 IP - 1 DP - 2000 TI - Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. PG - 101-11 AB - Recent studies have shown that high insulin-like growth factor I (IGF-I) blood level is a risk factor in breast and prostate cancer. The aim of this study was to determine whether the mitogenic activity of IGF-I in mammary cancer cells can be reduced by the dietary carotenoid lycopene. The anticancer activity of lycopene, the major tomato carotenoid, has been suggested by in vitro, in vivo, and epidemiological studies. Growth stimulation of MCF7 mammary cancer cells by IGF-I was markedly reduced by physiological concentrations of lycopene. The inhibitory effects of lycopene on MCF7 cell growth were not accompanied by apoptotic or necrotic cell death, as determined by annexin V binding to plasma membrane and propidium iodide staining of nuclei in unfixed cells. Lycopene treatment markedly reduced the IGF-I stimulation of tyrosine phosphorylation of insulin receptor substrate 1 and binding capacity of the AP-1 transcription complex. These effects were not associated with changes in the number or affinity of IGF-I receptors, but with an increase in membrane-associated IGF-binding proteins, which were previously shown in different cancer cells to negatively regulate IGF-I receptor activation. The inhibitory effect of lycopene on IGF signaling was associated with suppression of IGF-stimulated cell cycle progression of serum-starved, synchronized cells. Moreover, in cells synchronized by mimosine treatment, lycopene delayed cell cycle progression after release from the mimosine block. Collectively, the above data suggest that the inhibitory effects of lycopene on MCF7 cell growth are not due to the toxicity of the carotenoid but, rather, to interference in IGF-I receptor signaling and cell cycle progression. AD - Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. yoav@bgumail.bgu.ac.il FAU - Karas, M AU - Karas M FAU - Amir, H AU - Amir H FAU - Fishman, D AU - Fishman D FAU - Danilenko, M AU - Danilenko M FAU - Segal, S AU - Segal S FAU - Nahum, A AU - Nahum A FAU - Koifmann, A AU - Koifmann A FAU - Giat, Y AU - Giat Y FAU - Levy, J AU - Levy J FAU - Sharoni, Y AU - Sharoni Y LA - eng PT - Journal Article PL - UNITED STATES TA - Nutr Cancer JID - 7905040 RN - 0 (Anticarcinogenic Agents) RN - 0 (Dyes) RN - 36-88-4 (Carotenoids) RN - 36015-30-2 (Propidium) RN - 502-65-8 (lycopene) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9007-49-2 (DNA) SB - IM MH - Anticarcinogenic Agents/*pharmacology MH - Breast Neoplasms/*metabolism/pathology MH - Carotenoids/*pharmacology MH - Cell Cycle/*drug effects MH - Cell Death/drug effects MH - Cell Division MH - DNA/analysis/biosynthesis MH - Dyes MH - Humans MH - Insulin-Like Growth Factor I/*metabolism/pharmacology MH - Propidium MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured EDAT- 2000/05/08 09:00 MHDA- 2000/07/25 11:00 AID - 10.1207/S15327914NC3601_14 [doi] PST - ppublish SO - Nutr Cancer 2000;36(1):101-11. -------------------------------------------------------------------------------- 154: Molloy CA et al. Insulin receptor substrate-1 ...[PMID: 10777546] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10777546 OWN - NLM STAT- MEDLINE DA - 20000602 DCOM- 20000602 LR - 20041118 PUBM- Print IS - 0021-9258 VI - 275 IP - 17 DP - 2000 Apr 28 TI - Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line. PG - 12565-71 AB - Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. The mechanism underlying the increased proliferation could involve the induction of components of the insulin-like growth factor signal transduction pathway by estrogen. In this study we have examined the regulation of the expression of insulin receptor substrate-1, a major intracellular substrate of the type I insulin-like growth factor receptor tyrosine kinase. Estradiol increased insulin receptor substrate-1 mRNA and protein levels at concentrations consistent with a mechanism involving the estrogen receptor. Insulin receptor substrate-1 was not induced significantly by the antiestrogens tamoxifen and ICI 182,780, but they inhibited the induction of insulin receptor substrate-1 by estradiol. Analysis of tyrosine-phosphorylated insulin receptor substrate-1 showed that the highest levels were found in cells stimulated by estradiol and insulin-like growth factor-I, whereas low levels were found in the absence of estradiol irrespective of whether type I insulin-like growth factor ligands were present. Insulin receptor substrate-2, -3, and -4 were not induced by estradiol. These results suggest that estrogens and antiestrogens may regulate cell proliferation by controlling insulin receptor substrate-1 expression, thereby amplifying or attenuating signaling through the insulin-like growth factor signal transduction pathway. AD - Department of Pathology, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP, United Kingdom. FAU - Molloy, C A AU - Molloy CA FAU - May, F E AU - May FE FAU - Westley, B R AU - Westley BR LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Estrogen Antagonists) RN - 0 (Estrogen Receptor Modulators) RN - 0 (Estrogens) RN - 0 (IRS3L protein, human) RN - 0 (IRS4 protein, human) RN - 0 (Irs4 protein, mouse) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 10540-29-1 (Tamoxifen) RN - 11061-68-0 (Insulin) RN - 50-28-2 (Estradiol) RN - 55520-40-6 (Tyrosine) RN - 63231-63-0 (RNA) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Blotting, Northern MH - Cell Division MH - Dose-Response Relationship, Drug MH - Estradiol/metabolism MH - Estrogen Antagonists/pharmacology MH - Estrogen Receptor Modulators/metabolism MH - Estrogens/metabolism/*physiology MH - Humans MH - Immunoblotting MH - Insulin/pharmacology MH - Phosphoproteins/*metabolism MH - Phosphorylation/drug effects MH - RNA/metabolism MH - Receptor, IGF Type 1/metabolism MH - Research Support, Non-U.S. Gov't MH - Tamoxifen/pharmacology MH - Time Factors MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - *Up-Regulation EDAT- 2000/04/25 09:00 MHDA- 2000/06/10 09:00 PST - ppublish SO - J Biol Chem 2000 Apr 28;275(17):12565-71. -------------------------------------------------------------------------------- 155: Nakajima K et al. Selective attenuation of meta...[PMID: 10764799] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 10764799 OWN - NLM STAT- MEDLINE DA - 20000816 DCOM- 20000816 LR - 20050111 PUBM- Print IS - 0021-9258 VI - 275 IP - 27 DP - 2000 Jul 7 TI - Selective attenuation of metabolic branch of insulin receptor down-signaling by high glucose in a hepatoma cell line, HepG2 cells. PG - 20880-6 AB - The effects of a high concentration of glucose on the insulin receptor-down signaling were investigated in human hepatoma (HepG2) cells in vitro to delineate the molecular mechanism of insulin resistance under glucose toxicity. Treatment of the cells with high concentrations of glucose (15-33 mm) caused phosphorylation of serine residues of the insulin receptor substrate 1 (IRS-1), leading to reduced electrophoretic mobility of it. The phosphorylation of IRS-1 with high glucose treatment was blocked only by protein kinase C (PKC) inhibitors. The high glucose treatment attenuated insulin-induced association of IRS-1 and phosphatidylinositol 3-kinase and insulin-stimulated phosphorylation of Akt. A metabolic effect of insulin, stimulation of glycogen synthesis, was also inhibited by the treatment. In contrast, insulin-induced association of Shc and Grb2 was not inhibited. Treatment of the cells with high glucose promoted the translocation of PKCepsilon and PKCdelta from the cytosol to the plasma membrane but not that of other PKC isoforms. Finally, PKCepsilon and PKCdelta directly phosphorylated IRS-1 under cell-free conditions. We conclude that a high concentration of glucose causes phosphorylation of IRS-1, leading to selective attenuation of metabolic signaling of insulin. PKCepsilon and PKCdelta are involved in the down-regulation of insulin signaling, and they may lie in a pathway regulating the phosphorylation of IRS-1. AD - Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. FAU - Nakajima, K AU - Nakajima K FAU - Yamauchi, K AU - Yamauchi K FAU - Shigematsu, S AU - Shigematsu S FAU - Ikeo, S AU - Ikeo S FAU - Komatsu, M AU - Komatsu M FAU - Aizawa, T AU - Aizawa T FAU - Hashizume, K AU - Hashizume K LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Isoenzymes) RN - 0 (Phosphoamino Acids) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 50-99-7 (Glucose) RN - 9005-79-2 (Glycogen) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein Kinase C) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Carcinoma, Hepatocellular MH - Down-Regulation/drug effects MH - Glucose/*pharmacology MH - Glycogen/biosynthesis MH - Humans MH - Isoenzymes/metabolism MH - Phosphoamino Acids/analysis MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Kinase C/metabolism MH - Protein-Serine-Threonine Kinases/metabolism MH - Proteins/metabolism MH - *Proto-Oncogene Proteins MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured EDAT- 2000/04/15 09:00 MHDA- 2000/08/19 11:00 AID - 10.1074/jbc.M905410199 [doi] AID - M905410199 [pii] PST - ppublish SO - J Biol Chem 2000 Jul 7;275(27):20880-6. -------------------------------------------------------------------------------- 156: Chang TL et al. Interleukin-4 mediates cell g...[PMID: 10744706] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10744706 OWN - NLM STAT- MEDLINE DA - 20000508 DCOM- 20000508 LR - 20041217 PUBM- Print IS - 0021-9258 VI - 275 IP - 14 DP - 2000 Apr 7 TI - Interleukin-4 mediates cell growth inhibition through activation of Stat1. PG - 10212-7 AB - Interleukin-4 (IL-4) activates Stat6 (signal transducer and activator of transcription 6) and plays multiple roles in regulation of the immune system. IL-4 also triggers phosphorylation of insulin receptor substrate (IRS), leading to stimulation of cell growth. Moreover, IL-4 inhibits proliferation of a variety of cells, but the molecular mechanism of its growth inhibitory effect is not understood. In this study, we demonstrated that IL-4 inhibited cell growth of colon carcinoma cell lines (HT29 and WiDr) but promoted cell growth of Burkitt's lymphoma cell lines (BL30 and BL41) in a dose-dependent manner. The growth inhibition was not dependent on Stat6 activation, because Stat6 was activated at similar levels in all cell lines in response to IL-4. Strikingly, IL-4 activated Stat1 in colon carcinoma cell lines but not in Burkitt's lymphoma cell lines. Therefore, these results suggest that IL-4 induced Stat1 activation, resulting in growth inhibition of colon carcinoma cell lines. Importantly, we present evidence that Stat1 is necessary for IL-4-mediated growth inhibition using Stat1-deficient and Stat1-reconstituted cells. The growth inhibitory effect of IL-4 was diminished in Stat1-deficient cells, whereas it was restored in Stat1-reconstituted cells. In addition, the expression of dominant-negative Stat1 in HT29 cells led to the loss of growth inhibition in response to IL-4. Taken together, our data suggest that IL-4 activates Stat1, leading to cell growth inhibition in colon cancer cells. Thus, this study demonstrates, for the first time, a molecular mechanism by which IL-4 inhibits cell growth. AD - Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520-8023, USA. FAU - Chang, T L AU - Chang TL FAU - Peng, X AU - Peng X FAU - Fu, X Y AU - Fu XY LA - eng GR - KO4AE01356/PHS GR - RO1AI34522/AI/NIAID GR - RO1GM55590/GM/NIGMS PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (DNA-Binding Proteins) RN - 0 (Recombinant Proteins) RN - 0 (Stat1 protein) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 207137-56-2 (Interleukin-4) RN - 50-89-5 (Thymidine) SB - IM MH - Animals MH - Burkitt Lymphoma MH - Cell Division/drug effects/*physiology MH - Colonic Neoplasms MH - DNA-Binding Proteins/*metabolism MH - Humans MH - Interleukin-4/*pharmacology MH - Mice MH - Recombinant Proteins/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Thymidine/metabolism MH - Trans-Activators/*metabolism MH - Transfection MH - Tumor Cells, Cultured EDAT- 2000/04/01 09:00 MHDA- 2000/05/16 09:00 PST - ppublish SO - J Biol Chem 2000 Apr 7;275(14):10212-7. -------------------------------------------------------------------------------- 157: Gingras S et al. Multiple signaling pathways m...[PMID: 10674396] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10674396 OWN - NLM STAT- MEDLINE DA - 20000525 DCOM- 20000525 LR - 20041217 PUBM- Print IS - 0888-8809 VI - 14 IP - 2 DP - 2000 Feb TI - Multiple signaling pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene expression in human breast cancer cells. PG - 229-40 AB - The 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in breast human cancer cell lines and in normal human mammary epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the signal transducer and activator of transcription-6 (Stat6)-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. In fact, we have shown that Stat6 was activated by IL-4 in all cell lines studied where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. The present study was designed to investigate the potential contribution of IRS proteins and their downstream targets to IL-4-induced 3beta-HSD type 1 gene expression. IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in ZR-75-1 human breast cancer cell lines. Moreover, insulin-like growth factor (IGF)-I and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2-domain-containing proteins such as the phosphatidylinositol (PI) 3-kinase. In this light, the inhibition of IL-4-induced 3beta-HSD expression by wortmannin and LY294002, two potent PI 3-kinase inhibitors, indicates the probable involvement of the PI 3-kinase signaling molecules in this response to IL-4. Furthermore, it has been suggested that the IRS proteins are part of the signaling complexes that lead to activation of the mitogen-activated protein (MAP) kinase by insulin; thus we investigated the potential role of the MAP kinase (MAPK) cascade in the IL-4 action. In ZR-75-1 cells, both the activation of MAPK by IL-4 and the IL-4-induced 3beta-HSD activity were completely blocked by PD98059, an inhibitor of MAPK activation. Wortmannin also blocked MAPK activation by IL-4, IGF-I, and insulin, suggesting that the MAPK cascade acts as a downstream effector of PI 3-kinases. To further understand the cross-talk between signaling pathways involved in IL-4 action, we investigated the possible involvement of protein kinase C (PKC). The potential role of PKC was suggested by the observation that the well known PKC activator phorbol-12-myristate-13-acetate (PMA) potentiated the IL-4-induced 3beta-HSD activity. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involved the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAPK-dependent signaling pathway. The inability of IGF-I, insulin, and PMA to stimulate 3beta-HSD expression by themselves in the absence of IL-4 makes obvious the absolute requirement of an IL-4-specific signaling molecule. Our findings thus suggest that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with the IL-4-specific transcription factor Stat6 to mediate the induction of 31beta-HSD type 1 gene expression in ZR-75-1 human breast cancer cells. AD - Medical Research Council Group in Molecular Endocrinology CHUL Research Center and Laval University, Quebec City, Canada. FAU - Gingras, S AU - Gingras S FAU - Cote, S AU - Cote S FAU - Simard, J AU - Simard J LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase) RN - 0 (Androstadienes) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Morpholines) RN - 0 (Multienzyme Complexes) RN - 0 (PD 98059) RN - 0 (Phosphoproteins) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 16561-29-8 (Tetradecanoylphorbol Acetate) RN - 19545-26-7 (wortmannin) RN - 207137-56-2 (Interleukin-4) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 1.1.1.145 (Progesterone Reductase) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 5.3.3.- (Steroid Isomerases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism MH - Androstadienes/pharmacology MH - Breast Neoplasms/drug therapy/*metabolism MH - Chromones/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Female MH - Flavonoids/pharmacology MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Insulin/metabolism/pharmacology MH - Insulin-Like Growth Factor I/metabolism/pharmacology MH - Interleukin-4/*metabolism/pharmacology MH - Mitogen-Activated Protein Kinase Kinases/metabolism MH - Morpholines/pharmacology MH - Multienzyme Complexes/drug effects/*genetics/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Progesterone Reductase/drug effects/*genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Steroid Isomerases/drug effects/*genetics/metabolism MH - Tetradecanoylphorbol Acetate/pharmacology MH - Trans-Activators/metabolism MH - Tumor Cells, Cultured EDAT- 2000/02/16 09:00 MHDA- 2000/06/08 09:00 PST - ppublish SO - Mol Endocrinol 2000 Feb;14(2):229-40. -------------------------------------------------------------------------------- 158: Lee AV et al. Insulin-like growth factor I-...[PMID: 10669726] Related Articles, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 10669726 OWN - NLM STAT- MEDLINE DA - 20000316 DCOM- 20000316 LR - 20041117 PUBM- Print IS - 0270-7306 VI - 20 IP - 5 DP - 2000 Mar TI - Insulin-like growth factor I-induced degradation of insulin receptor substrate 1 is mediated by the 26S proteasome and blocked by phosphatidylinositol 3'-kinase inhibition. PG - 1489-96 AB - Insulin receptor substrate 1 (IRS-1) is a critical adapter protein involved in both insulin and insulin-like growth factor (IGF) signaling. Due to the fact that alteration of IRS-1 levels can affect the sensitivity and response to both insulin and IGF-I, we examined the ability of each of these ligands to affect IRS-1 expression. IGF-I (10 nM) stimulation of MCF-7 breast cancer cells caused a transient tyrosine phosphorylation of IRS-1 that was maximal at 15 min and decreased thereafter. The decrease in tyrosine phosphorylation of IRS-1 was paralleled by an apparent decrease in IRS-1 levels. The IGF-mediated decrease in IRS-1 expression was posttranscriptional and due to a decrease in the half-life of the IRS-1 protein. Insulin (10 nM) caused tyrosine phosphorylation of IRS-1 but not degradation, whereas high concentrations of insulin (10 microM) resulted in degradation of IRS-1. IGF-I (10 nM) stimulation resulted in transient IRS-1 phosphorylation and extracellular signal-related kinase (ERK) activation. In contrast, insulin (10 nM) caused sustained IRS-1 phosphorylation and ERK activation. Inhibition of 26S proteasome activity by the use of lactacystin or MG132 completely blocked IGF-mediated degradation of IRS-1. Furthermore, coimmunoprecipitation experiments showed an association between ubiquitin and IRS-1 that was increased by treatment of cells with IGF-I. Finally, IGF-mediated degradation of IRS-1 was blocked by inhibition of phosphatidylinositol 3'-kinase activity but was not affected by inhibition of ERK, suggesting that this may represent a direct negative-feedback mechanism resulting from downstream IRS-1 signaling. We conclude that IGF-I can cause ligand-mediated degradation of IRS-1 via the ubiquitin-mediated 26S proteasome and a phosphatidylinositol 3'-kinase-dependent mechanism and that control of degradation may have profound effects on downstream activation of signaling pathways. AD - Division of Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78284-7884, USA. avlee@bcm.tmc.edu FAU - Lee, A V AU - Lee AV FAU - Gooch, J L AU - Gooch JL FAU - Oesterreich, S AU - Oesterreich S FAU - Guler, R L AU - Guler RL FAU - Yee, D AU - Yee D LA - eng GR - K01CA77674/CA/NCI GR - P50CA58183/CA/NCI GR - R01CA74285/CA/NCI GR - etc. PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.4.- (Peptide Hydrolases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - EC 3.4.99.- (ATP dependent 26S protease) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism MH - Animals MH - Cell Line MH - Enzyme Inhibitors/pharmacology MH - Insulin-Like Growth Factor I/*metabolism MH - Peptide Hydrolases/*metabolism MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - *Proteasome Endopeptidase Complex MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction/drug effects EDAT- 2000/02/12 09:00 MHDA- 2000/03/18 09:00 PST - ppublish SO - Mol Cell Biol 2000 Mar;20(5):1489-96. -------------------------------------------------------------------------------- 159: Baserga R et al. Differentiation and malignant...[PMID: 10629105] Related Articles, Substance via MeSH, Books, LinkOut PMID- 10629105 OWN - NLM STAT- MEDLINE DA - 20000202 DCOM- 20000202 LR - 20041117 PUBM- Print IS - 0730-2312 VI - Suppl 32-33 DP - 1999 TI - Differentiation and malignant transformation: two roads diverged in a wood. PG - 68-75 AB - Growth factors and their receptors are known to send at times contradictory signals, such as proliferation or differentiation. Recent developments in our knowledge of growth factor receptors and their signaling pathways have clarified the basis for this puzzling behavior. Separate domains of a receptor and/or the availability of specific substrates determine the fate of a cell stimulated by the same growth factor. In some models, the difference between malignant transformation and differentiation (leading to cell death) may depend on the presence or absence of a single agonist or antagonist molecule. The type 1 insulin-like growth factor receptor will serve as the paradigm for this review. J. Cell. Biochem. Suppls. 32/33:68-75, 1999. CI - Copyright 1999 Wiley-Liss, Inc. AD - Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. r_baserga@lac.jci.tju.edu FAU - Baserga, R AU - Baserga R FAU - Morrione, A AU - Morrione A LA - eng GR - CA78890/CA/NCI GR - GM33694/GM/NIGMS PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - J Cell Biochem JID - 8205768 RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Cell Differentiation/drug effects MH - Cell Division/drug effects MH - Cell Transformation, Neoplastic/*pathology MH - Hematopoietic System/cytology/drug effects MH - Humans MH - Insulin-Like Growth Factor I/pharmacology/*physiology MH - Receptor, IGF Type 1/genetics/*physiology MH - Receptor, Insulin/physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects RF - 35 EDAT- 2000/01/11 MHDA- 2000/01/11 00:01 AID - 10.1002/(SICI)1097-4644(1999)75:32+<68::AID-JCB9>3.0.CO;2-0 [pii] PST - ppublish SO - J Cell Biochem 1999;Suppl 32-33:68-75. -------------------------------------------------------------------------------- 160: Ito S et al. Human rhabdomyosarcoma cells ...[PMID: 10620325] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10620325 OWN - NLM STAT- MEDLINE DA - 20000209 DCOM- 20000209 LR - 20050129 PUBM- Print IS - 0003-9861 VI - 373 IP - 1 DP - 2000 Jan 1 TI - Human rhabdomyosarcoma cells retain insulin-regulated glucose transport activity through glucose transporter 1. PG - 72-82 AB - We evaluated the expression of glucose transporter (glut) isoforms and its function in RD cells, human rhabdomyosarcoma, which retain the potential to differentiate into muscle. Gluts 1, 3, and 4 were expressed in RD cells, as detected by reverse-transcription polymerase chain reaction and immunocytochemistry. Supraphysiological concentration (1 microM) of insulin treatment increased 2-deoxy glucose transport by up to 1.68-fold together with concomitant tyrosine phosphorylation of the insulin receptor beta subunit and of insulin receptor substrate 1. Suppression of glut 1 mRNA by 38% by antisense oligonucleotide transfection led to a reduction of basal and insulin-stimulated 2-deoxy glucose transport by 38 and 55%, respectively. Suppression of gluts 3 and 4 by antisense oligonucleotide transfection did not affect both basal and insulin-stimulated 2-deoxy glucose transport. Thus, glut 1 accounts for the major part of basal and insulin-stimulated glucose transport in RD cells. Next, we transfected expression vectors carrying human gluts 1 and 4 cDNAs into RD cells to add further support for the role of glut 1 in glucose transport. Overexpression of glut 1 stimulated basal and insulin-stimulated 2-deoxy glucose transport by 1.66- and 1.43-fold, respectively. Glut 4 overexpression did not affect basal and insulin-stimulated 2-deoxy glucose transport. Western blot analysis using glut 1 antibody showed that glut 1 was redistributed from intracellular membrane to plasma membrane. These observations support the notion that RD cells, with the potential to differentiate into muscle, retain insulin responsiveness. As human muscle cell lines are not available at this point, RD cells can serve as a useful alternative to human muscle for studies related to insulin signal transduction and glucose transport. CI - Copyright 2000 Academic Press. AD - Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. FAU - Ito, S AU - Ito S FAU - Nemoto, T AU - Nemoto T FAU - Satoh, S AU - Satoh S FAU - Sekihara, H AU - Sekihara H FAU - Seyama, Y AU - Seyama Y FAU - Kubota, S AU - Kubota S LA - eng PT - Journal Article PL - UNITED STATES TA - Arch Biochem Biophys JID - 0372430 RN - 0 (DNA Primers) RN - 0 (DNA, Complementary) RN - 0 (GLUT1 protein) RN - 0 (GLUT3 protein) RN - 0 (GLUT4 protein) RN - 0 (Monosaccharide Transport Proteins) RN - 0 (Muscle Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Oligonucleotides, Antisense) RN - 0 (RNA, Messenger) RN - 11061-68-0 (Insulin) RN - 146-72-5 (3-O-Methylglucose) RN - 154-17-6 (Deoxyglucose) RN - 50-99-7 (Glucose) SB - IM MH - 3-O-Methylglucose/metabolism MH - Base Sequence MH - Biological Transport, Active/drug effects MH - DNA Primers/genetics MH - DNA, Complementary/genetics MH - Deoxyglucose/metabolism MH - Gene Expression MH - Glucose/*metabolism MH - Humans MH - Immunohistochemistry MH - Insulin/*pharmacology MH - Monosaccharide Transport Proteins/chemistry/genetics/*metabolism MH - *Muscle Proteins MH - *Nerve Tissue Proteins MH - Oligonucleotides, Antisense/genetics MH - RNA, Messenger/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Reverse Transcriptase Polymerase Chain Reaction MH - Rhabdomyosarcoma/*metabolism MH - Transfection MH - Tumor Cells, Cultured EDAT- 2000/01/06 MHDA- 2000/01/06 00:01 AID - 10.1006/abbi.1999.1535 [doi] AID - S0003986199915357 [pii] PST - ppublish SO - Arch Biochem Biophys 2000 Jan 1;373(1):72-82. -------------------------------------------------------------------------------- 161: Storz P et al. Insulin selectively activates...[PMID: 10618497] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10618497 OWN - NLM STAT- MEDLINE DA - 20000210 DCOM- 20000210 LR - 20041217 PUBM- Print IS - 0014-5793 VI - 464 IP - 3 DP - 1999 Dec 31 TI - Insulin selectively activates STAT5b, but not STAT5a, via a JAK2-independent signalling pathway in Kym-1 rhabdomyosarcoma cells. PG - 159-63 AB - The STAT multigene family of transcriptional regulators conveys signals from several cytokines and growth factors upon phosphorylation by janus kinases (JAK). Activation of STAT5 is typically mediated by JAK2, but more recent data indicate a direct activation by the insulin receptor kinase. STAT5 exists in two closely homologous isoforms, STAT5a and b. We here describe the selective tyrosine phosphorylation of STAT5b in Kym-1 cells in response to insulin. Blocking insulin signalling by HNMPA-(AM)(3), an insulin receptor kinase inhibitor, resulted in the loss of insulin-induced STAT5b tyrosine phosphorylation, whereas the inhibition of JAK2 by the JAK selective inhibitor tyrphostin AG490 had no effect. By contrast, in the same cells, IFNgamma-induced STAT5b activation was JAK2-dependent, indicating that this signal pathway is functional in Kym-1 cells. We conclude from this rhabdomyosarcoma model that STAT5b, but not STAT5a is a direct target of the insulin receptor kinase. AD - Institute of Cell Biology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany. peter.storz@po.uni-stuttgart.de FAU - Storz, P AU - Storz P FAU - Doppler, H AU - Doppler H FAU - Pfizenmaier, K AU - Pfizenmaier K FAU - Muller, G AU - Muller G LA - eng PT - Journal Article PL - NETHERLANDS TA - FEBS Lett JID - 0155157 RN - 0 (DNA-Binding Proteins) RN - 0 (Milk Proteins) RN - 0 (Protein Isoforms) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Stat5 protein) RN - 0 (Trans-Activators) RN - 11061-68-0 (Insulin) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - DNA-Binding Proteins/*metabolism MH - Humans MH - Insulin/*pharmacology MH - *Milk Proteins MH - Phosphorylation MH - Protein Isoforms/*metabolism MH - Protein-Tyrosine Kinase/*metabolism MH - *Proto-Oncogene Proteins MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Rhabdomyosarcoma/enzymology/*metabolism/pathology MH - *Signal Transduction MH - Trans-Activators/*metabolism MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 2000/01/05 MHDA- 2000/01/05 00:01 AID - S0014579399016890 [pii] PST - ppublish SO - FEBS Lett 1999 Dec 31;464(3):159-63. -------------------------------------------------------------------------------- 162: Yau L et al. Insulin-like growth factor-I ...[PMID: 10583412] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10583412 OWN - NLM STAT- MEDLINE DA - 20000131 DCOM- 20000131 LR - 20041117 PUBM- Print IS - 0014-2956 VI - 266 IP - 3 DP - 1999 Dec TI - Insulin-like growth factor-I (IGF-I)-dependent activation of pp42/44 mitogen-activated protein kinase occurs independently of IGF-I receptor kinase activation and IRS-1 tyrosine phosphorylation. PG - 1147-57 AB - The proliferation and metabolism of H4IIE hepatoma cells is apparently mediated through the insulin receptor. These cells, however, also have high-affinity binding sites for insulin-like growth factor-I (IGF-I). Addition of insulin to H4IIE cells increased RNA synthesis, DNA synthesis and cell number. IGF-I, on the other hand, was ineffective at concentrations equivalent to the lowest effective insulin dose, although stimulation was observed with concentrations 100-fold higher. Similar results were obtained when glucose uptake was measured. Western blot analysis demonstrated that tyrosine phosphorylation patterns produced by insulin and IGF-I differed. In particular, phosphorylation of insulin receptor substrate-1 (IRS-1) was evident after treatment with insulin, but not after treatment with IGF-I. Correspondingly, insulin, but not IGF-I, stimulated receptor tyrosine kinase activity. In contrast with these results, both insulin and IGF-I induced mitogen-activated protein (MAP) kinase phosphorylation and activity at a concentration of 10 nM. The correlation between insulin-dependent and IGF-I-dependent MAP kinase activation was confirmed by Western blot analysis of phosphorylated MAP kinase kinase (MEK). These results suggest that phosphorylation of IRS-1 is essential for both cell proliferation and glucose metabolism, but is uncoupled from the MAP kinase cascade. Furthermore, stimulation of MEK and MAP kinase is independent of receptor tyrosine kinase activity. AD - Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Canada. FAU - Yau, L AU - Yau L FAU - Lukes, H AU - Lukes H FAU - McDiarmid, H AU - McDiarmid H FAU - Werner, J AU - Werner J FAU - Zahradka, P AU - Zahradka P LA - eng PT - Journal Article PL - GERMANY TA - Eur J Biochem JID - 0107600 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 50-99-7 (Glucose) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Biological Transport, Active/drug effects MH - Cell Division/drug effects MH - Enzyme Activation MH - Glucose/metabolism MH - Insulin/pharmacology MH - Insulin-Like Growth Factor I/*metabolism/pharmacology MH - Liver Neoplasms, Experimental/metabolism MH - Mitogen-Activated Protein Kinase 1/*metabolism MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinases/*metabolism MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Rats MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 1999/12/03 MHDA- 1999/12/03 00:01 AID - ejb968 [pii] PST - ppublish SO - Eur J Biochem 1999 Dec;266(3):1147-57. -------------------------------------------------------------------------------- 163: Toyoda M et al. Increased activity and expres...[PMID: 10551398] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10551398 OWN - NLM STAT- MEDLINE DA - 19991206 DCOM- 19991206 LR - 20031114 PUBM- Print IS - 0168-8278 VI - 31 IP - 4 DP - 1999 Oct TI - Increased activity and expression of MAP kinase in HCC model rats induced by 3'-methyl-4-dimethylamino-azobenzene. PG - 725-33 AB - BACKGROUND/AIMS: The ras-mitogen-activated protein kinase (MAPK) cascade plays an important role not only in the mitogenic signal transduction pathway but also in the development of cancer, and it is believed to be one of the important regulators in normal hepatocytes and hepatocellular carcinoma. The aim of this study was to determine the role of insulin receptor substrate-1 and the MAPK cascade in rats with hepatocellular carcinoma induced by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB). METHODS: Liver cancer was induced in rats by feeding 3'-MeDAB, and the changes in expression of IRS-1 and MAPK were analyzed in tumorous, non-tumorous and control liver. RESULTS: Expression of insulin receptor substrate-1 (IRS-1) showed a 1.4-fold increase at protein level in the tumors (p<0.01), but the tyrosine phosphorylation of IRS-1 did not differ between the tumor and control liver. Expression of MAPK and its activity were elevated 4.5-7.5-fold (p<0.01) and 4.6-fold (p<0.01) in the tumor compared with control liver. In non-tumorous lesions from rats fed with 3'-MeDAB, expression of MAPK, but not IRS-1, increased significantly (p<0.01). Between tumorous and adjacent non-tumorous lesions, there was a significant difference in MAPK expression (p<0.05) and activities (p<0.05). CONCLUSIONS: The increased expression of MAPK may play an important role in the progression or initiation of HCC in this rat model. AD - The Second Department of Internal Medicine, Chiba University School of Medicine, Japan. FAU - Toyoda, M AU - Toyoda M FAU - Hashimoto, N AU - Hashimoto N FAU - Tokita, K AU - Tokita K FAU - Goldstein, B J AU - Goldstein BJ FAU - Yokosuka, O AU - Yokosuka O FAU - Kanatsuka, A AU - Kanatsuka A FAU - Suzuki, Y AU - Suzuki Y FAU - Saito, Y AU - Saito Y LA - eng PT - Journal Article PL - DENMARK TA - J Hepatol JID - 8503886 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 35282-69-0 (3'-hydroxymethyl-4-(dimethylamino)azobenzene) RN - 55-80-1 (Methyldimethylaminoazobenzene) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Blotting, Northern MH - Blotting, Western MH - Carcinoma, Hepatocellular/*chemically induced/*enzymology/metabolism/pathology MH - Liver/metabolism MH - Liver Neoplasms/*chemically induced/*enzymology/metabolism/pathology MH - Male MH - Methyldimethylaminoazobenzene/*analogs & derivatives MH - Mitogen-Activated Protein Kinases/*metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - Reference Values MH - Tyrosine/metabolism EDAT- 1999/11/07 MHDA- 1999/11/07 00:01 AID - S0168827899803547 [pii] PST - ppublish SO - J Hepatol 1999 Oct;31(4):725-33. -------------------------------------------------------------------------------- 164: Jackson JG et al. IRS-1 expression and activati...[PMID: 10543935] Related Articles, Substance via MeSH, Books, LinkOut PMID- 10543935 OWN - NLM STAT- MEDLINE DA - 19991124 DCOM- 19991124 LR - 20041117 PUBM- Print IS - 1096-6374 VI - 9 IP - 5 DP - 1999 Oct TI - IRS-1 expression and activation are not sufficient to activate downstream pathways and enable IGF-I growth response in estrogen receptor negative breast cancer cells. PG - 280-9 AB - IGF-responsive breast cancer cells activate insulin receptor substrate (IRS)-1 after IGF-I treatment. To determine if IRS-1 expression was sufficient to enable IGF-responsiveness, two IGF-I unresponsive breast cancer cell lines (MDA-MB-435A and MDA-MB-468) were transfected with IRS-1. While IGF-I caused tyrosine phosphorylation of IRS-1 in both transfected cell lines, increased MAP kinase activity was not seen. IGF-I treatment of 435A IRS-1 transfected cells resulted in minimal increased PI3 kinase activity associated with IRS-1, while IRS-2/PI3 kinase was greatly reduced. In MDA-MB-468 IRS-1 transfected cells, IGF-I caused increased IRS-1 associated PI3 kinase activity compared to parental cells, but at levels far below those observed in IGF-responsive MCF-7 cells. The transfected cells were also not responsive to IGF-I in monolayer growth. Thus, IRS-1 expression and activation alone are insufficient to mediate a proliferative response to IGF-I in breast cancer cells, and it is likely that maximal activation of downstream signaling pathways must also occur. CI - Copyright 1999 Harcourt Publishers Ltd. AD - Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78284-7884, USA. FAU - Jackson, J G AU - Jackson JG FAU - Yee, D AU - Yee D LA - eng GR - P30 CA54174/CA/NCI GR - R01CA74285/CA/NCI PT - Journal Article PL - SCOTLAND TA - Growth Horm IGF Res JID - 9814320 RN - 0 (Phosphoproteins) RN - 0 (Plasmids) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, Somatomedin) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Animals MH - Ascites/metabolism MH - Blotting, Western MH - Breast Neoplasms/*metabolism MH - Cell Division/physiology MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Insulin-Like Growth Factor I/*metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Plasmids/metabolism MH - Precipitin Tests MH - Rats MH - Receptors, Estrogen/*metabolism MH - Receptors, Somatomedin/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Transfection MH - Tumor Cells, Cultured/cytology EDAT- 1999/11/02 MHDA- 1999/11/02 00:01 AID - 10.1054/ghir.1999.0113 [doi] AID - S1096637499901132 [pii] PST - ppublish SO - Growth Horm IGF Res 1999 Oct;9(5):280-9. -------------------------------------------------------------------------------- 165: Book CB et al. Selective insulin resistance ...[PMID: 10487672] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10487672 OWN - NLM STAT- MEDLINE DA - 19991006 DCOM- 19991006 LR - 20041117 PUBM- Print IS - 0021-972X VI - 84 IP - 9 DP - 1999 Sep TI - Selective insulin resistance in the polycystic ovary syndrome. PG - 3110-6 AB - Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia that is amplified by insulin in the presence of resistance to insulin's action to stimulate glucose uptake in muscle and fat. To explore the mechanisms for this paradox, we examined the metabolic and mitogenic actions of insulin and insulin-like growth factor I (IGF-I) in cultured skin fibroblasts from PCOS (n = 16) and control (n = 11) women. There were no significant decreases in the number or affinity of insulin- or IGF-I-binding sites in PCOS compared to control fibroblasts. Basal rates were similar, but there were significant decreases in insulin-stimulated (control, 51.8 +/- 7.0; PCOS, 29.5 +/- 2.9 nmol/10(6) cells x 2 h at 1,000,000 pmol/L; P < 0.005) and IGF-I-stimulated (control, 48.9 +/- 6.7; PCOS, 33.0 +/- 3.2 PCOS nmol/10(6) cells x 2 h at 100,000 pmol/L IGF-I; P < 0.05) glucose incorporation into glycogen in PCOS fibroblasts, a metabolic action of insulin. Stimulation of thymidine incorporation, a mitogenic action of insulin, was similar in PCOS and control fibroblasts in response to both insulin and IGF-I. There were also no significant differences in insulin- or IGF-I-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in PCOS compared to control fibroblast cells. We conclude that 1) there is a selective defect in insulin action in PCOS fibroblasts that affects metabolic, but not mitogenic, signaling pathways; 2) there is a similar defect in IGF-I action, suggesting that insulin and IGF-I stimulate glycogen synthesis by the same postreceptor pathways; and 3) insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activation by insulin and IGF-I is similar to the control value, suggesting that the metabolic signaling defect is in another pathway or downstream of this signaling step in PCOS fibroblasts. AD - Department of Medicine, Pennsylvania State University College of Medicine, Hershey 17033, USA. FAU - Book, C B AU - Book CB FAU - Dunaif, A AU - Dunaif A LA - eng GR - R01-DK-40605/DK/NIDDK GR - T32-DK-07684/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Clin Endocrinol Metab JID - 0375362 RN - 11061-68-0 (Insulin) RN - 50-99-7 (Glucose) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9005-79-2 (Glycogen) RN - 9007-49-2 (DNA) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Adolescent MH - Adult MH - Cells, Cultured MH - DNA/biosynthesis MH - Female MH - Fibroblasts/drug effects/metabolism MH - Glucose/metabolism MH - Glycogen/metabolism MH - Humans MH - Insulin/metabolism/pharmacology MH - *Insulin Resistance MH - Insulin-Like Growth Factor I/metabolism/pharmacology MH - Polycystic Ovary Syndrome/*physiopathology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction EDAT- 1999/09/16 MHDA- 1999/09/16 00:01 PST - ppublish SO - J Clin Endocrinol Metab 1999 Sep;84(9):3110-6. -------------------------------------------------------------------------------- 166: Martin DC et al. Insulin-like growth factor II...[PMID: 10459021] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10459021 OWN - NLM STAT- MEDLINE DA - 19990923 DCOM- 19990923 LR - 20041117 PUBM- Print IS - 0021-9525 VI - 146 IP - 4 DP - 1999 Aug 23 TI - Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. PG - 881-92 AB - Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])-induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1-overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1-overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1-overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer. AD - Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada. FAU - Martin, D C AU - Martin DC FAU - Fowlkes, J L AU - Fowlkes JL FAU - Babic, B AU - Babic B FAU - Khokha, R AU - Khokha R LA - eng GR - DK02776/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Cell Biol JID - 0375356 RN - 0 (Antigens, Polyomavirus Transforming) RN - 0 (Insulin-Like Growth Factor Binding Protein 3) RN - 0 (Protein p53) RN - 0 (RNA, Messenger) RN - 0 (Retinoblastoma Protein) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 3.4.24 (Metalloendopeptidases) SB - IM MH - Animals MH - Antigens, Polyomavirus Transforming/genetics/metabolism MH - Cell Division MH - *Cell Transformation, Neoplastic MH - Hyperplasia MH - Insulin-Like Growth Factor Binding Protein 3/genetics/*metabolism MH - Insulin-Like Growth Factor II/genetics/*metabolism MH - Liver Neoplasms/enzymology/genetics/metabolism/pathology MH - Metalloendopeptidases/antagonists & inhibitors/metabolism MH - Mice MH - Mice, Transgenic MH - Phosphorylation MH - Protein p53/metabolism MH - RNA, Messenger/genetics/metabolism MH - Receptor, IGF Type 1/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Retinoblastoma Protein/metabolism MH - *Signal Transduction MH - Tissue Inhibitor of Metalloproteinase-1/genetics/*metabolism MH - Transgenes/genetics/physiology EDAT- 1999/08/25 MHDA- 1999/08/25 00:01 PST - ppublish SO - J Cell Biol 1999 Aug 23;146(4):881-92. -------------------------------------------------------------------------------- 167: Rubini M et al. Characterization of an antibo...[PMID: 10438568] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10438568 OWN - NLM STAT- MEDLINE DA - 19990914 DCOM- 19990914 LR - 20041117 PUBM- Print IS - 0014-4827 VI - 251 IP - 1 DP - 1999 Aug 25 TI - Characterization of an antibody that can detect an activated IGF-I receptor in human cancers. PG - 22-32 AB - The type 1 insulin-like growth factor receptor (IGF-IR) plays an important role in malignant transformation and in apoptosis. Its role in human cancer has now been firmly established. IGF-IR signaling occurs only when the receptor is activated by its ligands, which induce autophosphorylation of the receptor at several tyrosine residues. Although the IGF-IR (phosphorylated or not) can be detected in human cancers with conventional antibodies, it would be desirable to obtain antibodies that can detect the IGF-IR only when activated by its ligands. We describe and characterize in this paper such an antibody and show that it can be used in sections of human cancers to detect an autophosphorylated IGF-IR. This antibody will be useful in detecting autocrine or paracrine influences on normal and tumor cells and could eventually be also useful in diagnostic and prognostic studies of human primary and metastatic cancer. CI - Copyright 1999 Academic Press. AD - University of Ferrara, Via L. Borsari 46, Ferrara, 44100, Italy. FAU - Rubini, M AU - Rubini M FAU - D'Ambrosio, C AU - D'Ambrosio C FAU - Carturan, S AU - Carturan S FAU - Yumet, G AU - Yumet G FAU - Catalano, E AU - Catalano E FAU - Shan, S AU - Shan S FAU - Huang, Z AU - Huang Z FAU - Criscuolo, M AU - Criscuolo M FAU - Pifferi, M AU - Pifferi M FAU - Baserga, R AU - Baserga R LA - eng GR - CA 53424/CA/NCI GR - CA 56309/CA/NCI PT - Journal Article PL - UNITED STATES TA - Exp Cell Res JID - 0373226 RN - 0 (Antibodies, Monoclonal) RN - 0 (Epitopes) RN - 0 (Ligands) RN - 0 (Tumor Markers, Biological) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Amino Acid Sequence MH - Animals MH - Antibodies, Monoclonal/*immunology MH - Antibody Specificity MH - Binding, Competitive MH - Breast Neoplasms/immunology/*metabolism MH - Cell Line MH - Colonic Neoplasms/immunology/metabolism MH - Cross Reactions MH - Epitopes/immunology MH - Humans MH - Ligands MH - Mice MH - Molecular Sequence Data MH - Mutation MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Precipitin Tests MH - Receptor, IGF Type 1/genetics/*immunology/*metabolism MH - Receptor, Insulin/immunology MH - Research Support, U.S. Gov't, P.H.S. MH - Transfection MH - Tumor Markers, Biological/immunology EDAT- 1999/08/10 MHDA- 1999/08/10 00:01 AID - 10.1006/excr.1999.4562 [doi] AID - S0014482799945627 [pii] PST - ppublish SO - Exp Cell Res 1999 Aug 25;251(1):22-32. -------------------------------------------------------------------------------- 168: Porzio O et al. The Gly972-->Arg amino acid p...[PMID: 10430617] Related Articles, Compound via MeSH, Substance via MeSH, OMIM, Free in PMC, Cited in PMC, Books, LinkOut PMID- 10430617 OWN - NLM STAT- MEDLINE DA - 19990817 DCOM- 19990817 LR - 20041117 PUBM- Print IS - 0021-9738 VI - 104 IP - 3 DP - 1999 Aug TI - The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. PG - 357-64 AB - Recent studies have identified several polymorphisms in the human insulin receptor substrate-1 (IRS-1) gene. The most prevalent IRS-1 variant, a Gly-->Arg change at the codon 972, has been reported to be increased in prevalence among patients with type 2 diabetes. Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. Compared with control RIN cells, insulin content was reduced to the same extent in RIN-WT or RIN-Arg(972) at both the protein and mRNA levels. Both glucose- and sulfonylurea-induced insulin secretion was increased in RIN-WT compared with control RIN cells. By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. AD - Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. FAU - Porzio, O AU - Porzio O FAU - Federici, M AU - Federici M FAU - Hribal, M L AU - Hribal ML FAU - Lauro, D AU - Lauro D FAU - Accili, D AU - Accili D FAU - Lauro, R AU - Lauro R FAU - Borboni, P AU - Borboni P FAU - Sesti, G AU - Sesti G LA - eng PT - Journal Article PL - UNITED STATES TA - J Clin Invest JID - 7802877 RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (Recombinant Proteins) RN - 0 (Sulfonylurea Compounds) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 50-99-7 (Glucose) RN - 55520-40-6 (Tyrosine) RN - 56-40-6 (Glycine) RN - 74-79-3 (Arginine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Amino Acid Substitution/*genetics MH - Animals MH - Arginine/*genetics MH - Glucose/pharmacology MH - Glycine/*genetics MH - Humans MH - Insulin/genetics/metabolism/*secretion MH - Insulinoma/enzymology/genetics/metabolism MH - Intracellular Fluid/metabolism MH - Islets of Langerhans/drug effects/enzymology/*secretion MH - Phosphoproteins/*genetics/metabolism MH - Phosphorylation MH - *Polymorphism, Genetic MH - RNA, Messenger/metabolism MH - Rats MH - Receptor, Insulin/genetics/metabolism MH - Recombinant Proteins/biosynthesis/genetics MH - Research Support, Non-U.S. Gov't MH - Substrate Specificity/genetics MH - Sulfonylurea Compounds/pharmacology MH - Transfection MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 1999/08/03 MHDA- 1999/08/03 00:01 PST - ppublish SO - J Clin Invest 1999 Aug;104(3):357-64. -------------------------------------------------------------------------------- 169: Pandini G et al. Insulin and insulin-like grow...[PMID: 10430101] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10430101 OWN - NLM STAT- MEDLINE DA - 19990922 DCOM- 19990922 LR - 20041117 PUBM- Print IS - 1078-0432 VI - 5 IP - 7 DP - 1999 Jul TI - Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. PG - 1935-44 AB - The insulin receptor (IR) form hybrids with the closely related insulin-like growth factor-I (IGF-I) receptor (IGF-I-R). Because most human breast carcinomas overexpress both the IR and the IGF-I-R, we evaluated whether the insulin/IGF-I hybrid receptor (Hybrid-R) is also overexpressed in these tumors and what role it plays in breast cancer biology. Using specific ELISAs and Western blots, we measured Hybrid-R content and function in 8 human cultured breast cancer cell lines and 39 human breast cancer specimens. Hybrid-R content and function were also compared to the content and function of the IR and the IGF-I-R. Hybrid-R content exceeded the IGF-I-R content in >75% of breast cancer specimens and was directly related to the molar ratio of both the IR and IGF-I-R content, suggesting that Hybrid-R formation occurred by random assembly of IR and IGF-I-R half-receptors. Hybrid-Rs became tyrosine autophosphorylated when breast cancer cells were exposed to IGF-I but not when they were exposed to insulin. In cells with an elevated Hybrid-R content, Hybrid-R autophosphorylation in response to IGF-I exceeded IGF-I-R autophosphorylation, suggesting that most of the IGF-I effect occurred via the Hybrid-R. Furthermore, Hybrid-Rs mediated growth in response to IGF-I, as indicated by experiments with blocking antibodies to the IGF-I-R. These data indicated therefore that: (a) Hybrid-Rs are present and play a major role in mediating the IGF-I signal in breast cancer; (b) their expression is directly related to IR overexpression; and (c) potential therapies designed to block IGF-I actions in breast cancer must take into account the role of these Hybrid-Rs. AD - Istituto di Medicina Interna, Malattie Endocrine e del Metabolismo, Universita di Catania, Ospedale Garibaldi, Italy. FAU - Pandini, G AU - Pandini G FAU - Vigneri, R AU - Vigneri R FAU - Costantino, A AU - Costantino A FAU - Frasca, F AU - Frasca F FAU - Ippolito, A AU - Ippolito A FAU - Fujita-Yamaguchi, Y AU - Fujita-Yamaguchi Y FAU - Siddle, K AU - Siddle K FAU - Goldfine, I D AU - Goldfine ID FAU - Belfiore, A AU - Belfiore A LA - eng PT - Journal Article PL - UNITED STATES TA - Clin Cancer Res JID - 9502500 RN - 0 (Antibodies, Monoclonal) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Antibodies, Monoclonal/immunology MH - Blotting, Western MH - Breast Neoplasms/immunology/*metabolism MH - Cell Division MH - Comparative Study MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Humans MH - Insulin/metabolism MH - Insulin-Like Growth Factor I/metabolism MH - Phosphorylation MH - Precipitin Tests MH - Receptor, IGF Type 1/*biosynthesis MH - Receptor, Insulin/*biosynthesis MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1999/08/03 MHDA- 1999/08/03 00:01 PST - ppublish SO - Clin Cancer Res 1999 Jul;5(7):1935-44. -------------------------------------------------------------------------------- 170: Belfiore A et al. Insulin/IGF-I hybrid receptor...[PMID: 10401676] Related Articles, Substance via MeSH, Books, LinkOut PMID- 10401676 OWN - NLM STAT- MEDLINE DA - 19990908 DCOM- 19990908 LR - 20041117 PUBM- Print IS - 0300-9084 VI - 81 IP - 4 DP - 1999 Apr TI - Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer. PG - 403-7 AB - The insulin-like growth factor-I (IGF-I) plays an important role in determining the biological behavior of a variety of malignancies. We measured IGF-I, its receptor and related receptors in thyroid cancer. IGF-I was present both in normal thyroid tissue and in thyroid cancer tissue and it was produced by stromal cells but not by thyrocytes. Values were significantly higher in malignant than in normal tissue. IGF-I receptors (IGF-I-Rs) and the homologous insulin receptors (IRs) were found overexpressed in both thyroid cancer cell lines (n = 4) and specimens (n = 17) as compared to normal values. In addition, high levels of hybrid IGF-I/insulin receptors (IR/IGF-I-Rs) were present in both thyroid cancer specimens and cell lines. IR/IGF-I-R hybrids were the most represented type of receptor in 14/17 specimens and exceeded the IGF-I-R content in all cases. Hybrid content correlated with the IR and IGF-I-R content, suggesting that in thyroid tissue hybrid formation occurs by random assembly of IR and IGF-I-R half receptors. Hybrid receptor autophosphorylation was stimulated by IGF-I with high affinity. In cells with a high IR/IGF-I-Rs content, blocking antibodies specific to these receptors substantially inhibited IGF-I induced cell growth. These data indicate that the IGF-I system is overactivated in thyroid cancer and that IR/IGF-I-R hybrid receptors play an important role in IGF-I mitogenic signaling in these tumors. AD - Istituto di Medicina Interna, Malattie Endocrine e del Metabolismo, Universita di Catania, Ospedale Garibaldi, Italy. FAU - Belfiore, A AU - Belfiore A FAU - Pandini, G AU - Pandini G FAU - Vella, V AU - Vella V FAU - Squatrito, S AU - Squatrito S FAU - Vigneri, R AU - Vigneri R LA - eng PT - Journal Article PL - FRANCE TA - Biochimie JID - 1264604 RN - 0 (Mitogens) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Cell Line MH - Humans MH - Insulin-Like Growth Factor I/*metabolism/pharmacology MH - Mitogens/metabolism/pharmacology MH - Receptor, IGF Type 1/metabolism/*physiology MH - Receptor, Insulin/metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - *Signal Transduction MH - Thyroid Neoplasms/*metabolism EDAT- 1999/07/13 MHDA- 1999/07/13 00:01 AID - S0300908499800881 [pii] PST - ppublish SO - Biochimie 1999 Apr;81(4):403-7. -------------------------------------------------------------------------------- 171: Hotamisligil GS. The role of TNFalpha and TNF ...[PMID: 10395191] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10395191 OWN - NLM STAT- MEDLINE DA - 19990714 DCOM- 19990714 LR - 20041117 PUBM- Print IS - 0954-6820 VI - 245 IP - 6 DP - 1999 Jun TI - The role of TNFalpha and TNF receptors in obesity and insulin resistance. PG - 621-5 AB - Insulin resistance, a smaller than expected response to a given dose of insulin, is associated with many common diseases including, ageing, polycystic ovarian disease, syndrome X, cancer, infections, trauma and, most significantly, obesity and type 2 diabetes mellitus. The biochemical basis of insulin resistance in type 2 diabetes has been the subject of many studies. Earlier studies have indicated that quantitative regulation of the insulin sensitive glucose transporters (Glut-4) and insulin receptors themselves may contribute to this disorder, however, these two factors are probably inadequate to explain the extent of insulin resistance. This point also became apparent by the development of only mild hyperinsulinaemia in mice with a targeted mutation in the Glut-4 gene. Studies on postreceptor defects in type 2 diabetes has recently focused on the intrinsic catalytic activity of the insulin receptor and downstream signalling events. A reduction in tyrosine phosphorylation of both the insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1) has been noted in both animal and human type 2 diabetes. Importantly, this appears to occur in all of the major insulin-sensitive tissues, namely the muscle, fat and liver. It is now clear that decreased signalling capacity of the insulin receptor is an important component of this disease. I will review some of the potential mechanisms underlying this deficiency. AD - Department of Nutrition, Harvard University, School of Public Health, Boston, Massachusetts 02115, USA. ghota-mis@hsph.harvard.edu FAU - Hotamisligil, G S AU - Hotamisligil GS LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - ENGLAND TA - J Intern Med JID - 8904841 RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Diabetes Mellitus, Type 2/genetics/*metabolism MH - Humans MH - *Insulin Resistance/genetics MH - Mice MH - Mice, Transgenic MH - Obesity/genetics/*metabolism MH - Receptors, Tumor Necrosis Factor/genetics/*metabolism MH - Tumor Necrosis Factor-alpha/genetics/*metabolism RF - 37 EDAT- 1999/07/08 MHDA- 1999/07/08 00:01 PST - ppublish SO - J Intern Med 1999 Jun;245(6):621-5. -------------------------------------------------------------------------------- 172: Mihaylova VT et al. The PTEN tumor suppressor hom...[PMID: 10377431] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 10377431 OWN - NLM STAT- MEDLINE DA - 19990719 DCOM- 19990719 LR - 20050523 PUBM- Print IS - 0027-8424 VI - 96 IP - 13 DP - 1999 Jun 22 TI - The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. PG - 7427-32 AB - Inactivation of the tumor suppressor PTEN gene is found in a variety of human cancers and in cancer predisposition syndromes. Recently, PTEN protein has been shown to possess phosphatase activity on phosphatidylinositol 3,4,5-trisphosphate, a product of phosphatidylinositol 3-kinase. We have identified a homolog of PTEN in Caenorhabditis elegans and have found that it corresponds to the daf-18 gene, which had been defined by a single, phenotypically weak allele, daf-18(e1375). By analyzing an allele, daf-18(nr2037), which bears a deletion of the catalytic portion of CePTEN/DAF-18, we have shown that mutation in daf-18 can completely suppress the dauer-constitutive phenotype caused by inactivation of daf-2 or age-1, which encode an insulin receptor-like molecule and the catalytic subunit of phosphatidylinositol 3-kinase, respectively. In addition, daf-18(nr2037) dramatically shortens lifespan, both in a wild-type background and in a daf-2 mutant background that normally prolongs lifespan. The lifespan in a daf-18(nr2037) mutant can be restored to essentially that of wild type when combined with a daf-2 mutation. Our studies provide genetic evidence that, in C. elegans, the PTEN homolog DAF-18 functions as a negative regulator of the DAF-2 and AGE-1 signaling pathway, consistent with the notion that DAF-18 acts a phosphatidylinositol 3,4,5-trisphosphate phosphatase in vivo. Furthermore, our studies have uncovered a longevity-promoting activity of the PTEN homolog in C. elegans. AD - Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. FAU - Mihaylova, V T AU - Mihaylova VT FAU - Borland, C Z AU - Borland CZ FAU - Manjarrez, L AU - Manjarrez L FAU - Stern, M J AU - Stern MJ FAU - Sun, H AU - Sun H LA - eng PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Caenorhabditis elegans Proteins) RN - 0 (DAF-18 protein, C elegans) RN - 0 (DAF-2 protein, C elegans) RN - 0 (Helminth Proteins) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.137 (AGE-1 protein, C elegans) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTEN protein) SB - IM MH - *1-Phosphatidylinositol 3-Kinase MH - Amino Acid Sequence MH - Animals MH - Caenorhabditis elegans/*physiology MH - *Caenorhabditis elegans Proteins MH - Gene Expression Regulation/physiology MH - Genes, Tumor Suppressor MH - Helminth Proteins/*physiology MH - Humans MH - Molecular Sequence Data MH - Phosphoric Monoester Hydrolases/*genetics MH - Receptor, Insulin/*physiology MH - Research Support, Non-U.S. Gov't MH - Sequence Alignment MH - Signal Transduction/genetics MH - *Tumor Suppressor Proteins EDAT- 1999/06/23 MHDA- 1999/06/23 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1999 Jun 22;96(13):7427-32. -------------------------------------------------------------------------------- 173: Dunaif A. Insulin action in the polycys...[PMID: 10352922] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10352922 OWN - NLM STAT- MEDLINE DA - 19990715 DCOM- 19990715 LR - 20041117 PUBM- Print IS - 0889-8529 VI - 28 IP - 2 DP - 1999 Jun TI - Insulin action in the polycystic ovary syndrome. PG - 341-59 AB - Research on insulin action in PCOS has been intensive after the identification of insulin resistance as a feature of the syndrome in 1980. It is now clear that PCOS is a metabolic as well as a reproductive disorder and an important cause of type 2 diabetes mellitus in women. The cellular and molecular mechanisms of insulin resistance in PCOS are distinct from those in other insulin resistance syndromes. Elucidating these mechanisms promises to provide considerable insight into insulin receptor signal specificity. Conversely, insulin resistance is now known to have an important role in the pathogenesis of the reproductive disturbances of PCOS. It is thought that one or several genetic defects may cause both the insulin resistance and reproductive abnormalities characteristic of PCOS. AD - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. adunaif@bics.bwh.harvard.edu FAU - Dunaif, A AU - Dunaif A LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Endocrinol Metab Clin North Am JID - 8800104 RN - 0 (Androgens) RN - 11061-68-0 (Insulin) SB - IM MH - Androgens/physiology MH - Diabetes Mellitus, Type 2/etiology MH - Female MH - Humans MH - Insulin/pharmacology/*physiology/secretion MH - Insulin Resistance MH - Polycystic Ovary Syndrome/complications/*physiopathology RF - 57 EDAT- 1999/06/03 MHDA- 1999/06/03 00:01 PST - ppublish SO - Endocrinol Metab Clin North Am 1999 Jun;28(2):341-59. -------------------------------------------------------------------------------- 174: Lee AV et al. Enhancement of insulin-like g...[PMID: 10319328] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10319328 OWN - NLM STAT- MEDLINE DA - 19990708 DCOM- 19990708 LR - 20041117 PUBM- Print IS - 0888-8809 VI - 13 IP - 5 DP - 1999 May TI - Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. PG - 787-96 AB - Cross-talk between insulin-like growth factor (IGF)- and estrogen receptor (ER)-signaling pathways results in synergistic growth. We show here that estrogen enhances IGF signaling by inducing expression of three key IGF-regulatory molecules, the type 1 IGF receptor (IGFR1) and its downstream signaling molecules, insulin receptor substrate (IRS)-1 and IRS-2. Estrogen induction of IGFR1 and IRS expression resulted in enhanced tyrosine phosphorylation of IRS-1 after IGF-I stimulation, followed by enhanced mitogen-activated protein kinase activation. To examine whether these pathways were similarly activated in vivo, we examined MCF-7 cells grown as xenografts in athymic mice. IRS-1 was expressed at high levels in estrogen-dependent growth of MCF-7 xenografts, but withdrawal of estrogen, which decreased tumor growth, resulted in a dramatic decrease in IRS-1 expression. Finally, we have shown that high IRS-1 expression is an indicator of early disease recurrence in ER-positive human primary breast tumors. Taken together, these data not only reinforce the concept of cross-talk between IGF- and ER-signaling pathways, but indicate that IGF molecules may be critical regulators of estrogen-mediated growth and breast cancer pathogenesis. AD - Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7884, USA. adrian@oncology.uthscsa.edu FAU - Lee, A V AU - Lee AV FAU - Jackson, J G AU - Jackson JG FAU - Gooch, J L AU - Gooch JL FAU - Hilsenbeck, S G AU - Hilsenbeck SG FAU - Coronado-Heinsohn, E AU - Coronado-Heinsohn E FAU - Osborne, C K AU - Osborne CK FAU - Yee, D AU - Yee D LA - eng GR - P01CA-30195/CA/NCI GR - P30CA-54174/CA/NCI GR - P50CA-58183-06/CA/NCI PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Estrogen Antagonists) RN - 0 (Estrogens) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, Somatomedin) RN - 0 (Somatomedins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 129453-61-8 (fulvestrant) RN - 50-28-2 (Estradiol) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) SB - IM MH - Animals MH - Breast Neoplasms/drug therapy/*metabolism MH - Ca(2+)-Calmodulin Dependent Protein Kinase/drug effects/metabolism MH - Estradiol/analogs & derivatives/pharmacology MH - Estrogen Antagonists/pharmacology MH - Estrogens/*metabolism MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Insulin-Like Growth Factor I/metabolism/pharmacology MH - Mammary Neoplasms, Experimental/metabolism MH - Mice MH - Phosphoproteins/genetics/*metabolism MH - Phosphorylation MH - Receptor, Insulin/genetics/metabolism MH - Receptors, Estrogen/metabolism MH - Receptors, Somatomedin/genetics/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Somatomedins/*metabolism MH - Survival Rate MH - Transplantation, Heterologous MH - Tumor Cells, Cultured EDAT- 1999/05/13 MHDA- 1999/05/13 00:01 PST - ppublish SO - Mol Endocrinol 1999 May;13(5):787-96. -------------------------------------------------------------------------------- 175: Garant MJ et al. Reversible change in thiol re...[PMID: 10231542] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10231542 OWN - NLM STAT- MEDLINE DA - 19990601 DCOM- 19990601 LR - 20041117 PUBM- Print IS - 0006-2960 VI - 38 IP - 18 DP - 1999 May 4 TI - Reversible change in thiol redox status of the insulin receptor alpha-subunit in intact cells. PG - 5896-904 AB - In this study, we used maleimidobutyrylbiocytin to examine possible alteration that may occur in the redox state of the insulin receptor (IR) sulfhydryl groups in response to reduced glutathione (GSH) or N-acetyl-L-cysteine (NAC). Short-term treatment of intact cells expressing large numbers of IR with GSH or NAC led to a rapid and reversible reduction of IR alpha-subunit disulfides, without affecting the receptor beta-subunit thiol reactivity. The overall integrity of the oligomeric structure of IR was maintained, indicating that neither class I nor class II disulfides were targeted by these agents. Similar findings were obtained in cells transfected with IR mutants lacking cysteine524, one of the class I disulfides that link the two IR alpha-subunits. Membrane-associated thiols did not participate in GSH- or NAC-mediated reduction of IR alpha-subunit disulfides. No difference in insulin binding was observed in GSH-treated cells; however, ligand-mediated increases in IR autophosphorylation, tyrosine phosphorylation of cellular substrates, and dual phosphorylation of the downstream target mitogen-activated protein kinase were inhibited at concentrations of GSH (10 mM or greater) that yielded a significant increase in IR alpha-subunit thiol reactivity. GSH did not affect IR signaling in the absence of insulin. Our results provide the first evidence that the IR alpha-subunit contains a select group of disulfides whose redox status can be rapidly altered by the reducing agents GSH and NAC. AD - Diabetes Section, Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825, USA. FAU - Garant, M J AU - Garant MJ FAU - Kole, S AU - Kole S FAU - Maksimova, E M AU - Maksimova EM FAU - Bernier, M AU - Bernier M LA - eng PT - Journal Article PL - UNITED STATES TA - Biochemistry JID - 0370623 RN - 0 (Culture Media) RN - 0 (Sulfhydryl Compounds) RN - 616-91-1 (Acetylcysteine) RN - 70-18-8 (Glutathione) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Acetylcysteine/pharmacology MH - Animals MH - CHO Cells MH - Carcinoma, Hepatocellular MH - Culture Media MH - Glutathione/metabolism/pharmacology MH - Hamsters MH - Humans MH - Oxidation-Reduction MH - Protein Binding/drug effects MH - Rats MH - Receptor, Insulin/*chemistry/*metabolism/physiology MH - Sulfhydryl Compounds/*chemistry/*metabolism MH - Time Factors MH - Tumor Cells, Cultured EDAT- 1999/05/08 MHDA- 1999/05/08 00:01 AID - 10.1021/bi982844p [doi] AID - bi982844p [pii] PST - ppublish SO - Biochemistry 1999 May 4;38(18):5896-904. -------------------------------------------------------------------------------- 176: Spector SA et al. Human insulin receptor and in...[PMID: 10210639] Related Articles, Books, LinkOut PMID- 10210639 OWN - NLM STAT- MEDLINE DA - 19990513 DCOM- 19990513 LR - 20041117 PUBM- Print IS - 0022-4804 VI - 83 IP - 1 DP - 1999 May 1 TI - Human insulin receptor and insulin signaling proteins in hepatic disease. PG - 32-5 AB - Insulin regulates hepatocellular metabolism and growth following insulin receptor (IR) autophosphorylation and activation of the intracellular adapter protein, insulin receptor substrate 1 (IRS-1). IRS-1 activates SH2 domain proteins such as Grb2, which may be vital to hepatocyte growth. To determine if these substances are abnormally expressed under pathophysiologic conditions, IR, IRS-1, Grb2 protein, and IR mRNA were studied in normal human liver (n = 10), cirrhotic liver (n = 10), and hepatocellular carcinoma (HCC) (n = 10) that had been procured during operative procedures. IR mRNA was quantified by S1-nuclease assay using a 195-bp digoxigenin-labeled IR DNA probe and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Protein concentrations were determined by immunoblot analysis following SDS-PAGE of liver homogenate samples. Labeled DNA and antibody-complexed protein were detected by chemiluminescent means and quantified by densitometric analysis (mean densitometric units +/- standard error). Similar levels of IR mRNA were observed in normal tissue, cirrhosis, and HCC. IR protein concentration was significantly greater in HCC than in normal liver (1.82 +/- 0.2 vs 1. 25 +/- 0.17; P < 0.05). IRS-1 was significantly increased in cirrhosis compared to normal liver (1.61 +/- 0.31 vs 0.86 +/- 0.21; P < 0.05). No differences were observed in Grb2 in the three tissue types. Insulin receptor overexpression, previously seen in other tumor types, may confer an insulin-mediated growth advantage in HCC if added receptors reflect functional high affinity binding sites. Although an altered mass of IRS-1 protein was not observed in HCC, an IRS-1 increase in cirrhosis may favor hepatic regeneration. CI - Copyright 1999 Academic Press. AD - Surgical Service, VA Connecticut Healthcare System, West Haven, Connecticut 06516, USA. FAU - Spector, S A AU - Spector SA FAU - Olson, E T AU - Olson ET FAU - Gumbs, A A AU - Gumbs AA FAU - Friess, H AU - Friess H FAU - Buchler, M W AU - Buchler MW FAU - Seymour, N E AU - Seymour NE LA - eng PT - Journal Article PL - UNITED STATES TA - J Surg Res JID - 0376340 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (RNA, Messenger) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Carcinoma, Hepatocellular/metabolism MH - Electrophoresis, Polyacrylamide Gel MH - Gene Expression MH - Humans MH - Immunoblotting MH - Liver/chemistry/metabolism MH - Liver Cirrhosis/metabolism MH - Liver Diseases/*metabolism MH - Liver Neoplasms/metabolism MH - Phosphoproteins/*metabolism MH - Proteins/*metabolism MH - RNA, Messenger/analysis MH - Receptor, Insulin/genetics/*metabolism MH - *Signal Transduction EDAT- 1999/04/22 MHDA- 1999/04/22 00:01 AID - S0022480498955536 [pii] PST - ppublish SO - J Surg Res 1999 May 1;83(1):32-5. -------------------------------------------------------------------------------- 177: Rouault JP et al. Regulation of dauer larva dev...[PMID: 10209098] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 10209098 OWN - NLM STAT- MEDLINE DA - 19990601 DCOM- 19990601 LR - 20050523 PUBM- Print IS - 0960-9822 VI - 9 IP - 6 DP - 1999 Mar 25 TI - Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. PG - 329-32 AB - The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade. AD - Unite INSERM U453, Centre Leon Berard, 69373 Lyon Cedex 08, France. FAU - Rouault, J P AU - Rouault JP FAU - Kuwabara, P E AU - Kuwabara PE FAU - Sinilnikova, O M AU - Sinilnikova OM FAU - Duret, L AU - Duret L FAU - Thierry-Mieg, D AU - Thierry-Mieg D FAU - Billaud, M AU - Billaud M LA - eng PT - Journal Article PL - ENGLAND TA - Curr Biol JID - 9107782 RN - 0 (Caenorhabditis elegans Proteins) RN - 0 (DAF-18 protein, C elegans) RN - 0 (DAF-2 protein, C elegans) RN - 0 (DNA, Complementary) RN - 0 (Helminth Proteins) RN - 0 (Membrane Lipids) RN - 0 (Phosphatidylinositol Phosphates) RN - 0 (Tumor Suppressor Proteins) RN - 0 (phosphatidylinositol 3,4,5-triphosphate) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.137 (AGE-1 protein, C elegans) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTEN protein) SB - IM MH - *1-Phosphatidylinositol 3-Kinase MH - Animals MH - Caenorhabditis elegans/genetics/*growth & development MH - *Caenorhabditis elegans Proteins MH - Catalysis MH - DNA, Complementary/genetics MH - *Genes, Structural, Helminth MH - *Genes, Tumor Suppressor MH - Helminth Proteins/genetics/*physiology MH - Humans MH - Larva/growth & development MH - Longevity/genetics MH - Membrane Lipids/metabolism MH - Multigene Family MH - Phosphatidylinositol Phosphates/metabolism MH - Phosphoric Monoester Hydrolases/*genetics MH - Phosphorylation MH - Receptor, Insulin/genetics/physiology MH - Research Support, Non-U.S. Gov't MH - *Tumor Suppressor Proteins EDAT- 1999/04/21 MHDA- 1999/04/21 00:01 AID - S0960982299801432 [pii] PST - ppublish SO - Curr Biol 1999 Mar 25;9(6):329-32. -------------------------------------------------------------------------------- 178: Frasca F et al. Insulin receptor isoform A, a...[PMID: 10207053] Related Articles, Substance via MeSH, Free in PMC, Cited in PMC, Cited in Books, Books, LinkOut PMID- 10207053 OWN - NLM STAT- MEDLINE DA - 19990518 DCOM- 19990518 LR - 20041117 PUBM- Print IS - 0270-7306 VI - 19 IP - 5 DP - 1999 May TI - Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. PG - 3278-88 AB - Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin led primarily to metabolic effects, whereas activation of IR-A by IGF-II led primarily to mitogenic effects. These differences in the biological effects of IR-A when activated by either IGF-II or insulin were associated with differential recruitment and activation of intracellular substrates. IR-A was preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney and had a relatively increased proportion of isoform A. IR-A expression was also increased in several tumors including those of the breast and colon. These data indicate, therefore, that there are two receptors for IGF-II, both IGF-I-R and IR-A. Further, they suggest that interaction of IGF-II with IR-A may play a role both in fetal growth and cancer biology. AD - Istituto di Medicina Interna, Malattie Endocrine e del Metabolismo, University of Catania, Ospedale Garibaldi, 95123 Catania, Italy. FAU - Frasca, F AU - Frasca F FAU - Pandini, G AU - Pandini G FAU - Scalia, P AU - Scalia P FAU - Sciacca, L AU - Sciacca L FAU - Mineo, R AU - Mineo R FAU - Costantino, A AU - Costantino A FAU - Goldfine, I D AU - Goldfine ID FAU - Belfiore, A AU - Belfiore A FAU - Vigneri, R AU - Vigneri R LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Mitogens) RN - 0 (Protein Isoforms) RN - 0 (RNA, Messenger) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - 3T3 Cells MH - Animals MH - CHO Cells MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cell Division MH - Hamsters MH - Insulin-Like Growth Factor II/*metabolism MH - Mice MH - Mitogen-Activated Protein Kinase 1 MH - Mitogen-Activated Protein Kinase 3 MH - *Mitogen-Activated Protein Kinases MH - Mitogens/metabolism MH - Phosphorylation MH - Protein Binding MH - Protein Isoforms/*metabolism MH - RNA, Messenger/analysis MH - Receptor Protein-Tyrosine Kinases/metabolism MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Transfection EDAT- 1999/04/17 MHDA- 1999/04/17 00:01 PST - ppublish SO - Mol Cell Biol 1999 May;19(5):3278-88. -------------------------------------------------------------------------------- 179: Salerno M et al. Insulin receptor substrate 1 ...[PMID: 10188734] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10188734 OWN - NLM STAT- MEDLINE DA - 19990413 DCOM- 19990413 LR - 20041117 PUBM- Print IS - 0020-7136 VI - 81 IP - 2 DP - 1999 Apr 12 TI - Insulin receptor substrate 1 is a target for the pure antiestrogen ICI 182,780 in breast cancer cells. PG - 299-304 AB - The pure antiestrogen ICI 182,780 inhibits insulin-like growth factor (IGF)-dependent proliferation in hormone-responsive breast cancer cells. However, the interactions of ICI 182,780 with IGF-I receptor (IGF-IR) intracellular signaling have not been characterized. Here, we studied the effects of ICI 182,780 on IGF-IR signal transduction in MCF-7 breast cancer cells and in MCF-7-derived clones overexpressing either the IGF-IR or its 2 major substrates, insulin receptor substrate 1 (IRS-1) or src/collagen homology proteins (SHC). ICI 182,780 blocked the basal and IGF-I-induced growth in all studied cells in a dose-dependent manner; however, the clones with the greatest IRS-1 overexpression were clearly least sensitive to the drug. Pursuing ICI 182,780 interaction with IRS-1, we found that the antiestrogen reduced IRS-1 expression and tyrosine phosphorylation in several cell lines in the presence or absence of IGF-I. Moreover, in IRS-1-overexpressing cells, ICI 182,780 decreased IRS-1/p85 and IRS-1/GRB2 binding. The effects of ICI 182,780 on IGF-IR protein expression were not significant; however, the drug suppressed IGF-I-induced (but not basal) IGF-IR tyrosine phosphorylation. The expression and tyrosine phosphorylation of SHC as well as SHC/GRB binding were not influenced by ICI 182,780. In summary, downregulation of IRS-1 may represent one of the mechanisms by which ICI 182,780 inhibits the growth of breast cancer cells. Thus, overexpression of IRS-1 in breast tumors could contribute to the development of antiestrogen resistance. AD - Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Salerno, M AU - Salerno M FAU - Sisci, D AU - Sisci D FAU - Mauro, L AU - Mauro L FAU - Guvakova, M A AU - Guvakova MA FAU - Ando, S AU - Ando S FAU - Surmacz, E AU - Surmacz E LA - eng GR - DK 48969/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Int J Cancer JID - 0042124 RN - 0 (Estrogen Antagonists) RN - 0 (Insulin-Like Growth Factor Binding Proteins) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-1 protein) RN - 129453-61-8 (fulvestrant) RN - 50-28-2 (Estradiol) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Breast Neoplasms/*drug therapy/metabolism/pathology MH - Cell Division/drug effects MH - Estradiol/*analogs & derivatives/pharmacology MH - Estrogen Antagonists/*pharmacology MH - Female MH - Humans MH - Insulin-Like Growth Factor Binding Proteins/*drug effects MH - Phosphoproteins/genetics MH - RNA, Messenger/biosynthesis MH - Receptor, Insulin/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured EDAT- 1999/04/03 03:15 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1097-0215(19990412)81:2<299::AID-IJC21>3.0.CO;2-8 [pii] PST - ppublish SO - Int J Cancer 1999 Apr 12;81(2):299-304. -------------------------------------------------------------------------------- 180: Sanchez-Margalet V. Modulation of insulin recepto...[PMID: 10096784] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10096784 OWN - NLM STAT- MEDLINE DA - 19990517 DCOM- 19990517 LR - 20041117 PUBM- Print IS - 0012-186X VI - 42 IP - 3 DP - 1999 Mar TI - Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells. PG - 317-25 AB - Pancreastatin, a neuropeptide derived from chromogranin A, has a glycogenolytic and counterregulatory effect to insulin in the rat liver. This effect is mediated by calcium and protein kinase C activity. Our aim was to study the possible cross-talk between pancreastatin and the insulin signalling system, by using the well-studied insulin sensitive rat hepatoma HTC cells. First, we checked the counterregulatory effect of pancreastatin on insulin action. Pancreastatin dose-dependently inhibited insulin stimulated glycogen synthesis. This effect was not due to competition for insulin receptors. Moreover, when protein kinase C activation was blocked with staurosporine, this effect of pancreastatin was not observed. Next, we found a dose-dependent inhibition of insulin receptor autophosphorylation by pancreastatin. In addition, phosphorylation of the major substrates of insulin receptor in HTC, i. e. insulin-receptor substrate (IRS)-1/IRS-2 and p62 was also blunted and so was its association with p85 regulatory subunit of phosphatidylinositol-3-kinase. Moreover, the insulin activation of S6 kinase was also blocked by pancreastatin. Again, all these inhibitory effects of pancreastatin were prevented by staurosporine. Furthermore, pancreastatin produced Ser/Thr phosphorylation of insulin receptor by a staurosporine-sensitive mechanism. Finally, we checked the pancreastatin activation of protein kinase C in HTC cells and found that a "classical" isoform of this protein is translocated to the plasma membrane. These findings suggest that pancreastatin could exert its anti-insulin effect in the hepatocyte by interrupting the stimulation of early insulin receptor signalling as a result of phosphorylation. This interaction might have a role in the mechanisms of insulin resistance. AD - Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena Hospital, University of Seville, Spain. FAU - Sanchez-Margalet, V AU - Sanchez-Margalet V LA - eng PT - Journal Article PL - GERMANY TA - Diabetologia JID - 0006777 RN - 0 (Pancreatic Hormones) RN - 0 (insulin, iodo-) RN - 106477-83-2 (pancreastatin) RN - 11061-68-0 (Insulin) RN - 62996-74-1 (Staurosporine) RN - 7440-70-2 (Calcium) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM MH - Animals MH - Calcium/metabolism MH - Insulin/analogs & derivatives/metabolism/pharmacokinetics/*pharmacology MH - Kinetics MH - Liver Neoplasms, Experimental MH - Pancreatic Hormones/*pharmacology MH - Phosphorylation MH - Protein Kinase C/metabolism MH - Rats MH - Receptor, Insulin/drug effects/*physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects/physiology MH - Staurosporine/pharmacology EDAT- 1999/03/30 MHDA- 1999/03/30 00:01 PST - ppublish SO - Diabetologia 1999 Mar;42(3):317-25. -------------------------------------------------------------------------------- 181: Manes S et al. Concerted activity of tyrosin...[PMID: 10082579] Related Articles, Gene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 10082579 OWN - NLM STAT- MEDLINE DA - 19990420 DCOM- 19990420 LR - 20050317 PUBM- Print IS - 0270-7306 VI - 19 IP - 4 DP - 1999 Apr TI - Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. PG - 3125-35 AB - The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed. AD - Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Cientificas, Universidad Autonoma de Madrid, Campus de Cantoblanco, E-28049 Madrid, Spain. smanes@cnb.uam.es FAU - Manes, S AU - Manes S FAU - Mira, E AU - Mira E FAU - Gomez-Mouton, C AU - Gomez-Mouton C FAU - Zhao, Z J AU - Zhao ZJ FAU - Lacalle, R A AU - Lacalle RA FAU - Martinez-A, C AU - Martinez-A C LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Cell Adhesion Molecules) RN - 0 (Chemotactic Factors) RN - 0 (Cytoskeletal Proteins) RN - 0 (Integrins) RN - 0 (Phosphoproteins) RN - 0 (RANTES) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (paxillin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - Cell Adhesion/physiology MH - Cell Adhesion Molecules/*metabolism MH - Cell Movement/*physiology MH - Chemotactic Factors/metabolism MH - Chemotaxis/physiology MH - Cytoskeletal Proteins/metabolism MH - Humans MH - Insulin-Like Growth Factor I/*pharmacology MH - Integrins/metabolism MH - Models, Biological MH - Neoplasm Invasiveness MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Binding MH - Protein-Tyrosine Kinase/*metabolism MH - Protein-Tyrosine-Phosphatase/genetics/*metabolism MH - RANTES/pharmacology MH - Receptor Cross-Talk/*physiology MH - Receptor, IGF Type 1/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1999/03/19 MHDA- 1999/03/19 00:01 PST - ppublish SO - Mol Cell Biol 1999 Apr;19(4):3125-35. -------------------------------------------------------------------------------- 182: Gil EB et al. Regulation of the insulin-lik...[PMID: 10077613] Related Articles, Gene, HomoloGene, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 10077613 OWN - NLM STAT- MEDLINE DA - 19990520 DCOM- 19990520 LR - 20050523 PUBM- Print IS - 0027-8424 VI - 96 IP - 6 DP - 1999 Mar 16 TI - Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene. PG - 2925-30 AB - The human PTEN tumor suppressor gene is mutated in a wide variety of sporadic tumors. To determine the function of PTEN in vivo we have studied a PTEN homolog in Caenorhabditis elegans. We have generated a strong loss-of-function allele of the PTEN homolog and shown that the deficient strain is unable to enter dauer diapause. An insulin-like phosphatidylinositol 3-OH kinase (PI3'K) signaling pathway regulates dauer-stage entry. Mutations in either the daf-2 insulin receptor-like (IRL) gene or the age-1 encoded PI3'K catalytic subunit homolog cause constitutive dauer formation and also affect the life span, brood size, and metabolism of nondauer animals. Strikingly, loss-of-function mutations in the age-1 PI3'K and daf-2 IRL genes are suppressed by loss-of-function mutations in the PTEN homolog. We establish that the PTEN homolog is encoded by daf-18, a previously uncloned gene that has been shown to interact genetically with the DAF-2 IRL AGE-1 PI3'K signaling pathway. This interaction provides clear genetic evidence that PTEN acts to antagonize PI3'K function in vivo. Given the conservation of the PI3'K signaling pathway between C. elegans and mammals, the analysis of daf-18 PTEN mutant nematodes should shed light on the role of human PTEN in the etiology of metabolic disease, aging, and cancer. AD - Department of Biology, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. FAU - Gil, E B AU - Gil EB FAU - Malone Link, E AU - Malone Link E FAU - Liu, L X AU - Liu LX FAU - Johnson, C D AU - Johnson CD FAU - Lees, J A AU - Lees JA LA - eng SI - GENBANK/AF126286 PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (DAF-2 protein, C elegans) RN - 0 (Tumor Suppressor Proteins) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (PTEN protein) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/genetics/metabolism MH - Alleles MH - Amino Acid Sequence MH - Animals MH - Caenorhabditis elegans/*genetics/metabolism MH - *Gene Expression Regulation MH - *Genes, Tumor Suppressor MH - Humans MH - Insulin-Like Growth Factor I/*genetics/metabolism MH - Molecular Sequence Data MH - Mutation MH - Phosphoric Monoester Hydrolases/*genetics MH - Receptor, Insulin/genetics/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Homology, Nucleic Acid MH - Signal Transduction/*genetics MH - *Tumor Suppressor Proteins EDAT- 1999/03/17 MHDA- 1999/03/17 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1999 Mar 16;96(6):2925-30. -------------------------------------------------------------------------------- 183: Sanchez-Margalet V et al. Insulin activates G alpha il,...[PMID: 10065161] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10065161 OWN - NLM STAT- MEDLINE DA - 19990329 DCOM- 19990329 LR - 20041117 PUBM- Print IS - 1420-682X VI - 55 IP - 1 DP - 1999 Jan TI - Insulin activates G alpha il,2 protein in rat hepatoma (HTC) cell membranes. PG - 142-7 AB - Insulin action is initiated by binding to its cognate receptor, which then triggers multiple cellular responses by activating different signaling pathways. There is evidence that insulin receptor signaling may involve G protein activation in different target cells. We have studied the activation of G proteins in rat hepatoma (HTC) cells. We found that insulin stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-35S) to plasma membrane proteins of HTC cells, in a dose-dependent manner. This effect was completely blocked by pertussis toxin treatment of the membranes, suggesting the involvement of G proteins of the G alpha i/G alpha o family. The expression of these G alpha proteins was checked by Western blotting. Next, we used blocking antibodies to sort out the specific G alpha protein activated by insulin stimulation. Anti-G alpha il,2 antibodies completely prevented insulin-stimulated GTP binding, whereas anti-G alpha o,i3 did not modify this effect of insulin on GTP binding. Moreover, we found physical association of the insulin receptor with G alpha il,2 by copurification studies. These results further support the involvement of a pertussis toxin-sensitive G protein in insulin receptor signaling and provides some evidence of specific association and activation of G alpha il,2 protein by insulin. These findings suggest that G alpha il,2 proteins might be involved in insulin action. AD - Departamento de Bioquimica Medica y Biologia Molecular, Facultad de Medicina, Hospital Universitario Virgen Macarena, Sevilla, Spain. FAU - Sanchez-Margalet, V AU - Sanchez-Margalet V FAU - Gonzalez-Yanes, C AU - Gonzalez-Yanes C FAU - Santos-Alvarez, J AU - Santos-Alvarez J FAU - Najib, S AU - Najib S LA - eng PT - Journal Article PL - SWITZERLAND TA - Cell Mol Life Sci JID - 9705402 RN - 0 (Antibodies) RN - 0 (Virulence Factors, Bordetella) RN - 11061-68-0 (Insulin) RN - 86-01-1 (Guanosine Triphosphate) RN - EC 2.4.2.31 (Pertussis Toxin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.6.1.- (GTP-Binding Proteins) SB - IM MH - Animals MH - Antibodies/pharmacology MH - Carcinoma, Hepatocellular/*metabolism MH - Cell Membrane/*metabolism MH - Cells, Cultured MH - GTP-Binding Proteins/immunology/*metabolism MH - Guanosine Triphosphate/metabolism MH - Insulin/*pharmacology MH - Pertussis Toxin MH - Protein Binding/drug effects MH - Rats MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Virulence Factors, Bordetella/pharmacology EDAT- 1999/03/05 MHDA- 1999/03/05 00:01 PST - ppublish SO - Cell Mol Life Sci 1999 Jan;55(1):142-7. -------------------------------------------------------------------------------- 184: Arbet-Engels C et al. C-terminal Src kinase associa...[PMID: 10026153] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 10026153 OWN - NLM STAT- MEDLINE DA - 19990318 DCOM- 19990318 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 274 IP - 9 DP - 1999 Feb 26 TI - C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor. PG - 5422-8 AB - Increased expression of the insulin-like growth factor-I receptor (IGF-IR) protein-tyrosine kinase occurs in several kinds of cancer and induces neoplastic transformation in fibroblast cell lines. The transformed phenotype can be reversed by interfering with the function of the IGF-IR. The IGF-IR is required for transformation by a number of viral and cellular oncoproteins, including SV40 large T antigen, Ras, Raf, and Src. The IGF-IR is a substrate for Src in vitro and is phosphorylated in v-Src-transformed cells. We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation. We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR. We determined the tyrosine residues in the IGF-IR and in the IR responsible for this interaction. We also observed that fibroblasts stimulated with IGF-I or insulin showed a rapid and transient decrease in c-Src tyrosine kinase activity. The results suggest that c-Src and CSK are involved in IGF-IR and IR signaling and that the interaction of CSK with the IGF-IR may play a role in the decrease in c-Src activity following IGF-I stimulation. AD - Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. arbet@axp1.salk.edu FAU - Arbet-Engels, C AU - Arbet-Engels C FAU - Tartare-Deckert, S AU - Tartare-Deckert S FAU - Eckhart, W AU - Eckhart W LA - eng GR - CA 13884/CA/NCI GR - CA 14195/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Ligands) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (protein-tyrosine kinase c-src) SB - IM MH - Cell Line MH - Humans MH - Ligands MH - Protein Binding MH - Protein-Tyrosine Kinase/*metabolism MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - src Homology Domains EDAT- 1999/02/20 MHDA- 1999/02/20 00:01 PST - ppublish SO - J Biol Chem 1999 Feb 26;274(9):5422-8. -------------------------------------------------------------------------------- 185: Banerjee K et al. Ethanol inhibition of insulin...[PMID: 9884156] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9884156 OWN - NLM STAT- MEDLINE DA - 19990329 DCOM- 19990329 LR - 20041117 PUBM- Print IS - 0145-6008 VI - 22 IP - 9 DP - 1998 Dec TI - Ethanol inhibition of insulin signaling in hepatocellular carcinoma cells. PG - 2093-101 AB - Chronic ethanol toxicity impairs liver regeneration, inhibits DNA synthesis, and mutes cellular responses to growth factor stimulation. Previous studies demonstrated that the adverse effects of ethanol are mediated by inhibition of tyrosyl phosphorylation of the insulin receptor and the insulin receptor substrate-type 1 (IRS-1). However, overexpression of IRS-1 leads to increased DNA synthesis and cellular transformation due to constitutive activation of mitogen-activated protein (MAP) kinase. The present study examines the effects of ethanol on insulin signaling through IRS-1 in FOCUS hepatocellular carcinoma cells, which overexpress IRS-1, to determine whether such cells were resistant to the inhibitory effects of ethanol. The results demonstrated that ethanol treatment (100 mM) caused 30 to 50% reductions in the levels of insulin-stimulated tyrosyl phosphorylation of the insulin receptor beta-subunit, tyrosyl phosphorylation of IRS-1, phosphorylation of Erk2, association of phosphatidylinositol-3 kinase with tyrosyl-phosphorylated IRS-1, and MAP kinase and phosphatidylinositol-3 kinase activities. In contrast, ethanol treatment had no effect on epidermal growth factor-stimulated tyrosyl phosphorylation of Shc. Corresponding with the pronounced inhibition of MAP kinase, ethanol treatment resulted in 30 to 50% reductions in the expression levels of two important insulin-responsive genes: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and proliferating cell nuclear antigen (PCNA). The findings suggest that, in FOCUS hepatocellular carcinoma cells, which overexpress IRS-1, ethanol treatment substantially inhibits IRS-1 and MAP kinase signaling and growth-associated gene expression, but has no effect on Shc phosphorylation, which activates p21ras through an IRS-1 independent pathway. AD - MGH East Cancer Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA. FAU - Banerjee, K AU - Banerjee K FAU - Mohr, L AU - Mohr L FAU - Wands, J R AU - Wands JR FAU - de la Monte, S M AU - de la Monte SM LA - eng GR - AA-02666/AA/NIAAA GR - AA-10102/AA/NIAAA GR - CA-35711/CA/NCI PT - Journal Article PL - UNITED STATES TA - Alcohol Clin Exp Res JID - 7707242 RN - 0 (Phosphoproteins) RN - 0 (Proliferating Cell Nuclear Antigen) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 64-17-5 (Ethanol) RN - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases) SB - IM MH - Carcinoma, Hepatocellular MH - Dose-Response Relationship, Drug MH - Ethanol/*toxicity MH - Gene Expression Regulation, Neoplastic/physiology MH - Glyceraldehyde-3-Phosphate Dehydrogenases/genetics MH - Humans MH - Insulin/*physiology MH - Liver Neoplasms MH - Liver Regeneration/*drug effects MH - Phosphoproteins/genetics MH - Proliferating Cell Nuclear Antigen/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured/*drug effects EDAT- 1999/01/12 MHDA- 1999/01/12 00:01 AID - 00000374-199812000-00028 [pii] PST - ppublish SO - Alcohol Clin Exp Res 1998 Dec;22(9):2093-101. -------------------------------------------------------------------------------- 186: Ando' S et al. Role of IRS-1 signaling in in...[PMID: 9878535] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9878535 OWN - NLM STAT- MEDLINE DA - 19990120 DCOM- 19990120 LR - 20041117 PUBM- Print IS - 0006-291X VI - 253 IP - 2 DP - 1998 Dec 18 TI - Role of IRS-1 signaling in insulin-induced modulation of estrogen receptors in breast cancer cells. PG - 315-9 AB - Cross-talk between steroid hormones and polypeptide growth factors regulates the growth of hormone-responsive breast cancer cells. For example, in the MCF-7 human breast cancer cell line, insulin up-regulates estrogen receptor (ER) content and binding capacity. Since the insulin receptor (IR) substrate 1 (IRS-1) is one of the core signaling elements transmitting mitogenic and metabolic effects of insulin, we investigated whether IRS-1 is also required for the insulin-induced function of the ER. The effects of insulin on the ER were compared in MCF-7 cells and MCF-7-derived cell lines with decreased levels (by approximately 80%) of IRS-1 due to the expression of IRS-1 antisense RNA. The severe IRS-1 deficiency in MCF-7 cells was associated with (1) reduced mitogenic response to 20 ng/ml insulin and 10% calf serum (CS), but not to 1 nM estradiol (E2); (2) loss of insulin-E2 synergism; (3) up-regulation of ER protein expression and binding capacity; and (4) loss of insulin-induced regulation of ER tyrosine phosphorylation. In conclusion, the data confirm the existence of the IR-ER cross-talk and suggest that IRS-1-dependent signaling may contribute to the negative regulation of the ER expression and function in MCF-7 cells. CI - Copyright 1998 Academic Press. AD - Dipartimento di Biologia Cellulare, Universita' degli Studi della Calabria, Cosenza, Italy. sando@diemme.it FAU - Ando', S AU - Ando' S FAU - Panno, M L AU - Panno ML FAU - Salerno, M AU - Salerno M FAU - Sisci, D AU - Sisci D FAU - Mauro, L AU - Mauro L FAU - Lanzino, M AU - Lanzino M FAU - Surmacz, E AU - Surmacz E LA - eng GR - DK48969/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (Culture Media, Conditioned) RN - 0 (Growth Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Estrogen) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 50-28-2 (Estradiol) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Breast Neoplasms/*metabolism MH - Culture Media, Conditioned/pharmacology MH - Down-Regulation/physiology MH - Estradiol/pharmacology MH - Growth Inhibitors/physiology MH - Humans MH - Insulin/*pharmacology MH - Phosphoproteins/*physiology MH - Phosphorylation MH - Protein Binding/physiology MH - Receptor Cross-Talk/physiology MH - Receptor, Insulin/*metabolism MH - Receptors, Estrogen/biosynthesis/drug effects/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/*physiology MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 1999/01/08 MHDA- 1999/01/08 00:01 AID - S0006291X98993305 [pii] PST - ppublish SO - Biochem Biophys Res Commun 1998 Dec 18;253(2):315-9. -------------------------------------------------------------------------------- 187: Holte J. Polycystic ovary syndrome and...[PMID: 9856413] Related Articles, Books, LinkOut PMID- 9856413 OWN - NLM STAT- MEDLINE DA - 19990223 DCOM- 19990223 LR - 20041117 PUBM- Print IS - 0391-4097 VI - 21 IP - 9 DP - 1998 Oct TI - Polycystic ovary syndrome and insulin resistance: thrifty genes struggling with over-feeding and sedentary life style? PG - 589-601 AB - Almost two decades of research have greatly increased our knowledge in the complex field of metabolic aberrations in polycystic ovary syndrome, but still many problems remain unsolved. The statistical association between insulin levels and androgens originally put the focus on possible direct cause-and-effect relationships between these factors. Indeed there is evidence that insulin may affect ovarian functions in multiple ways, presumably in some cases causing anovulation and hyperandrogenism. Clearly, insulin may increase biologically active testosterone through reducing SHBG levels. Conversely, major increases in androgen levels may induce muscular changes leading to reduced insulin-mediated glucose uptake. There are suggestions of increased steroidogenesis in both ovarian and adrenal pathways, with the net result of increased androgen production. There are also findings supporting increased corticosteroid production, which could contribute to insulin resistance directly or through promoting accumulation of abdominal fat, a typical feature of over-weight women with PCOS. Free fatty acids, released in great amounts from abdominal fat, may induce insulin resistance. Insulin resistance may also be due to a primary aberration in the insulin receptor. Putatively increased serine phosphorylation may cause both impairment of the insulin signal and increased 17,20 lyase activity, thus suggesting a common cause for insulin resistance and increased androgen production. There are also findings supporting a high prevalence of beta-cell dysfunction in PCOS, ranging from increased insulin secretion, not explained by insulin resistance or BMI, to failing beta-cell function, mainly in obese women during progress to glucose intolerance and NIDDM. Recent genetic findings also support a multifactorial genesis to PCOS, notably with positive findings both in genes regulating steroidogenesis and insulin secretion. It is suggested that PCOS is the result of "thrifty" genes, providing advantages in times of shortage of nutrition such as muscular strength, moderate abdominal fatness and decreased insulin sensitivity, i.e. an anabolic, energy saving constitution. However, when this constitution is exposed to unlimited food supplies and modern sedentary life style a full-blown PCOS with insulin resistance and infertility is triggered, presumably via several mechanisms, which follow a logical amplification system between two basic anabolic hormones, insulin and testosterone. AD - Department of Obstetrics and Gynaecology, Uppsala University, Akademiska Hospital, Sweden. FAU - Holte, J AU - Holte J LA - eng PT - Journal Article PT - Review PL - ITALY TA - J Endocrinol Invest JID - 7806594 SB - IM MH - Body Composition MH - Body Constitution MH - Diabetes Mellitus, Type 2 MH - Exercise MH - Female MH - Humans MH - *Hyperphagia MH - Insulin Resistance/*genetics MH - *Life Style MH - Polycystic Ovary Syndrome/*genetics RF - 101 EDAT- 1998/12/18 MHDA- 1998/12/18 00:01 PST - ppublish SO - J Endocrinol Invest 1998 Oct;21(9):589-601. -------------------------------------------------------------------------------- 188: Kim B et al. Insulin receptor substrate 2 ...[PMID: 9852124] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 9852124 OWN - NLM STAT- MEDLINE DA - 19990126 DCOM- 19990126 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 273 IP - 51 DP - 1998 Dec 18 TI - Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling. PG - 34543-50 AB - The major substrates for the type I insulin-like growth factor (IGF-I) receptor are Shc and insulin receptor substrate (IRS) proteins. In the current study, we report that IGF-I induces a sustained tyrosine phosphorylation of Shc and its association with Grb2 in SH-SY5Y human neuroblastoma cells. The time course of Shc tyrosine phosphorylation parallels the time course of IGF-I-stimulated activation of extracellular signal-regulated kinase (ERK). Transfection of SH-SY5Y cells with a p52 Shc mutant decreases Shc tyrosine phosphorylation and Shc-Grb2 association. This results in the inhibition of IGF-I-mediated ERK tyrosine phosphorylation and neurite outgrowth. In contrast, IGF-I induces a transient tyrosine phosphorylation of IRS-2 and an association of IRS-2 with Grb2. The time course of IRS-2 tyrosine phosphorylation and IRS-2-Grb2 and IRS-2-p85 association closely resembles the time course of IGF-I-mediated membrane ruffling. Treating cells with the phosphatidylinositol 3'-kinase inhibitors wortmannin and LY294002 blocks IGF-I-induced membrane ruffling. The ERK kinase inhibitor PD98059, as well as transfection with the p52 Shc mutant, has no effect on IGF-I-mediated membrane ruffling. Immunolocalization studies show IRS-2 and Grb2, but not Shc, concentrated at the tip of the extending growth cone where membrane ruffling is most active. Collectively, these results suggest that the association of Shc with Grb2 is essential for IGF-I-mediated neurite outgrowth, whereas the IRS-2-Grb2-phosphatidylinositol 3'-kinase complex may regulate growth cone extension and membrane ruffling. AD - Neuroscience Program and Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA. FAU - Kim, B AU - Kim B FAU - Cheng, H L AU - Cheng HL FAU - Margolis, B AU - Margolis B FAU - Feldman, E L AU - Feldman EL LA - eng GR - R01 NS36778/NS/NINDS GR - R01 NS38849/NS/NINDS PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Androstadienes) RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Morpholines) RN - 0 (PD 98059) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Recombinant Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-2 protein) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 19545-26-7 (wortmannin) RN - 21820-51-9 (Phosphotyrosine) RN - 62229-50-9 (Epidermal Growth Factor) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Androstadienes/pharmacology MH - Cell Membrane/physiology/ultrastructure MH - Chromones/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Epidermal Growth Factor/pharmacology/physiology MH - Flavonoids/pharmacology MH - Humans MH - Insulin-Like Growth Factor I/*pharmacology/physiology MH - Models, Biological MH - Morpholines/pharmacology MH - Neurites/physiology MH - Neuroblastoma MH - Phosphoproteins/genetics/*metabolism MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Proteins/genetics/*metabolism MH - Receptor, Insulin/*physiology MH - Recombinant Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*physiology MH - Transfection MH - Tumor Cells, Cultured MH - src Homology Domains EDAT- 1998/12/16 MHDA- 1998/12/16 00:01 PST - ppublish SO - J Biol Chem 1998 Dec 18;273(51):34543-50. -------------------------------------------------------------------------------- 189: Kim B et al. Differential regulation of in...[PMID: 9832424] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9832424 OWN - NLM STAT- MEDLINE DA - 19981224 DCOM- 19981224 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 139 IP - 12 DP - 1998 Dec TI - Differential regulation of insulin receptor substrate-2 and mitogen-activated protein kinase tyrosine phosphorylation by phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human neuroblastoma cells. PG - 4881-9 AB - Insulin-like growth factor I (IGF-I) is a potent neurotropic factor promoting the differentiation and survival of neuronal cells. SH-SY5Y human neuroblastoma cells are a well characterized in vitro model of nervous system growth. We report here that IGF-I stimulated the tyrosine phosphorylation of the type I IGF receptor (IGF-IR) and insulin receptor substrate-2 (IRS-2) in a time- and concentration-dependent manner. These cells lacked IRS-1. After being tyrosine phosphorylated, IRS-2 associated transiently with downstream signaling molecules, including phosphatidylinositol 3-kinase (PI 3-K) and Grb2. Treatment of the cells with PI 3-K inhibitors (wortmannin and LY294002) increased IGF-I-induced tyrosine phosphorylation of IRS-2. We also observed a concomitant increase in the mobility of IRS-2, suggesting that PI 3-K mediates or is required for IRS-2 serine/threonine phosphorylation, and that this phosphorylation inhibits IRS-2 tyrosine phosphorylation. Treatment with PI 3-K inhibitors induced an increased association of IRS-2 with Grb2, probably as a result of the increased IRS-2 tyrosine phosphorylation. However, even though the PI 3-K inhibitors enhanced the association of Grb2 with IRS-2, these compounds suppressed IGF-I-induced mitogen-activated protein kinase activation and neurite outgrowth. Together, these results indicate that although PI 3-K participates in a negative regulation of IRS-2 tyrosine phosphorylation, its activity is required for IGF-IR-mediated mitogen-activated protein kinase activation and neurite outgrowth. AD - Department of Neurology, University of Michigan, Ann Arbor 48109-0588, USA. FAU - Kim, B AU - Kim B FAU - Leventhal, P S AU - Leventhal PS FAU - White, M F AU - White MF FAU - Feldman, E L AU - Feldman EL LA - eng GR - R01-NS-36778/NS/NINDS GR - R29-NS-32843/NS/NINDS PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Enzyme Inhibitors) RN - 0 (Isoenzymes) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/*antagonists & inhibitors/metabolism MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Ca(2+)-Calmodulin Dependent Protein Kinase/antagonists & inhibitors/*metabolism MH - Electrophoresis, Polyacrylamide Gel MH - Enzyme Inhibitors/*pharmacology MH - Humans MH - Insulin-Like Growth Factor I/pharmacology MH - Isoenzymes/metabolism MH - Mitogen-Activated Protein Kinase 1 MH - Neurites/drug effects/physiology MH - Neuroblastoma/*metabolism/pathology MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - Tyrosine/*metabolism EDAT- 1998/12/01 MHDA- 1998/12/01 00:01 PST - ppublish SO - Endocrinology 1998 Dec;139(12):4881-9. -------------------------------------------------------------------------------- 190: Harder KW et al. Protein-tyrosine phosphatase ...[PMID: 9822658] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 9822658 OWN - NLM STAT- MEDLINE DA - 19981223 DCOM- 19981223 LR - 20050209 PUBM- Print IS - 0021-9258 VI - 273 IP - 48 DP - 1998 Nov 27 TI - Protein-tyrosine phosphatase alpha regulates Src family kinases and alters cell-substratum adhesion. PG - 31890-900 AB - The roles of protein-tyrosine phosphatases (PTPs) in processes such as cell growth and adhesion are poorly understood. To explore the ability of specific PTPs to regulate cell signaling pathways initiated by stimulation of growth factor receptors, we expressed the receptor-like PTP, PTPalpha, in A431 epidermoid carcinoma cells. These cells express high levels of the epidermal growth factor (EGF) receptor and proliferate in response to the autocrine production of transforming growth factor-alpha. Conversely, EGF stimulation of A431 cells in vitro leads to growth inhibition and triggers the rapid detachment of these cells from the substratum. Although PTPalpha expression did not alter the growth characteristics of either unstimulated or EGF-stimulated cells, this phosphatase was associated with increased cell-substratum adhesion. Furthermore, PTPalpha-expressing A431 cells were strikingly resistant to EGF-induced cell rounding. Overexpression of PTPalpha in A431 cells was associated with the dephosphorylation/activation of specific Src family kinases, suggesting a potential mechanism for the observed alteration in A431 cell-substratum adhesion. Src kinase activation was dependent on the D1 catalytic subunit of PTPalpha, and there was evidence of association between PTPalpha and Src kinase(s). PTPalpha expression also led to increased association of Src kinase with the integrin-associated focal adhesion kinase, pp125(FAK). In addition, paxillin, a Src and/or pp125(FAK) substrate, displayed increased levels of tyrosine phosphorylation in PTPalpha-expressing cells and was associated with elevated amounts of Csk. In view of these alterations in focal adhesion-associated molecules in PTPalpha-expressing A431 cells, as well as the changes in adhesion demonstrated by these cells, we propose that PTPalpha may have a role in regulating cell-substratum adhesion. AD - Centre for Molecular Medicine and Therapeutics and the Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. FAU - Harder, K W AU - Harder KW FAU - Moller, N P AU - Moller NP FAU - Peacock, J W AU - Peacock JW FAU - Jirik, F R AU - Jirik FR LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Cell Adhesion Molecules) RN - 0 (Cytoskeletal Proteins) RN - 0 (Peptide Fragments) RN - 0 (Phosphopeptides) RN - 0 (Phosphoproteins) RN - 0 (Recombinant Proteins) RN - 0 (Rosaniline Dyes) RN - 0 (Transforming Growth Factor alpha) RN - 0 (paxillin) RN - 10309-95-2 (malachite green) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - Amino Acid Sequence MH - Carcinoma, Squamous Cell MH - Cell Adhesion/drug effects/*physiology MH - Cell Adhesion Molecules/metabolism MH - Cell Division/drug effects MH - Cell Size/drug effects/physiology MH - Cloning, Organism MH - Cytoskeletal Proteins/metabolism MH - Epidermal Growth Factor/pharmacology/physiology MH - Humans MH - Kinetics MH - Molecular Sequence Data MH - Peptide Fragments/chemistry MH - Phosphopeptides/chemistry MH - Phosphoproteins/metabolism MH - Protein-Tyrosine Kinase/*metabolism MH - Protein-Tyrosine-Phosphatase/biosynthesis/*metabolism MH - Receptor, Epidermal Growth Factor/genetics/metabolism MH - Receptor, Insulin/metabolism MH - Recombinant Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Rosaniline Dyes/metabolism MH - Substrate Specificity MH - Transfection MH - Transforming Growth Factor alpha/pharmacology/physiology MH - Tumor Cells, Cultured MH - *src Homology Domains EDAT- 1998/11/21 MHDA- 1998/11/21 00:01 PST - ppublish SO - J Biol Chem 1998 Nov 27;273(48):31890-900. -------------------------------------------------------------------------------- 191: Murakami Y et al. Effect of herbimycin A on tyr...[PMID: 9821805] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9821805 OWN - NLM STAT- MEDLINE DA - 19990114 DCOM- 19990114 LR - 20041117 PUBM- Print IS - 0918-6158 VI - 21 IP - 10 DP - 1998 Oct TI - Effect of herbimycin A on tyrosine kinase receptors and platelet derived growth factor (PDGF)-induced signal transduction. PG - 1030-5 AB - Herbimycin A is widely used as an inhibitor of Src family protein tyrosine kinases but is also reported to induce the downregulation of epidermal growth factor (EGF) receptor number in A431 cells without inhibiting its tyrosine kinase activity. To determine the specificity of the receptor downregulation, we examined its effect on a variety of cell lines which express different levels of EGF receptor and on other tyrosine kinase receptors. Long-term herbimycin A treatment decreased the amounts of all the tyrosine kinase receptors examined in a dose-dependent manner. It also reduced ligand-stimulated receptor autophosphorylation in accordance with the reduction in the receptor level. Herbimycin A inhibited platelet derived growth factor (PDGF)-induced tyrosine phosphorylation of cellular proteins and DNA synthesis in NIH3T3 cells but did not affect the serum-stimulated DNA synthesis. PDGF-induced tyrosine phosphorylation and activation of c-Src was inhibited but the protein level of c-Src was not reduced by herbimycin A. The reduced level of c-Src kinase activity correlated with the levels of both PDGF receptor and DNA synthesis. These results indicate that the herbimycin A treatment selectively downregulates receptor tyrosine kinases, independent of the number of receptors, and suggest that c-Src is to some degree involved in the selective inhibition of PDGF-induced mitogenesis by herbimycin A. AD - Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan. FAU - Murakami, Y AU - Murakami Y FAU - Fukazawa, H AU - Fukazawa H FAU - Mizuno, S AU - Mizuno S FAU - Uehara, Y AU - Uehara Y LA - eng PT - Journal Article PL - JAPAN TA - Biol Pharm Bull JID - 9311984 RN - 0 (Anti-Bacterial Agents) RN - 0 (DNA, Neoplasm) RN - 0 (Enzyme Inhibitors) RN - 0 (Platelet-Derived Growth Factor) RN - 0 (Quinones) RN - 55520-40-6 (Tyrosine) RN - 70563-58-5 (herbimycin) RN - 9007-49-2 (DNA) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (Receptor, erbB-2) RN - EC 2.7.1.112 (Receptors, Platelet-Derived Growth Factor) RN - EC 2.7.1.112 (src-Family Kinases) SB - IM MH - 3T3 Cells MH - Animals MH - Anti-Bacterial Agents/*pharmacology MH - DNA/biosynthesis MH - DNA, Neoplasm/biosynthesis MH - Enzyme Inhibitors/*pharmacology MH - Hela Cells MH - Humans MH - KB Cells MH - Mice MH - Phosphorylation MH - Platelet-Derived Growth Factor/*pharmacology MH - Quinones/*pharmacology MH - Rats MH - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*drug effects MH - Receptor, Epidermal Growth Factor/drug effects/metabolism MH - Receptor, Insulin/drug effects/metabolism MH - Receptor, erbB-2/drug effects/metabolism MH - Receptors, Platelet-Derived Growth Factor/drug effects/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects/physiology MH - Stimulation, Chemical MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - src-Family Kinases/antagonists & inhibitors/drug effects EDAT- 1998/11/20 MHDA- 1998/11/20 00:01 PST - ppublish SO - Biol Pharm Bull 1998 Oct;21(10):1030-5. -------------------------------------------------------------------------------- 192: Buchdunger E et al. 4,5-bis(4-fluoroanilino)phtha...[PMID: 9816050] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9816050 OWN - NLM STAT- MEDLINE DA - 19990218 DCOM- 19990218 LR - 20041117 PUBM- Print IS - 1078-0432 VI - 1 IP - 8 DP - 1995 Aug TI - 4,5-bis(4-fluoroanilino)phthalimide: A selective inhibitor of the epidermal growth factor receptor signal transduction pathway with potent in vivo antitumor activity. PG - 813-21 AB - Deregulated signal transduction via the epidermal growth factor (EGF) receptor family of tyrosine protein kinase growth factor receptors is associated with proliferative diseases such as cancer and psoriasis. In an attempt to selectively block signal transduction from the EGF receptor, we have synthesized a new class of dianilino-phthalimide tyrosine protein kinase inhibitors with selectivity for the EGF receptor tyrosine protein kinase. 4, 5-Dianilino-phthalimide (DAPH 1) was metabolized in vitro by mouse liver fractions and in vivo. The major metabolite has been identified as 4-(4-hydroxyanilino)-5-anilino-phthalimide. To specifically block this biotransformation (hydroxylation), we have synthesized 4,5-bis(4-fluoroanilino)phthalimide (DAPH 2), a potent and selective EGF receptor tyrosine protein kinase inhibitor. DAPH 2 inhibits the EGF receptor and protein kinase C beta2 enzymes with equal potency. In cells, DAPH 2 inhibits signal output from the EGF receptor, but not from other classes of receptor protein tyrosine kinases, such as the platelet-derived growth factor receptor, fibroblast growth factor receptor, insulin-like growth factor I receptor, and insulin receptor. Selective antitumor activity was demonstrated in vivo at well-tolerated doses in mice. This publication describes the biological profile of DAPH 2 and investigates its cellular and in vivo mechanism of action. AD - Pharmaceuticals Division, Oncology Research and Preclinical Safety Departments, Ciba-Geigy Limited, CH-4002 Basel, Switzerland. FAU - Buchdunger, E AU - Buchdunger E FAU - Mett, H AU - Mett H FAU - Trinks, U AU - Trinks U FAU - Regenass, U AU - Regenass U FAU - Muller, M AU - Muller M FAU - Meyer, T AU - Meyer T FAU - Beilstein, P AU - Beilstein P FAU - Wirz, B AU - Wirz B FAU - Schneider, P AU - Schneider P FAU - Traxler, P AU - Traxler P AU - et al. LA - eng PT - Journal Article PL - UNITED STATES TA - Clin Cancer Res JID - 9502500 RN - 0 (4,5-bis(4-fluoroanilino)phthalimide) RN - 0 (Antineoplastic Agents) RN - 0 (Phthalimides) RN - 157168-02-0 (4,5-dianilinophthalimide) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) SB - IM MH - 3T3 Cells MH - Animals MH - Antineoplastic Agents/*pharmacokinetics/*therapeutic use/toxicity MH - Biotransformation MH - Bladder Neoplasms/*drug therapy MH - Carcinoma, Squamous Cell/*drug therapy MH - Cell Line, Transformed MH - Female MH - Humans MH - Liver/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred Strains MH - Phthalimides/*pharmacokinetics/*therapeutic use/toxicity MH - Rats MH - Rats, Inbred Strains MH - Receptor, Epidermal Growth Factor/antagonists & inhibitors/*physiology MH - Signal Transduction/*drug effects MH - Transplantation, Heterologous MH - Tumor Cells, Cultured EDAT- 1998/11/17 MHDA- 1998/11/17 00:01 PST - ppublish SO - Clin Cancer Res 1995 Aug;1(8):813-21. -------------------------------------------------------------------------------- 193: Surmacz E et al. Overexpression of insulin rec...[PMID: 9815941] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9815941 OWN - NLM STAT- MEDLINE DA - 19990209 DCOM- 19990209 LR - 20041117 PUBM- Print IS - 1078-0432 VI - 1 IP - 11 DP - 1995 Nov TI - Overexpression of insulin receptor substrate 1 (IRS-1) in the human breast cancer cell line MCF-7 induces loss of estrogen requirements for growth and transformation. PG - 1429-36 AB - The synergistic action of estrogens and insulin-like growth factors (IGFs) promotes the growth of many human breast cancer cell lines. This synergistic effect involves estrogen-dependent induction of the IGF system, i.e., estrogens augment the number of IGF-I receptors, stimulate the secretion of IGF-II, and promote the synthesis of certain IGF-binding proteins. On the other hand, the sustained activation of the IGF-I receptor (IGF-IR) by the overexpression of IGF-II has been found to contribute to the development of the estrogen-independent phenotype in breast cancer cells. In this study, we have investigated whether the amplification of the IGF-IR intracellular signaling in MCF-7 cells can abolish or reduce estrogen requirements for growth and transformation. To this end we developed several MCF-7 clones that overexpressed insulin receptor substrate 1 (IRS-1), one of the principal substrates of the IGF-IR. We report here that in MCF-7 cells overexpressing IRS-1, estrogen requirements for growth in monolayer culture as well as in soft agar were reduced. The decreased estrogen requirements depended on the level of the overexpressed IRS-1 protein, and in cells which contained several-fold more functional IRS-1 than the parental cells, we observed total loss of estrogen dependence for growth. In addition, the importance of IRS-1 in proliferation of MCF-7 cells has been confirmed through the use of antisense strategies. AD - Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Surmacz, E AU - Surmacz E FAU - Burgaud, J L AU - Burgaud JL LA - eng GR - DK 48969/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Clin Cancer Res JID - 9502500 RN - 0 (Estrogens) RN - 0 (Genetic Vectors) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor-related receptor) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Breast Neoplasms/metabolism/pathology MH - Cell Adhesion/drug effects MH - Cell Division/drug effects MH - Cell Transformation, Neoplastic/*metabolism/pathology MH - Estrogens/*pharmacology MH - Female MH - Genetic Vectors MH - Humans MH - Insulin-Like Growth Factor I/metabolism MH - Neoplasm Proteins/genetics/*metabolism MH - Phosphoproteins/genetics/*metabolism MH - Receptor, Insulin/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Transfection MH - Tumor Cells, Cultured/drug effects/metabolism/pathology MH - Tumor Stem Cell Assay EDAT- 1998/11/17 MHDA- 1998/11/17 00:01 PST - ppublish SO - Clin Cancer Res 1995 Nov;1(11):1429-36. -------------------------------------------------------------------------------- 194: Rocha RL et al. Insulin-like growth factor bi...[PMID: 9815544] Related Articles, Cited in PMC, Books, LinkOut PMID- 9815544 OWN - NLM STAT- MEDLINE DA - 19990216 DCOM- 19990216 LR - 20041117 PUBM- Print IS - 1078-0432 VI - 3 IP - 1 DP - 1997 Jan TI - Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. PG - 103-9 AB - Insulin-like growth factors (IGFs) interact with specific cell surface receptors to mediate cell growth. Intracellular effects of the IGFs are mediated by activation of secondary messenger molecules. One of these proteins, insulin receptor substrate-1 (IRS-1), is phosphorylated after type I IGF receptor activation and has a major role in IGF signaling. Receptor activation also is influenced by high-affinity IGF binding proteins (IGFBPs). In serum, IGFBP-3 is the predominant species. The role of IGFBP-3 in the regulation of breast cancer cell growth is unclear; both growth inhibition and stimulation have been documented in tissue culture systems. To investigate the influence of IGFBP-3 and IRS-1 in breast cancer, we measured levels of these proteins by ELISA and immunoblotting in 195 node-negative primary human breast cancers and compared their levels with known prognostic factors and disease-free survival (DFS). IGFBP-3 levels correlated positively with tumor size (r = 0.27, P < 0.0001) and negatively with estrogen receptor (r = -0.35, P < 0. 0001) and progesterone receptor (r = -0.16, P = 0.021). In contrast, IRS-1 did not correlate with prognostic factors, but higher levels of IRS-1 predicted worse DFS for the subset of patients with tumors 3.0.CO;2-Z [pii] PST - ppublish SO - Head Neck 1998 Dec;20(8):745-52. -------------------------------------------------------------------------------- 197: Kornmann M et al. Enhanced expression of the in...[PMID: 9766646] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9766646 OWN - NLM STAT- MEDLINE DA - 19981103 DCOM- 19981103 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 58 IP - 19 DP - 1998 Oct 1 TI - Enhanced expression of the insulin receptor substrate-2 docking protein in human pancreatic cancer. PG - 4250-4 AB - Insulin receptor substrate-2 (IRS-2) is a multisite docking protein implicated in mitogenic signaling after activation of the insulin and insulin-like growth factor (IGF)-I receptors. In the present study, we characterized IRS-2 expression and function in human pancreatic cancer. IRS-2 mRNA and protein were expressed in ASPC-1 and COLO-357 human pancreatic cancer cell lines. Insulin, IGF-I, and IGF-II enhanced the growth of both cell lines, stimulated tyrosine phosphorylation of IRS-2, and increased IRS-2-associated phosphatidylinositol (PI) 3-kinase activity. The mitogenic effects of insulin, IGF-I, and IGF-II were markedly attenuated by the PI 3-kinase inhibitor LY 294002. Northern blot analysis of total RNA extracted from normal and cancerous tissues revealed that IRS-2 mRNA levels were increased in the cancer tissues (P = 0.032). In the normal pancreas, IRS-2 immunoreactivity was present at low levels in some ductal and acinar cells and at moderate levels in a heterogeneous pattern in all of the endocrine islets. In the pancreatic cancers, IRS-2 was abundant in the ductal-like cancer cells. These findings indicate that IRS-2 is overexpressed in human pancreatic cancer and suggest that it may contribute to enhanced mitogenic signaling via the PI 3-kinase pathway, thereby leading to excessive growth stimulation in this malignancy. AD - Department of Medicine, University of California, Irvine 92697, USA. FAU - Kornmann, M AU - Kornmann M FAU - Maruyama, H AU - Maruyama H FAU - Bergmann, U AU - Bergmann U FAU - Tangvoranuntakul, P AU - Tangvoranuntakul P FAU - Beger, H G AU - Beger HG FAU - White, M F AU - White MF FAU - Korc, M AU - Korc M LA - eng GR - CA-40162/CA/NCI PT - Journal Article PL - UNITED STATES TA - Cancer Res JID - 2984705R RN - 0 (Growth Substances) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Colonic Neoplasms MH - Gene Expression Regulation, Neoplastic/drug effects/*physiology MH - Growth Substances/*pharmacology/physiology MH - Humans MH - Insulin/pharmacology MH - Insulin-Like Growth Factor I/pharmacology MH - Insulin-Like Growth Factor II/pharmacology MH - Pancreas/cytology/*metabolism MH - Pancreatic Neoplasms/genetics/*metabolism/pathology MH - Phosphoproteins/biosynthesis/*genetics MH - Protein Biosynthesis MH - RNA, Messenger/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Transcription, Genetic MH - Tumor Cells, Cultured EDAT- 1998/10/10 MHDA- 1998/10/10 00:01 PST - ppublish SO - Cancer Res 1998 Oct 1;58(19):4250-4. -------------------------------------------------------------------------------- 198: Ciaraldi TP et al. Lack of insulin resistance in...[PMID: 9711989] Related Articles, Books, LinkOut PMID- 9711989 OWN - NLM STAT- MEDLINE DA - 19980828 DCOM- 19980828 LR - 20041117 PUBM- Print IS - 0026-0495 VI - 47 IP - 8 DP - 1998 Aug TI - Lack of insulin resistance in fibroblasts from subjects with polycystic ovary syndrome. PG - 940-6 AB - Insulin resistance in polycystic ovary syndrome (PCOS) is characterized by a novel defect in insulin signal transduction expressed in isolated human adipocytes as impaired insulin sensitivity for glucose transport and antilipolysis. To determine whether this is a generalized defect of a potentially genetic basis, or possibly a tissue-specific one, fibroblast cultures were established from age- and weight-matched obese normal cycling (NC; n = 5) and PCOS (n = 6) subjects. Adipocytes from the current PCOS subjects displayed impaired sensitivity for glucose transport stimulation (half-maximal effective concentration [EC50], 317 +/- 58 pmol/L in PCOS v 130 +/- 40 in NC; P < .025). Specific insulin binding was similar in fibroblasts from NC (0.57% +/- 0.10%/10(6) cells) and PCOS (0.45% +/- 0.10%) subjects. Fibroblasts from NC (4.9- +/- 0.5-fold stimulation) and PCOS (4.6- +/- 0.3-fold) subjects were equally responsive to insulin for stimulation of glucose incorporation into glycogen. Insulin sensitivity for glycogen synthesis in fibroblasts did not differ between NC (EC50, 9.6 +/- 0.9 nmol/L) and PCOS (9.1 +/- 0.9) cells. For thymidine incorporation into DNA, relative insulin responsiveness was similar in NC (2.3- +/- 0.3-fold stimulation) and PCOS (2.1- +/- 0.1-fold) fibroblasts. Insulin sensitivity for DNA synthesis was similar in NC (EC50, 12.9 +/- 2.4 nmol/L) and PCOS (7.6 +/- 1.3) cells. In summary, (1) insulin receptor binding is normal in PCOS fibroblasts; and (2) PCOS fibroblasts have normal insulin sensitivity and responsiveness for metabolic and mitogenic responses. Impaired insulin signal transduction, while present in adipocytes from a group of PCOS subjects, is not found in fibroblasts from the same subjects. This defect is not generalized to all cell types, but may be limited to specific tissues and responses. AD - Department of Medicine, University of California, San Diego, La Jolla 92093, USA. FAU - Ciaraldi, T P AU - Ciaraldi TP FAU - Morales, A J AU - Morales AJ FAU - Hickman, M G AU - Hickman MG FAU - Odom-Ford, R AU - Odom-Ford R FAU - Yen, S S AU - Yen SS FAU - Olefsky, J M AU - Olefsky JM LA - eng GR - DK-33651/DK/NIDDK GR - DK33649/DK/NIDDK GR - HD-12303-19/HD/NICHD GR - etc. PT - Journal Article PL - UNITED STATES TA - Metabolism JID - 0375267 SB - IM MH - Adipose Tissue/metabolism MH - Adult MH - Case-Control Studies MH - Female MH - Fibroblasts/*metabolism MH - Humans MH - *Insulin Resistance MH - Obesity/complications/*metabolism MH - Polycystic Ovary Syndrome/complications/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. EDAT- 1998/08/26 MHDA- 1998/08/26 00:01 PST - ppublish SO - Metabolism 1998 Aug;47(8):940-6. -------------------------------------------------------------------------------- 199: Licato LL et al. Analysis of signaling protein...[PMID: 9690379] Related Articles, Cited in PMC, Books, LinkOut PMID- 9690379 OWN - NLM STAT- MEDLINE DA - 19980819 DCOM- 19980819 LR - 20050209 PUBM- Print IS - 0163-2116 VI - 43 IP - 7 DP - 1998 Jul TI - Analysis of signaling protein kinases in human colon or colorectal carcinomas. PG - 1454-64 AB - Extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases are highly activated in an in vivo rat model of colorectal carcinogenesis. In addition, other protein kinases such as c-Src and c-Yes have been shown to be up-regulated in some human colon cancers. To evaluate the activity of these kinases in human colorectal carcinomas, we examined colon cancers and adjacent normal intestinal mucosa from 11 patients. Moderate increases in ERK and JNK activities, in addition to up-regulation of c-Src, p125FAK, and tyrosine-phosphorylated proteins, were observed in a subset of the colorectal carcinomas. There was a significant correlation found between levels of c-Src, p125FAK, and tyrosine-phosphorylated proteins, as well as between c-Src protein levels and JNK activity. This is the first report that examines several different kinases as markers to characterize colorectal cancers in the same carcinoma sample, allowing the determination of correlations between markers in the same tumors. AD - Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 27599, USA. FAU - Licato, L L AU - Licato LL FAU - Brenner, D A AU - Brenner DA LA - eng GR - 5 P01CA50528/CA/NCI GR - DK-34987/DK/NIDDK GR - R01 7GM41804/GM/NIGMS PT - Journal Article PL - UNITED STATES TA - Dig Dis Sci JID - 7902782 RN - 0 (Cell Adhesion Molecules) RN - 0 (Transcription Factor AP-1) RN - 0 (Tumor Markers, Biological) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 2.7.1.112 (protein-tyrosine kinase c-src) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.37 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein Kinases) RN - EC 3.6.1.- (ras Proteins) SB - AIM SB - IM MH - Adenocarcinoma/*enzymology/metabolism MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cell Adhesion Molecules/metabolism MH - Colon/*enzymology MH - Colonic Neoplasms/*enzymology/metabolism MH - Humans MH - Immunoblotting MH - JNK Mitogen-Activated Protein Kinases MH - Mitogen-Activated Protein Kinase 3 MH - *Mitogen-Activated Protein Kinases MH - Protein Kinases/*metabolism MH - Protein-Tyrosine Kinase/metabolism MH - Receptor, Insulin/metabolism MH - Rectal Neoplasms/*enzymology/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Transcription Factor AP-1/metabolism MH - Tumor Markers, Biological/metabolism MH - *Up-Regulation MH - ras Proteins/metabolism MH - src Homology Domains EDAT- 1998/08/05 MHDA- 1998/08/05 00:01 PST - ppublish SO - Dig Dis Sci 1998 Jul;43(7):1454-64. -------------------------------------------------------------------------------- 200: Gliozzo B et al. Insulin-stimulated cell growt...[PMID: 9671232] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9671232 OWN - NLM STAT- MEDLINE DA - 19981020 DCOM- 19981020 LR - 20041118 PUBM- Print IS - 0730-2312 VI - 70 IP - 2 DP - 1998 Aug 1 TI - Insulin-stimulated cell growth in insulin receptor substrate-1-deficient ZR-75-1 cells is mediated by a phosphatidylinositol-3-kinase-independent pathway. PG - 268-80 AB - In many human breast cancers and cultured cell lines, insulin receptor expression is elevated, and insulin, via its own insulin receptor, can stimulate cell growth. It has recently been demonstrated that the enzyme phosphatidylinositol-3-kinase (PI3-K) mediates various aspects of insulin receptor signaling including cell growth. In order to understand the mechanisms for insulin-stimulated cell growth in human breast cancer, we measured insulin-stimulable PI3-K activity in a non-transformed breast epithelial cell line, MCF-10A, and in two malignantly transformed cell lines, ZR-75-1 and MDA-MB157. All three cell lines express comparable amounts of insulin receptors whose tyrosine autophosphorylation is increased by insulin, and in these cell lines insulin stimulates growth. In MDA-MB157 and MCF-10A cells, insulin stimulated PI3-K activity three- to fourfold. In ZR-75-1 cells, however, insulin did not stimulate PI3-K activity. In ZR-75-1 cells PI3-K protein was present, and its activity was stimulated by epidermal growth factor, suggesting that there might be a defect in insulin receptor signaling upstream of PI3-K and downstream of the insulin receptor. Next, we studied insulin receptor substrate-1 (IRS-1), a major endogenous substrate for the insulin receptor which, when tyrosine is phosphorylated by the insulin receptor, interacts with and activates PI3-K. In ZR-75-1 cells, there were reduced levels of protein for IRS-1. In these cells, both Shc tyrosine phosphorylation and mitogen-activated protein kinase (MAP-K) activity were increased by the insulin receptor (indicating that the p21ras pathway may account for insulin-stimulated cell growth in ZR-75-1 cells). The PI3-K inhibitor LY294002 (50 microM) reduced insulin-stimulated growth in MCF-10A and MDA-MB157 cell lines, whereas it did not modify insulin effect on ZR-75-1 cell growth. The MAP-K/Erk (MEK) inhibitor PD98059 (50 microM) consistently reduced insulin-dependent growth in all three cell lines. Taken together, these data suggest that in breast cancer cells insulin may stimulate cell growth via PI3-K-dependent or-independent pathways. AD - Istituto di Medicina Interna, Malattie Endocrine e del Metabolismo, Universita di Catania, Ospedale Garibaldi, Italy. FAU - Gliozzo, B AU - Gliozzo B FAU - Sung, C K AU - Sung CK FAU - Scalia, P AU - Scalia P FAU - Papa, V AU - Papa V FAU - Frasca, F AU - Frasca F FAU - Sciacca, L AU - Sciacca L FAU - Giorgino, F AU - Giorgino F FAU - Milazzo, G AU - Milazzo G FAU - Goldfine, I D AU - Goldfine ID FAU - Vigneri, R AU - Vigneri R FAU - Pezzino, V AU - Pezzino V LA - eng GR - R01 CA68528-01/CA/NCI GR - R29 DK51015/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Cell Biochem JID - 8205768 RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Morpholines) RN - 0 (PD 98059) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.- (MAP Kinase Kinase 1) RN - EC 2.7.1.- (MAP2K1 protein, human) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (Ribosomal Protein S6 Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/*metabolism MH - Breast Neoplasms/enzymology/pathology MH - Ca(2+)-Calmodulin Dependent Protein Kinase/antagonists & inhibitors MH - Cell Division/*drug effects/physiology MH - Cell Line, Transformed MH - Chromones/pharmacology MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Flavonoids/pharmacology MH - Humans MH - Insulin/metabolism/*pharmacology MH - MAP Kinase Kinase 1 MH - *Mitogen-Activated Protein Kinase Kinases MH - Morpholines/pharmacology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein-Serine-Threonine Kinases/antagonists & inhibitors MH - Protein-Tyrosine Kinase/antagonists & inhibitors MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Ribosomal Protein S6 Kinases/metabolism MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 1998/07/22 02:13 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1097-4644(19980801)70:2<268::AID-JCB12>3.0.CO;2-J [pii] PST - ppublish SO - J Cell Biochem 1998 Aug 1;70(2):268-80. -------------------------------------------------------------------------------- 201: Nakamura K et al. B cell antigen receptor (BCR)...[PMID: 9670943] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9670943 OWN - NLM STAT- MEDLINE DA - 19980730 DCOM- 19980730 LR - 20050317 PUBM- Print IS - 0022-1767 VI - 161 IP - 2 DP - 1998 Jul 15 TI - B cell antigen receptor (BCR)-mediated formation of a SHP-2-pp120 complex and its inhibition by Fc gamma RIIB1-BCR coligation. PG - 684-91 AB - Accumulating evidence indicates that the Src homology 2-containing tyrosine phosphatase 2 (SHP-2) plays an important role in signal transduction through receptor tyrosine kinase and cytokine receptors. In most models, SHP-2 appears to be a positive mediator of signaling. However, coligation of Fc gamma RIIB1 with B cell Ag receptors (BCR) inhibits BCR-mediated signaling by a mechanism that may involve recruitment of phosphatases SHP-1, SHP-2, and the SH2 containing inositol 5'phosphatase (SHIP) to the phosphorylated Fc gamma RIIB1 immunoreceptor tyrosine-based inhibitory motif. The role of SHP-2 in BCR-mediated cell activation and in Fc gamma RIIB1-mediated inhibitory signaling is unclear. In this study we assessed the association of SHP-2 with phosphotyrosine-containing cellular protein(s) before and after stimulation through these receptors. BCR stimulation induced the association of SHP-2 with a single major tyrosyl-phosphorylated molecule (pp120) that had an apparent molecular mass of 120 kDa. Coligation of Fc gamma RIIB1 with BCR led to a rapid decrease in SHP-2 association with pp120. Analysis of the subcellular localization of pp120 showed that the complex of SHP-2 and tyrosyl-phosphorylated p120 occurs predominantly in the cytosol. Furthermore, the binding of the two molecules was mediated by the interaction of tyrosyl-phosphorylated p120 with the SHP-2 N-terminal SH2 domain. These findings indicate that SHP-2 and pp120 function in BCR signaling, and this function may be inhibited by Fc gamma RIIB1 signaling. AD - Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA. FAU - Nakamura, K AU - Nakamura K FAU - Cambier, J C AU - Cambier JC LA - eng PT - Journal Article PL - UNITED STATES TA - J Immunol JID - 2985117R RN - 0 (Cell Adhesion Molecules) RN - 0 (Macromolecular Substances) RN - 0 (Receptors, Antigen, B-Cell) RN - 0 (Receptors, IgG) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - AIM SB - IM MH - Animals MH - B-Lymphocytes/enzymology/metabolism MH - Cell Adhesion Molecules/*chemistry/*metabolism MH - Cytosol/enzymology/metabolism MH - Humans MH - Lymphocyte Activation MH - Lymphoma, B-Cell MH - Macromolecular Substances MH - Mice MH - Phosphorylation MH - Protein-Tyrosine Kinase/*chemistry/*metabolism MH - Protein-Tyrosine-Phosphatase/*antagonists & inhibitors/*metabolism MH - Receptor, Insulin/metabolism MH - Receptors, Antigen, B-Cell/immunology/metabolism/*physiology MH - Receptors, IgG/immunology/metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - src Homology Domains/immunology EDAT- 1998/07/22 MHDA- 1998/07/22 00:01 PST - ppublish SO - J Immunol 1998 Jul 15;161(2):684-91. -------------------------------------------------------------------------------- 202: Schuppin GT et al. A specific increased expressi...[PMID: 9648831] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 9648831 OWN - NLM STAT- MEDLINE DA - 19980710 DCOM- 19980710 LR - 20041117 PUBM- Print IS - 0012-1797 VI - 47 IP - 7 DP - 1998 Jul TI - A specific increased expression of insulin receptor substrate 2 in pancreatic beta-cell lines is involved in mediating serum-stimulated beta-cell growth. PG - 1074-85 AB - Certain nutrients and growth factors can stimulate pancreatic beta-cell growth. However, the appropriate mitogenic signaling pathways in beta-cells have been relatively undefined. In this study, differential gene expression in NEDH rat insulinoma was compared with NEDH rat primary islet beta-cells. Differential mRNA display analysis revealed an elevated expression in insulinoma of VL30 transposons, S24 ribosomal protein, and cytochrome-C oxidaseVIIc that is typical for cells undergoing mitosis. A gene candidate approach revealed that mRNA levels of the oncogenes c-fos and c-jun were equivalently expressed in insulinoma and islet cells, as was the mRNA for the mitogenic signal transduction molecule insulin receptor substrate (IRS)-1. However, in contrast to that of IRS-1, IRS-2 gene expression was 60- to 70-fold higher in the insulinoma tissue compared with islets, which was reflected at the protein as well as the mRNA level. The specific elevated IRS-2 expression was a consistent observation across all rodent pancreatic beta-cell lines. To investigate whether IRS-2 was functional, serum-stimulated beta-cell proliferation was examined in isolated insulinoma cells. After a 48-h period of serum withdrawal, 24 h of serum refeeding rendered an 8- to 10-fold increase in [3H]thymidine incorporation into insulinoma cells. This serum-stimulated DNA synthesis was prevented by inhibitors of tyrosine protein kinase and phosphatidylinositol (PI) 3-kinase activities, as well as the activation of mitogen-activated protein (MAP) kinase and p70S6K. Examination of IRS-mediated signal transduction pathways indicated that after 10-15 min of serum refeeding, there was increased tyrosine phosphorylation of IRS-2 and pp60, and PI 3-kinase recruitment to IRS-2. Serum also increased the association of growth factor-bound protein 2/murine sons of sevenless 1 protein to a PI 3-kinase/IRS-2 protein complex. Moreover, serum also activated MAP-kinase (erk-1 and erk-2 isoforms) and 70 kD S6 kinase. Thus IRS-mediated signal transduction pathways are functional in pancreatic beta-cells. It is conceivable that IRS-2 expression in beta-cells contributes to maintaining the islet beta-cell population, complementary to observations in the IRS-2 knockout mouse in which beta-cell mass is markedly reduced. AD - Department of Internal Medicine, Gifford Laboratories for Diabetes Research, University of Texas Southwestern Medical Center, Dallas 75235-8854, USA. FAU - Schuppin, G T AU - Schuppin GT FAU - Pons, S AU - Pons S FAU - Hugl, S AU - Hugl S FAU - Aiello, L P AU - Aiello LP FAU - King, G L AU - King GL FAU - White, M AU - White M FAU - Rhodes, C J AU - Rhodes CJ LA - eng GR - DK-43808/DK/NIDDK GR - DK-50610/DK/NIDDK GR - EY-10827/EY/NEI GR - etc. PT - Journal Article PL - UNITED STATES TA - Diabetes JID - 0372763 RN - 0 (Mitogens) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (Retroelements) RN - 0 (insulin receptor substrate-2 protein) RN - 9007-49-2 (DNA) SB - AIM SB - IM MH - Animals MH - Base Sequence MH - *Blood MH - Cell Differentiation MH - Cell Division/*physiology MH - DNA/biosynthesis MH - *Gene Expression MH - Genes, fos/genetics MH - Genes, jun/genetics MH - Insulinoma MH - Islets of Langerhans/*metabolism/*pathology MH - Mitogens MH - Molecular Sequence Data MH - Pancreatic Neoplasms MH - Phosphoproteins/*genetics MH - RNA, Messenger/metabolism MH - Rats MH - Research Support, U.S. Gov't, P.H.S. MH - Retroelements MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1998/07/02 MHDA- 1998/07/02 00:01 PST - ppublish SO - Diabetes 1998 Jul;47(7):1074-85. -------------------------------------------------------------------------------- 203: Patrone C et al. Divergent pathways regulate l...[PMID: 9626659] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9626659 OWN - NLM STAT- MEDLINE DA - 19980923 DCOM- 19980923 LR - 20041117 PUBM- Print IS - 0888-8809 VI - 12 IP - 6 DP - 1998 Jun TI - Divergent pathways regulate ligand-independent activation of ER alpha in SK-N-BE neuroblastoma and COS-1 renal carcinoma cells. PG - 835-41 AB - The alpha-estrogen receptor (ER alpha) transcriptional activity can be regulated either by binding to the cognate ligand or by intracellular signaling pathways responsive to a variety of factors acting through cell membrane receptors. Studies carried out in HeLa and COS-1 cells demonstrated that the cross-coupling between estrogen and growth factor receptors is mediated by p21ras and requires phosphorylation of a specific serine residue (Ser 118 in the human ER alpha and Ser 122 in mouse ER alpha) located in the ER alpha N-terminal activation function 1 (AF-1). Likewise, in the SK-N-BE neuroblastoma cell line p21ras is involved in the cross-coupling between insulin and ER alpha receptors. However, in this cell line Ser 122 is not necessary for insulin-dependent activation of unliganded ER alpha. In addition, after insulin activation, the electrophoretic mobility associated to serine hyperphosphorylation of ER alpha in SK-N-BE and in COS-1 cells is different. Our study rules out the possibility of tyrosine phosphorylation in unliganded ER alpha activation by means of transactivation studies of ER alpha tyrosine mutants and analysis of Tyr phosphorylation immunoreactivity. The two cofactors for steroid receptors RIP 140 and SRC-1 do not seem to be specifically involved in the insulin-induced ER alpha transactivation. The present study demonstrates the possibility of an alternative, cell-specific pathway of cross-coupling between intracellular and membrane receptors, which might be of importance for the understanding of the physiological significance of this mode of activation in the nervous system. AD - Centre Molecular Pharmaceology Laboratory, University of Milan, Italy. FAU - Patrone, C AU - Patrone C FAU - Gianazza, E AU - Gianazza E FAU - Santagati, S AU - Santagati S FAU - Agrati, P AU - Agrati P FAU - Maggi, A AU - Maggi A LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Estrogen Receptor alpha) RN - 0 (Ligands) RN - 0 (Neoplasm Proteins) RN - 0 (Receptors, Estrogen) RN - 0 (Recombinant Fusion Proteins) RN - 11061-68-0 (Insulin) RN - 17885-08-4 (Phosphoserine) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.6.1.- (Proto-Oncogene Protein p21(ras)) SB - IM MH - Animals MH - Carcinoma, Renal Cell/*pathology MH - Comparative Study MH - Estrogen Receptor alpha MH - Gene Expression Regulation, Neoplastic/*physiology MH - Hela Cells MH - Humans MH - Insulin/pharmacology MH - Kidney Neoplasms/*pathology MH - Ligands MH - Mice MH - Neoplasm Proteins/*metabolism MH - Neuroblastoma/*pathology MH - Phosphorylation MH - Phosphoserine/chemistry MH - Protein Processing, Post-Translational MH - Proto-Oncogene Protein p21(ras)/*physiology MH - Receptor, IGF Type 1/drug effects/*physiology MH - Receptor, Insulin/drug effects/*physiology MH - Receptors, Estrogen/*metabolism MH - Recombinant Fusion Proteins/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*physiology MH - Trans-Activation (Genetics)/*physiology MH - Transfection MH - Tumor Cells, Cultured EDAT- 1998/06/17 MHDA- 1998/06/17 00:01 PST - ppublish SO - Mol Endocrinol 1998 Jun;12(6):835-41. -------------------------------------------------------------------------------- 204: Nestler JE et al. Insulin stimulates testostero...[PMID: 9626131] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9626131 OWN - NLM STAT- MEDLINE DA - 19980702 DCOM- 19980702 LR - 20041117 PUBM- Print IS - 0021-972X VI - 83 IP - 6 DP - 1998 Jun TI - Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. PG - 2001-5 AB - To determine whether insulin stimulates human ovarian testosterone production in the polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system, thecal cells from polycystic ovary syndrome women were isolated and cultured. Insulin and insulin-like growth factor I stimulated thecal testosterone biosynthesis. Antibody blockade of the insulin receptor abolished insulin's stimulatory action, whereas effective antibody blockade of the insulin-like growth factor I receptor did not alter insulin's stimulation of thecal testosterone biosynthesis. A chiro-inositol containing glycan (INS-2) increased thecal testosterone biosynthesis. Preincubation of cells with an antiinositolglycan antibody (A23939 or alpha IGP) abolished insulin's stimulatory effect, but not that of hCG. These findings suggest that inositolglycans serve as the signal transduction system for insulin's stimulation of human thecal testosterone biosynthesis. AD - Department of Internal Medicine, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298, USA. nestler@hsc.vcu.edu FAU - Nestler, J E AU - Nestler JE FAU - Jakubowicz, D J AU - Jakubowicz DJ FAU - de Vargas, A F AU - de Vargas AF FAU - Brik, C AU - Brik C FAU - Quintero, N AU - Quintero N FAU - Medina, F AU - Medina F LA - eng GR - RO1-CA-64500/CA/NCI GR - RO1-HD-35629/HD/NICHD PT - Journal Article PL - UNITED STATES TA - J Clin Endocrinol Metab JID - 0375362 RN - 0 (Antibodies) RN - 0 (Polysaccharides) RN - 11061-68-0 (Insulin) RN - 58-22-0 (Testosterone) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 6917-35-7 (Inositol) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Adult MH - Antibodies/pharmacology MH - Female MH - Humans MH - Inositol/pharmacology MH - Insulin/*pharmacology MH - Insulin-Like Growth Factor I/pharmacology MH - Polycystic Ovary Syndrome/*metabolism MH - Polysaccharides/pharmacology MH - Receptor, Insulin/*drug effects/physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Testosterone/*biosynthesis MH - Theca Cells/*drug effects/*metabolism EDAT- 1998/06/17 MHDA- 1998/06/17 00:01 PST - ppublish SO - J Clin Endocrinol Metab 1998 Jun;83(6):2001-5. -------------------------------------------------------------------------------- 205: Taouis M et al. Insulin receptor substrate 1 ...[PMID: 9605520] Related Articles, Substance via MeSH, Books, LinkOut PMID- 9605520 OWN - NLM STAT- MEDLINE DA - 19980727 DCOM- 19980727 LR - 20041117 PUBM- Print IS - 0303-7207 VI - 137 IP - 2 DP - 1998 Feb TI - Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC). PG - 177-86 AB - In mammalian cells, the insulin receptor substrate 1 protein (IRS-1) is a specific substrate for insulin and IGF-1 receptor tyrosine kinases which is involved in mediating metabolic and mitogenic actions of insulin and IGFs. In order to determine if IRS-1 is also essential in a chicken derived hepatoma cell line (LMH cells), IRS-1 gene has been invalidated in these cells. For this, we subcloned chicken IRS-1 gene in an antisense orientation into a mammalian expression vector driven by the cytomegalovirus early promoter. LMH cells were stably transfected with this construct or with the empty vector carrying only the neomycin resistance gene and selected for cIRS-1 expression. One subclone, C2, showed a complete repression of cIRS-1 expression at both protein and mRNA levels. Proliferation of C2 cells was dramatically reduced (54%) compared with Neo(r) cells. Furthermore this reduction was accompanied by a decrease in insulin-dependent [3H]thymidine incorporation, indicating a reduction in DNA synthesis. Insulin-dependent [U-14C]glucose incorporation into cellular lipids was also significantly reduced in C2 cell line suggesting an alteration in lipogenesis. In wild type LMH cells, SHC which is involved in Ras pathway, also served as a substrate for insulin receptor tyrosine kinase. In C2 cells, SHC expression, its association with the insulin receptor and its tyrosine phosphorylation were largely increased. Two forms of the regulatory subunit of PI 3-kinase were present: p85 and p55 forms. Furthermore, C2 cells displayed increased basal phosphatidylinositol (PI) 3'-kinase activity. This report demonstrates a role for cIRS-1 in the metabolic and mitogenic actions of insulin in LMH cells. However, the overexpression of cIRS-1 antisense did not completely abolish cell proliferation. This may be explained by the exacerbation of an alternative pathway that only partly compensate for the knocking out of cIRS-1 gene: the overexpression of SHC. AD - Endocrinologie de la Croissance et du Metabolisme, Station de Recherches Avicoles, INRA, Nouzilly, France. taouis@tours.inra.fr FAU - Taouis, M AU - Taouis M FAU - Dupont, J AU - Dupont J FAU - Gillet, A AU - Gillet A FAU - Derouet, M AU - Derouet M FAU - Simon, J AU - Simon J LA - eng PT - Journal Article PL - IRELAND TA - Mol Cell Endocrinol JID - 7500844 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (DNA Primers) RN - 0 (DNA, Antisense) RN - 0 (Lipids) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 9007-34-5 (Collagen) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - Cell Division MH - Chickens MH - Collagen/*genetics MH - DNA Primers/genetics MH - DNA, Antisense/genetics MH - Gene Expression MH - Insulin/metabolism MH - Lipids/biosynthesis MH - Liver Neoplasms, Experimental/*genetics/metabolism/*pathology MH - Phosphoproteins/*genetics MH - Polymerase Chain Reaction MH - Proteins/*genetics MH - Receptor, Insulin/metabolism MH - Transfection MH - Tumor Cells, Cultured MH - src Homology Domains/*genetics EDAT- 1998/05/30 MHDA- 1998/05/30 00:01 AID - S0303720797002451 [pii] PST - ppublish SO - Mol Cell Endocrinol 1998 Feb;137(2):177-86. -------------------------------------------------------------------------------- 206: Jackson JG et al. Insulin receptor substrate-1 ...[PMID: 9545345] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9545345 OWN - NLM STAT- MEDLINE DA - 19980521 DCOM- 19980521 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 273 IP - 16 DP - 1998 Apr 17 TI - Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells. PG - 9994-10003 AB - Because insulin-like growth factor-I (IGF-I), insulin, and interleukin-4 (IL-4) have known biological effects in breast cancer cells and signal through insulin-receptor substrate (IRS) adaptor proteins, we examined the expression and function of IRS-1 and IRS-2 in breast tumors and cell lines. IRS-1 and IRS-2 were expressed by cell lines and primary breast tumor specimens. IGF-I, insulin, and IL-4 treatment of MCF-7 and ZR-75, and IGF-I treatment of T47-D breast cancer cells, resulted in much greater tyrosine phosphorylation of IRS-1 compared with IRS-2. Furthermore, IGF-I stimulated greater tyrosine phosphorylation of IRS-1 than either insulin or IL-4. IGF-I treatment also enhanced association of the p85 regulatory subunit of phosphatidylinositol 3-kinase with IRS-1 and stimulated increased enzymatic activity compared with IL-4 and insulin in all three cell lines. Similarly, mitogen-activated protein kinase activity was greater in IGF-I-stimulated cells. To determine the functional significance of the activation of these pathways, we inhibited activation of phosphatidylinositol 3-kinase with wortmannin and mitogen-activated protein kinase with PD098059. Both compounds inhibited IGF-stimulated growth, suggesting that both pathways contributed to the mitogenic response to IGF-I. We conclude that IRS-1, and not IRS-2, is the predominant signaling molecule activated by IGF-I, insulin, and IL-4. Furthermore, enhanced tyrosine phosphorylation of IRS-1 by IGF-I, compared with either insulin or IL-4, is associated with greater activation of mitogenic downstream signaling pathways resulting in enhanced cell growth. AD - Division of Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78284-7884, USA. FAU - Jackson, J G AU - Jackson JG FAU - White, M F AU - White MF FAU - Yee, D AU - Yee D LA - eng GR - KO4 CA 01670/CA/NCI GR - P30 CA 54174/CA/NCI GR - PO1 CA 30195/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Androstadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (PD 98059) RN - 0 (Phosphoproteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Receptors, Estrogen) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 19545-26-7 (wortmannin) RN - 207137-56-2 (Interleukin-4) RN - 21820-51-9 (Phosphotyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/chemistry/metabolism MH - Androstadienes/pharmacology MH - Breast Neoplasms MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Enzyme Inhibitors/pharmacology MH - Female MH - Flavonoids/pharmacology MH - Humans MH - Insulin/*pharmacology MH - Insulin-Like Growth Factor I/*pharmacology MH - Interleukin-4/*pharmacology MH - Kinetics MH - Mitogen-Activated Protein Kinase Kinases MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Protein Kinase Inhibitors MH - Protein Kinases/metabolism MH - Receptor, Insulin/physiology MH - Receptors, Estrogen/analysis MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/*physiology MH - Tumor Cells, Cultured EDAT- 1998/05/23 MHDA- 1998/05/23 00:01 PST - ppublish SO - J Biol Chem 1998 Apr 17;273(16):9994-10003. -------------------------------------------------------------------------------- 207: Wang HY et al. A role for the insulin-interl...[PMID: 9545332] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9545332 OWN - NLM STAT- MEDLINE DA - 19980521 DCOM- 19980521 LR - 20041217 PUBM- Print IS - 0021-9258 VI - 273 IP - 16 DP - 1998 Apr 17 TI - A role for the insulin-interleukin (IL)-4 receptor motif of the IL-4 receptor alpha-chain in regulating activation of the insulin receptor substrate 2 and signal transducer and activator of transcription 6 pathways. Analysis by mutagenesis. PG - 9898-905 AB - The interleukin (IL)-4 receptor alpha-chain (IL-4Ralpha) contains a sequence motif (488PLVIAGNPAYRSFSD) termed the insulin IL-4 receptor motif (I4R motif). Mutation of the central Tyr497 to Phe blocks the tyrosine phosphorylation of the insulin receptor substrate 1 (IRS1) and diminishes proliferation in response to IL-4. Recent data suggest that the I4R motif encodes binding sites for several protein tyrosine binding (PTB) domain-containing proteins such as IRS1 and Shc and potentially for the Src homology 2 domain of signal transducer and activator of transcription 6 (STAT6). To analyze the function of the I4R motif in regulating IL-4 signaling, we changed conserved residues upstream and downstream of the central Tyr to Ala in the human IL-4Ralpha. We analyzed the ability of these constructs to signal the tyrosine phosphorylation of IRS2 and STAT6, the induction of DNA binding activity, and CD23 induction in response to human IL-4 (huIL-4) in transfected M12.4.1 cells. Mutagenesis of residues downstream of Tyr497, such as Arg498 or Phe500, to Ala had no effect on any of these responses, suggesting that the I4R motif may not be important for functional Src homology 2 domain interactions. However, mutagenesis of Pro488 to Ala (P488A) greatly diminished the tyrosine phosphorylation of IRS2 and abolished tyrosine phosphorylation of STAT6, induction of DNA binding activity, and CD23 induction in response to huIL-4. By contrast, a P488G mutant signaled these responses to huIL-4. Mutagenesis of hydrophobic amino acids previously shown to contact the PTB domain of IRS1, Leu489 or Ile491, to Ala had only minimal effects on responses to huIL-4. However, changing both Leu498 and Ile491 to Ala greatly diminished the tyrosine phosphorylation of IRS2 and abolished STAT6 activation. Taken together, these results indicate the important role of the I4R motif in regulating IRS docking and suggest that I4R docking to a PTB domain-containing protein regulates activation of the STAT6 pathway. AD - Department of Immunology, Jerome Holland Labs, American Red Cross, Rockville, Maryland 20855, USA. FAU - Wang, H Y AU - Wang HY FAU - Zamorano, J AU - Zamorano J FAU - Keegan, A D AU - Keegan AD LA - eng GR - AI38985/AI/NIAID PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (DNA-Binding Proteins) RN - 0 (Macromolecular Substances) RN - 0 (Phosphoproteins) RN - 0 (Receptors, IgE) RN - 0 (Receptors, Interleukin-4) RN - 0 (Recombinant Proteins) RN - 0 (Stat4 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-2 protein) RN - 207137-56-2 (Interleukin-4) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 56-41-7 (Alanine) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Alanine MH - Amino Acid Sequence MH - Animals MH - Conserved Sequence MH - DNA-Binding Proteins/biosynthesis/*metabolism MH - Humans MH - Interleukin-4/*pharmacology MH - Lymphoma, B-Cell MH - Macromolecular Substances MH - Mice MH - Models, Biological MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - Phosphoproteins/*metabolism MH - Phosphotyrosine/metabolism MH - Point Mutation MH - Receptor, Insulin/physiology MH - Receptors, IgE/biosynthesis MH - Receptors, Interleukin-4/chemistry/*physiology MH - Recombinant Proteins/pharmacology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Alignment MH - Sequence Homology, Amino Acid MH - *Signal Transduction MH - Trans-Activators/*metabolism MH - Transfection MH - Tumor Cells, Cultured MH - Tyrosine MH - src Homology Domains EDAT- 1998/05/23 MHDA- 1998/05/23 00:01 PST - ppublish SO - J Biol Chem 1998 Apr 17;273(16):9898-905. -------------------------------------------------------------------------------- 208: Zhang Q et al. Insulin-like growth factor-I-...[PMID: 9582514] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9582514 OWN - NLM STAT- MEDLINE DA - 19980520 DCOM- 19980520 LR - 20041117 PUBM- Print IS - 0022-0795 VI - 156 IP - 3 DP - 1998 Mar TI - Insulin-like growth factor-I-induced DNA synthesis in insulin-secreting cell line RINm5F is associated with phosphorylation of the insulin-like growth factor-I receptor and the insulin receptor substrate-2. PG - 573-81 AB - A proliferative effect of insulin-like growth factor-I (IGF-I) was previously shown in pancreatic islets. However, the mechanism under which IGF-I actions are exerted in insulin-secreting cells is not clear. The rat insulinoma cell line, RINm5F, was shown to have both IGF-I receptors and IGF-Il/mannose-6-phosphate receptors. IGF-I binding to cell surface receptors stimulated phosphorylation of 97 kDa and 93 kDa subunits of the IGF-I receptor and incorporation of [3H]thymidine into RINm5F cells. Both the IGF-I-induced protein phosphorylation and [3H]thymidine incorporation were abolished in the presence of the tyrosine kinase inhibitor, genistein. Under basal conditions, IGF-I did not induce insulin release or changes in cytosolic free Ca2+ concentration. Immunoprecipitation of proteins from RINm5F cells, using phosphotyrosine antibodies, followed by western blotting using antibody against IRS-1 revealed no distinct band of phosphorylated insulin receptor substrate (IRS)-1. Instead, tyrosine-phosphorylated IRS-2 was detected and stimulated by IGF-I when western blotting was performed using antibody against IRS-2. These results indicate that IRS-1 is not likely to be involved in IGF-I signalling in RINm5F cells. Hence, IGF-I stimulated DNA synthesis in RINm5F cells was associated with phosphorylation of IGF-I receptors and IRS-2. AD - Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Stockholm, Sweden. FAU - Zhang, Q AU - Zhang Q FAU - Berggren, P O AU - Berggren PO FAU - Hansson, A AU - Hansson A FAU - Tally, M AU - Tally M LA - eng PT - Journal Article PL - ENGLAND TA - J Endocrinol JID - 0375363 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - 446-72-0 (Genistein) RN - 50-89-5 (Thymidine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 7440-70-2 (Calcium) RN - 9007-49-2 (DNA) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - Calcium/metabolism MH - DNA/*biosynthesis MH - Genistein/pharmacology MH - Insulin/secretion MH - Insulin-Like Growth Factor I/*pharmacology MH - Insulinoma/*metabolism/secretion MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Protein-Tyrosine Kinase/antagonists & inhibitors MH - Rats MH - Receptor, IGF Type 1/*metabolism MH - Research Support, Non-U.S. Gov't MH - Thymidine/metabolism MH - Tumor Cells, Cultured EDAT- 1998/05/16 MHDA- 1998/05/16 00:01 PST - ppublish SO - J Endocrinol 1998 Mar;156(3):573-81. -------------------------------------------------------------------------------- 209: Sung CK et al. Guanosine triphosphatase-acti...[PMID: 9564850] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 9564850 OWN - NLM STAT- MEDLINE DA - 19980508 DCOM- 19980508 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 139 IP - 5 DP - 1998 May TI - Guanosine triphosphatase-activating protein-associated protein, but not src-associated protein p68 in mitosis, is a part of insulin signaling complexes. PG - 2392-8 AB - The insulin receptor, following insulin stimulation of cells, triggers formation of various signaling complexes. In rat HTC hepatoma cells overexpressing normal human insulin receptors (HTC-IR), p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K) forms signaling complexes containing the insulin receptor, insulin receptor substrate 1 (IRS-1), guanosine triphosphatase-activating protein (GAP) and 60-70 kDa phosphotyrosine proteins (p60-70). In the present study, we demonstrate that p60-70 interacts directly with the p85 subunit via src homology 2 domain of the latter. Employing antibodies specific to two p85 isoforms, p85alpha and p85beta, we demonstrate that HTC-IR cells express both p85 isoforms, and these isoforms induce the formation of similar signaling complexes in response to insulin. p60-70, present in both alpha-p85alpha and alpha-p85beta immunoprecipitates, is a GAP-associated protein, but is distinct from the p68 src-associated protein in mitosis (Sam68) by several criteria. These data suggest that 1) GAP-associated protein, but not Sam68, is a part of insulin signaling complexes; and 2) p85alpha and p85beta form similar, but distinct, insulin receptor signaling complexes. AD - Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles 90033, USA. csung@hsc.usc.edu FAU - Sung, C K AU - Sung CK FAU - Choi, W S AU - Choi WS FAU - Sanchez-Margalet, V AU - Sanchez-Margalet V LA - eng GR - DK-51015/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (Carrier Proteins) RN - 0 (GTPase-Activating Proteins) RN - 0 (Proteins) RN - 0 (RNA-Binding Proteins) RN - 0 (Recombinant Proteins) RN - 0 (SRC-associated p68 protein) RN - 0 (Sulfhydryl Compounds) RN - 0 (maltose-binding protein) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase/metabolism MH - Animals MH - Carrier Proteins/metabolism MH - GTPase-Activating Proteins MH - Humans MH - Immunosorbent Techniques MH - Insulin/*metabolism MH - Liver Neoplasms, Experimental MH - *Mitosis MH - Phosphorylation MH - Phosphotyrosine/analysis/metabolism MH - Proteins/*metabolism MH - RNA-Binding Proteins/*metabolism MH - Rats MH - Receptor, Insulin/metabolism MH - Recombinant Proteins MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction MH - Sulfhydryl Compounds/metabolism MH - Tumor Cells, Cultured EDAT- 1998/05/16 MHDA- 1998/05/16 00:01 PST - ppublish SO - Endocrinology 1998 May;139(5):2392-8. -------------------------------------------------------------------------------- 210: Westley BR et al. Interactions between the oest...[PMID: 9513709] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9513709 OWN - NLM STAT- MEDLINE DA - 19980423 DCOM- 19980423 LR - 20041117 PUBM- Print IS - 0067-8694 VI - 63 DP - 1998 TI - Interactions between the oestrogen and insulin-like growth factor signalling pathways in the control of breast epithelial cell proliferation. PG - 35-44 AB - There is increasing evidence for interactions between steroid and growth factor signalling pathways. Oestrogens modulate the responsiveness of breast epithelial cells to insulin-like growth factors (IGFs), and this may be the mechanism by which oestrogens modulate cell proliferation. Oestrogens appear to act at several points in the IGF signal transduction pathway. Despite earlier studies suggesting that breast epithelial cells do not synthesize IGF-I, we have shown by PCR that IGF-I is expressed and that its expression is regulated by oestrogen. IGF-II is expressed at markedly higher levels than IGF-I and is also regulated by oestrogen, consistent with it being an oestrogen-regulated autocrine growth factor. Oestrogens regulate the expression of IGF binding proteins and the type I IGF receptor. The biological significance of oestrogen regulation of IGF binding protein expression is not clear. Experiments in which the type I IGF receptor has been constitutively overexpressed have suggested that oestrogen regulation of the receptor is not involved in mediating the effects of oestrogen on cell proliferation. Recent studies have started to assess the effects of oestrogen on the expression of components of the IGF signal transduction pathway, and have shown that the expression of insulin receptor substrate-1, the principal substrate for the tyrosine kinase of the type I IGF receptor, is regulated by oestradiol. AD - Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, U.K. FAU - Westley, B R AU - Westley BR FAU - Clayton, S J AU - Clayton SJ FAU - Daws, M R AU - Daws MR FAU - Molloy, C A AU - Molloy CA FAU - May, F E AU - May FE LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - ENGLAND TA - Biochem Soc Symp JID - 7506896 RN - 0 (Estrogens) RN - 0 (Insulin-Like Growth Factor Binding Proteins) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) SB - IM MH - Breast/cytology/*metabolism MH - Breast Neoplasms/metabolism/pathology MH - Cell Division/*physiology MH - Epithelial Cells/cytology/metabolism MH - Estrogens/*pharmacology MH - Female MH - Humans MH - Insulin-Like Growth Factor Binding Proteins/metabolism MH - Insulin-Like Growth Factor I/*metabolism MH - Insulin-Like Growth Factor II/*metabolism MH - *Signal Transduction RF - 44 EDAT- 1998/03/26 MHDA- 1998/03/26 00:01 PST - ppublish SO - Biochem Soc Symp 1998;63:35-44. -------------------------------------------------------------------------------- 211: Puscheck EE et al. Insulin receptor substrate-1 ...[PMID: 9508089] Related Articles, Cited in PMC, Books, LinkOut PMID- 9508089 OWN - NLM STAT- MEDLINE DA - 19980515 DCOM- 19980515 LR - 20041117 PUBM- Print IS - 1040-452X VI - 49 IP - 4 DP - 1998 Apr TI - Insulin receptor substrate-1 is expressed at high levels in all cells of the peri-implantation mouse embryo. PG - 386-93 AB - Insulin and insulinlike growth factors are important for embryonic growth and metabolism. Intracellular transduction for these factors has not been studied in the preimplantation mouse embryo. Peri-implantation mouse embryos synthesize insulinlike growth factor (IGF)-II ligand, insulin receptor, IGF-I receptor, and IGF-II receptor and respond to IGF-II, IGF-I, and insulin metabolically and mitogenically. Maternal tissues in the oviduct and uterus are also sources of IGF-I and insulin. Signaling of IGFs occurs through insulin receptor substrate (IRS)-1 and IRS-2. This paper shows that IRS-1 mRNA and protein are highly expressed in preimplantation mouse embryos, in embryonic cell lines, and in cultured blastocyst outgrowths. IRS-1 mRNA and protein are detected in embryo-derived cell lines cultured to produce the three cell lineages (stem cells, endoderm, and trophoblast cells). IRS-1 mRNA is detected by reverse transcription-polymerase chain reaction (RT-PCR) in the E3.5 blastocyst before implantation and in F9 teratocarcinoma stem cells and parietal endoderm cells. IRS-1 mRNA is detected by Northern blot hybridization at high levels in stem cells and in differentiated progeny of F9 cells and C3H/NE trophectoderm cells. IRS-1 protein was detected in these cell lines and in an overexpressing CHO-IRS-1 fibroblast cell line by immunocytochemistry. Cultured blastocyst outgrowths are a model for implantation events of the trophoblast/placenta lineage and endoderm/yolk sac lineage. In the blastocyst outgrowth, IRS-1 protein is detected in inner cell mass cells (ICM cells), primitive endoderm, parietal endoderm, and trophectoderm cells. These data suggest that IRS-1 is expressed in all cell lineages of the peri-implantation mouse embryo and mediates some effects of insulin and IGFs at this stage. AD - Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Illinois 60611, USA. FAU - Puscheck, E E AU - Puscheck EE FAU - Pergament, E AU - Pergament E FAU - Patel, Y AU - Patel Y FAU - Dreschler, J AU - Dreschler J FAU - Rappolee, D A AU - Rappolee DA LA - eng GR - HD30739-02/HD/NICHD PT - Journal Article PL - UNITED STATES TA - Mol Reprod Dev JID - 8903333 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Blastocyst/cytology/*metabolism MH - Blotting, Northern MH - Cell Division MH - Cell Line MH - Female MH - Mice MH - Mice, Inbred C3H MH - Mice, Inbred C57BL MH - Phosphoproteins/*biosynthesis MH - Polymerase Chain Reaction MH - Receptor, Insulin/*biosynthesis MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Teratocarcinoma/metabolism MH - Tumor Cells, Cultured EDAT- 1998/03/21 03:23 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1098-2795(199804)49:4<386::AID-MRD5>3.0.CO;2-J [pii] PST - ppublish SO - Mol Reprod Dev 1998 Apr;49(4):386-93. -------------------------------------------------------------------------------- 212: Linseman DA et al. Cytoskeletal and phosphoinosi...[PMID: 9489713] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9489713 OWN - NLM STAT- MEDLINE DA - 19980312 DCOM- 19980312 LR - 20050209 PUBM- Print IS - 0022-3042 VI - 70 IP - 3 DP - 1998 Mar TI - Cytoskeletal and phosphoinositide requirements for muscarinic receptor signaling to focal adhesion kinase and paxillin. PG - 940-50 AB - The mechanism whereby agonist occupancy of muscarinic cholinergic receptors elicits an increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin has been examined. Addition of oxotremorine-M to SH-SY5Y neuroblastoma cells resulted in rapid increases in the phosphorylation of FAK (t(1/2) = 2 min) and paxillin that were independent of integrin-extracellular matrix interactions, cell attachment, and the production of phosphoinositide-derived second messengers. In contrast, the increased tyrosine phosphorylations of FAK and paxillin were inhibited by inclusion of either cytochalasin D or mevastatin, agents that disrupt the cytoskeleton. Furthermore, phosphorylation of FAK and paxillin could be prevented by addition of either wortmannin or LY-294002, under conditions in which the synthesis of phosphatidylinositol 4-phosphate was markedly attenuated. These results indicate that muscarinic receptor-mediated increases in the tyrosine phosphorylation of FAK and paxillin in SH-SY5Y neuroblastoma cells depend on both the maintenance of an actin cytoskeleton and the ability of these cells to synthesize phosphoinositides. AD - Department of Pharmacology, Mental Health Research Institute, University of Michigan, Ann Arbor 48104-1687, USA. FAU - Linseman, D A AU - Linseman DA FAU - McEwen, E L AU - McEwen EL FAU - Sorensen, S D AU - Sorensen SD FAU - Fisher, S K AU - Fisher SK LA - eng GR - GM 07767/GM/NIGMS GR - MH 46252/MH/NIMH GR - NS 23831/NS/NINDS PT - Journal Article PL - UNITED STATES TA - J Neurochem JID - 2985190R RN - 0 (Actins) RN - 0 (Androstadienes) RN - 0 (Cell Adhesion Molecules) RN - 0 (Chromones) RN - 0 (Cytoskeletal Proteins) RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 0 (Muscarinic Agonists) RN - 0 (Nucleic Acid Synthesis Inhibitors) RN - 0 (Phosphatidylinositol Phosphates) RN - 0 (Phosphatidylinositols) RN - 0 (Phosphoproteins) RN - 0 (Phosphorus Radioisotopes) RN - 0 (Receptors, Muscarinic) RN - 0 (paxillin) RN - 0 (phosphatidylinositol 4-phosphate) RN - 154447-36-6 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 19545-26-7 (wortmannin) RN - 22144-77-0 (Cytochalasin D) RN - 55520-40-6 (Tyrosine) RN - 73573-88-3 (compactin) RN - 75330-75-5 (Lovastatin) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) RN - EC 3.6.1.- (GTP-Binding Proteins) SB - IM MH - Actins/metabolism MH - Androstadienes/pharmacology MH - Cell Adhesion/physiology MH - Cell Adhesion Molecules/*metabolism/physiology MH - Chromones/pharmacology MH - Cytochalasin D/pharmacology MH - Cytoskeletal Proteins/*physiology MH - Cytoskeleton/physiology MH - Enzyme Inhibitors/pharmacology MH - GTP-Binding Proteins/physiology MH - Humans MH - Lovastatin/analogs & derivatives/pharmacology MH - Morpholines/pharmacology MH - Muscarinic Agonists/pharmacology MH - Neuroblastoma MH - Nucleic Acid Synthesis Inhibitors/pharmacology MH - Phosphatidylinositol Phosphates/pharmacology MH - Phosphatidylinositols/*physiology MH - Phosphoproteins/*physiology MH - Phosphorus Radioisotopes/diagnostic use MH - Phosphorylation MH - Protein-Tyrosine Kinase/*metabolism MH - Receptor, Insulin/metabolism MH - Receptors, Muscarinic/*physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Second Messenger Systems/drug effects/*physiology MH - Tumor Cells, Cultured/enzymology MH - Tyrosine/metabolism EDAT- 1998/03/07 MHDA- 1998/03/07 00:01 PST - ppublish SO - J Neurochem 1998 Mar;70(3):940-50. -------------------------------------------------------------------------------- 213: Nehrbass D et al. Overexpression of insulin rec...[PMID: 9466558] Related Articles, Books, LinkOut PMID- 9466558 OWN - NLM STAT- MEDLINE DA - 19980306 DCOM- 19980306 LR - 20031114 PUBM- Print IS - 0002-9440 VI - 152 IP - 2 DP - 1998 Feb TI - Overexpression of insulin receptor substrate-1 emerges early in hepatocarcinogenesis and elicits preneoplastic hepatic glycogenosis. PG - 341-5 AB - Insulin receptor substrate-1 (IRS-1) is a multisite docking protein occupying a central position in signaling cascades stimulated by a number of growth factors including insulin. Using Western blotting and immunohistochemistry, we investigated the expression of IRS-1 in more than 400 preneoplastic foci of altered hepatocytes and in 12 hepatocellular carcinomas induced in rats by oral administration of N-nitrosomorpholine. In both N-nitrosomorpholine-treated and untreated rat livers, IRS-1 was demonstrable by Western blotting, but with the exception of a few single hepatocytes it was not detectable in the normal parenchyma by immunohistochemistry. In contrast, immunohistochemistry revealed that IRS-1 was strongly expressed in the majority of foci of altered hepatocytes particularly in approximately 97% of the clear/acidophilic and mixed cell foci showing excessive storage of glycogen (glycogenosis). In glycogen-poor basophilic foci of altered hepatocytes and hepatocellular carcinomas, IRS-1 was not detected by immunohistochemistry, but a weak expression was observed in small subpopulations of three hepatocellular carcinomas containing remnants of glycogen. These results indicate that the focal overexpression of IRS-1 is an early event in hepatocarcinogenesis, which is closely correlated with preneoplastic hepatic glycogenosis. During progression from glycogenotic foci to hepatocellular carcinomas, IRS-1-overexpression is gradually down-regulated, and this late event is associated with a fundamental metabolic shift leading to the malignant neoplastic phenotype. AD - Abteilung fur Cytopathologie, Deutsches Krebsforschungszentrum Im Neuenheimer Feld, Heidelberg, Germany. FAU - Nehrbass, D AU - Nehrbass D FAU - Klimek, F AU - Klimek F FAU - Bannasch, P AU - Bannasch P LA - eng PT - Journal Article PL - UNITED STATES TA - Am J Pathol JID - 0370502 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) SB - AIM SB - IM MH - Animals MH - Carcinoma/*metabolism MH - Glycogen Storage Disease/*metabolism MH - Immunohistochemistry MH - Liver/*metabolism MH - Liver Neoplasms/*metabolism MH - Male MH - Phosphoproteins/*metabolism MH - Precancerous Conditions/*metabolism MH - Rats MH - Rats, Sprague-Dawley EDAT- 1998/02/18 MHDA- 1998/02/18 00:01 PST - ppublish SO - Am J Pathol 1998 Feb;152(2):341-5. -------------------------------------------------------------------------------- 214: Band CJ et al. Early signaling events trigge...[PMID: 9415395] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9415395 OWN - NLM STAT- MEDLINE DA - 19980210 DCOM- 19980210 LR - 20050317 PUBM- Print IS - 0888-8809 VI - 11 IP - 13 DP - 1997 Dec TI - Early signaling events triggered by peroxovanadium [bpV(phen)] are insulin receptor kinase (IRK)-dependent: specificity of inhibition of IRK-associated protein tyrosine phosphatase(s) by bpV(phen). PG - 1899-910 AB - Peroxovanadiums (pVs) are potent protein tyrosine phosphatase (PTP) inhibitors with insulin-mimetic properties in vivo and in vitro. We have established the existence of an insulin receptor kinase (IRK)-associated PTP whose inhibition by pVs correlates closely with IRK tyrosine phosphorylation, activation, and downstream signaling. pVs have also been shown to activate various tyrosine kinases (TKs) that could participate in activation of the insulin-signaling pathway. In the present study we have sought to determine whether pV-induced IRK tyrosine phosphorylation requires the intrinsic kinase activity of the IRK, and whether IRK activation is necessary to realize the early steps in the insulin-signaling cascade. To address this we evaluated the effect of a pure pV compound, bis peroxovanadium 1,10-phenanthroline [bpV(phen)], in HTC rat hepatoma cells overexpressing normal (HTC-IR) or kinase-deficient (HTC-M1030) mutant IRKs. We showed that at a dose of 0.1 mM, but not 1 mM, bpV(phen) induced IRK-dependent events. Thus, 0.1 mM bpV(phen) increased tyrosine phosphorylation and IRK activity in HTC-IR but not HTC-M1030 cells. Tyrosine phosphorylation of insulin signal-transducing molecules was promoted in HTC-IR but not HTC-M1030 cells by bpV(phen). The association of p185 and p60 with the src homology-2 (SH2) domains of Syp and the p85-regulatory subunit of phosphatidylinositol 3'-kinase was induced by bpV(phen) in HTC-IR, but not in HTC-M1030 cells, as was insulin receptor substrate-1-associated phosphatidylinositol 3'-kinase activity. Thus autophosphorylation and activation of the IRK by bpV(phen) is effected by the IRK itself, and the early events in the insulin- signaling cascade follow from this activation event. This establishes a critical role for PTP(s) in the regulation of IRK activity. bpV(phen) could be distinguished from insulin only in its ability to activate ERK1 in HTC-M1030 cells, thus indicating that this event is IRK independent, consistent with our previous hypothesis that bpV(phen) inhibits a PTP involved in the negative regulation of mitogen-activated protein kinases. AD - Department of Medicine, McGill University, Montreal, Quebec, Canada. FAU - Band, C J AU - Band CJ FAU - Posner, B I AU - Posner BI FAU - Dumas, V AU - Dumas V FAU - Contreres, J O AU - Contreres JO LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Organometallic Compounds) RN - 0 (Phenanthrolines) RN - 0 (Phosphoproteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 55520-40-6 (Tyrosine) RN - 68832-78-0 (bisperoxo(1,10-phenanthroline)oxovanadate(1-)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase/drug effects/metabolism MH - Animals MH - Carcinoma, Hepatocellular MH - Dose-Response Relationship, Drug MH - Drug Synergism MH - Enzyme Activation/drug effects MH - Humans MH - Insulin/pharmacology MH - Liver Neoplasms MH - Organometallic Compounds/*pharmacology MH - Phenanthrolines/*pharmacology MH - Phosphoproteins/drug effects/metabolism MH - Phosphorylation/drug effects MH - Precipitin Tests MH - Protein-Tyrosine-Phosphatase/*antagonists & inhibitors/drug effects/genetics/metabolism MH - Rats MH - Receptor, Insulin/*antagonists & inhibitors/drug effects/metabolism/*physiology MH - Recombinant Fusion Proteins MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects MH - Substrate Specificity/drug effects MH - Tumor Cells, Cultured MH - Tyrosine/metabolism MH - src Homology Domains/drug effects/physiology EDAT- 1998/02/12 MHDA- 1998/02/12 00:01 PST - ppublish SO - Mol Endocrinol 1997 Dec;11(13):1899-910. -------------------------------------------------------------------------------- 215: Toretsky JA et al. The insulin-like growth facto...[PMID: 9388225] Related Articles, Cited in PMC, Cited in Books, Books, LinkOut PMID- 9388225 OWN - NLM STAT- MEDLINE DA - 19980108 DCOM- 19980108 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 272 IP - 49 DP - 1997 Dec 5 TI - The insulin-like growth factor-I receptor is required for EWS/FLI-1 transformation of fibroblasts. PG - 30822-7 AB - Ewing's family of tumors is characterized by a well described reciprocal translocation, t(11;22)(q24;q12), which produces a fusion protein (EWS/FLI-1) that transforms mouse fibroblasts. The EWS/FLI-1 fusion protein has been shown to act as a potent chimeric transcription factor. Overexpression of insulin-like growth factor-I receptor (IGF-IR) has been implicated in many tumor models as playing a role in cell growth and tumorigenesis. In addition, blockade of the IGF-IR inhibits the growth of Ewing's family of tumors cells. Therefore, we first studied whether the presence of the IGF-IR is required for transformation by the EWS/FLI-1 fusion protein. To perform this study, we used two previously described fibroblast cell lines, R- and W, derived from an IGF-IR knockout mouse and a wild-type littermate, respectively. Neither W nor R- cells without the fusion protein formed soft agar colonies. However, W clones expressing the fusion message (WF cells) formed soft agar colonies, whereas R- clones expressing the fusion message (R-F cells) did not form soft agar colonies. Because the IGF-IR is required for EWS/FLI-1 transformation, we chose to investigate whether altered signaling occurs from the IGF-IR when the EWS/FLI-1 fusion is present. WF cells demonstrated a greater degree of ligand-stimulated insulin receptor substrate-1 phosphorylation when compared with W cells, suggesting that expression of the EWS/FLI-1 fusion protein alters the IGF-IR signaling pathway. AD - Pediatric Oncology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. jt@helix.nih.gov FAU - Toretsky, J A AU - Toretsky JA FAU - Kalebic, T AU - Kalebic T FAU - Blakesley, V AU - Blakesley V FAU - LeRoith, D AU - LeRoith D FAU - Helman, L J AU - Helman LJ LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (EWS-FLI fusion protein) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Transcription Factors) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - Cell Line MH - *Cell Transformation, Neoplastic MH - Cloning, Molecular MH - Fibroblasts/*cytology MH - Mice MH - Mice, Knockout MH - Oncogene Proteins, Fusion/genetics/*metabolism MH - Receptor, IGF Type 1/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Transcription Factors/genetics/*metabolism MH - Transfection EDAT- 1998/01/10 MHDA- 1998/01/10 00:01 PST - ppublish SO - J Biol Chem 1997 Dec 5;272(49):30822-7. -------------------------------------------------------------------------------- 216: Dunaif A. Insulin resistance and the po...[PMID: 9408743] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9408743 OWN - NLM STAT- MEDLINE DA - 19980202 DCOM- 19980202 LR - 20041117 PUBM- Print IS - 0163-769X VI - 18 IP - 6 DP - 1997 Dec TI - Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. PG - 774-800 AB - It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this. AD - Pennsylvania State University College of Medicine, Hershey 17033, USA. FAU - Dunaif, A AU - Dunaif A LA - eng GR - MO1 RR-10732/RR/NCRR GR - RO1 DK-40605/DK/NIDDK PT - Journal Article PT - Review PL - UNITED STATES TA - Endocr Rev JID - 8006258 RN - 11061-68-0 (Insulin) SB - IM MH - Diabetes Mellitus, Type 2/metabolism/physiopathology MH - Female MH - Humans MH - Insulin/metabolism/physiology MH - Insulin Resistance/*physiology MH - Polycystic Ovary Syndrome/*etiology/metabolism/*physiopathology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. RF - 277 EDAT- 1997/12/31 MHDA- 1997/12/31 00:01 PST - ppublish SO - Endocr Rev 1997 Dec;18(6):774-800. -------------------------------------------------------------------------------- 217: Mathieu MC et al. Insulin receptor expression a...[PMID: 9394418] Related Articles, Books, LinkOut PMID- 9394418 OWN - NLM STAT- MEDLINE DA - 19980213 DCOM- 19980213 LR - 20041117 PUBM- Print IS - 1081-650X VI - 109 IP - 6 DP - 1997 Nov TI - Insulin receptor expression and clinical outcome in node-negative breast cancer. PG - 565-71 AB - The insulin receptor (IR), a ligand-activated tyrosine kinase, is present in breast cancers, but its relationship to patient survival is unknown. The IR was measured in 584 tumor specimens from patients with node-negative breast carcinoma by frozen-section immunohistochemistry and light microscopy. The immunostaining signal was quantitated in relation to both the staining intensity and the proportion of positive malignant epithelial cells. Analyses indicated that patients with tumors with undetectable IR content in malignant epithelial cells (260 cases) had a relatively lower predicted 5-year disease-free survival (DFS) (69% +/- 3%) than did patients with tumors with detectable IR content (324 cases; DFS 76% +/- 3%, p = .032). The significance of IR content in these breast malignant epithelial cells was then analyzed along with patient age, tumor size, progesterone and estrogen receptor status, p53 accumulation, and S-phase. Multivariate analysis of these data revealed that after adjustment for these other variables, IR content was the strongest independent predictive factor for DFS (relative risk = 1.73, p = .005). Interestingly, in a small subset of patients with very high IR content (n = 62), DFS was decreased. These data indicate that IR content in node-negative breast cancers is a significant major predictor of reduced DFS. Moreover, they raise the possibility that the measurement of IR content might provide important information concerning breast cancer biology. AD - Department of Medicine, Mount Zion Medical Center, University of California, San Francisco 94143-1616, USA. FAU - Mathieu, M C AU - Mathieu MC FAU - Clark, G M AU - Clark GM FAU - Allred, D C AU - Allred DC FAU - Goldfine, I D AU - Goldfine ID FAU - Vigneri, R AU - Vigneri R LA - eng GR - CA30195/CA/NCI GR - CA52582/CA/NCI GR - P50-CAA58183/CA/NCI GR - etc. PT - Journal Article PL - UNITED STATES TA - Proc Assoc Am Physicians JID - 9514310 RN - 0 (Protein p53) RN - 0 (Receptors, Estrogen) RN - 0 (Receptors, Progesterone) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Breast Neoplasms/*metabolism/mortality/pathology MH - Epithelial Cells/metabolism MH - Female MH - Humans MH - Middle Aged MH - Protein p53/metabolism MH - Receptor, Insulin/*metabolism MH - Receptors, Estrogen/metabolism MH - Receptors, Progesterone/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Survivors EDAT- 1997/12/12 MHDA- 1997/12/12 00:01 PST - ppublish SO - Proc Assoc Am Physicians 1997 Nov;109(6):565-71. -------------------------------------------------------------------------------- 218: Dong LQ et al. Cloning, chromosome localizat...[PMID: 9360986] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, OMIM, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 9360986 OWN - NLM STAT- MEDLINE DA - 19971211 DCOM- 19971211 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 272 IP - 46 DP - 1997 Nov 14 TI - Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma. PG - 29104-12 AB - hGrb10alpha (previously named Grb-IR) is a Src-homology 2 domain-containing protein that binds with high affinity to the tyrosine-phosphorylated insulin receptor and insulin-like growth factor-1 receptor. At least two isoforms of human Grb10, (hGrb10alpha and hGrb10beta), which differ in the pleckstrin homology (PH) domain and the N-terminal sequence, have previously been identified in insulin target tissues such as human skeletal muscle and fat cells. Here we report the cloning of the third isoform of the hGrb10 family (hGrb10gamma) from human skeletal muscle and its localization to human chromosome 7. We have also determined the human chromosome localization of Grb7 to 17q21-q22 and Grb14 to chromosome 2. hGrb10gamma contains an intact PH domain and an N-terminal sequence that is present in hGrb10alpha but absent in hGrb10beta. RNase protection assays and Western blot analysis showed that hGrb10alpha and hGrb10gamma are differentially expressed in insulin target cells including skeletal muscle, liver, and adipocyte cells. hGrb10gamma is also expressed in HeLa cells and various breast cancer cell lines. The protein bound with high affinity to the insulin receptor in cells, and the interaction was dependent on the tyrosine phosphorylation of the receptor. hGrb10gamma also underwent insulin-stimulated membrane translocation and serine phosphorylation. hGrb10gamma phosphorylation was inhibited by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase, and wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. Taken together, our data suggest that hGrb10 isoforms are potential downstream signaling components of the insulin receptor tyrosine kinase and that the PH domain may play an important role in the involvement of these isoforms in signal transduction pathways initiated by insulin and other growth factors. AD - Department of Pharmacology, The University of Texas Health Science Center, San Antonio, Texas 78284-7764, USA. FAU - Dong, L Q AU - Dong LQ FAU - Du, H AU - Du H FAU - Porter, S G AU - Porter SG FAU - Kolakowski, L F Jr AU - Kolakowski LF Jr FAU - Lee, A V AU - Lee AV FAU - Mandarino, L J AU - Mandarino LJ FAU - Fan, J AU - Fan J FAU - Yee, D AU - Yee D FAU - Liu, F AU - Liu F LA - eng SI - GENBANK/AF001534 PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Androstadienes) RN - 0 (DNA, Complementary) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (PD 98059) RN - 0 (Proteins) RN - 11061-68-0 (Insulin) RN - 151441-47-3 (growth factor receptor-bound protein 10) RN - 19545-26-7 (wortmannin) RN - 56-45-1 (Serine) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM EIN - J Biol Chem 1998 Feb 13;273(7):4288. Mandarino J [corrected to Mandarino LJ] MH - Amino Acid Sequence MH - Androstadienes/pharmacology MH - Chromosome Mapping MH - *Chromosomes, Human, Pair 17 MH - *Chromosomes, Human, Pair 7 MH - Cloning, Molecular MH - DNA, Complementary MH - Enzyme Inhibitors MH - Flavonoids/pharmacology MH - Humans MH - Insulin/pharmacology MH - Molecular Sequence Data MH - Phosphorylation MH - Protein Binding MH - Proteins/genetics/*metabolism MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't MH - Sequence Homology, Amino Acid MH - Serine/metabolism MH - Signal Transduction MH - *src Homology Domains EDAT- 1997/11/20 07:02 MHDA- 2001/03/28 10:01 PST - ppublish SO - J Biol Chem 1997 Nov 14;272(46):29104-12. -------------------------------------------------------------------------------- 219: Uddin S et al. The IRS-pathway operates dist...[PMID: 9326223] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9326223 OWN - NLM STAT- MEDLINE DA - 19971106 DCOM- 19971106 LR - 20041217 PUBM- Print IS - 0006-4971 VI - 90 IP - 7 DP - 1997 Oct 1 TI - The IRS-pathway operates distinctively from the Stat-pathway in hematopoietic cells and transduces common and distinct signals during engagement of the insulin or interferon-alpha receptors. PG - 2574-82 AB - Binding of interferon-alpha (IFN-alpha) to its receptor on hematopoietic cells activates the signal transducers and activators of transcription (Stat)- and insulin receptor substrate (IRS)-pathways, and regulates expression of antiproliferative and antiviral activities. However, it remains unknown whether these two pathways cooperate in the generation of IFN-alpha responses or function independently, and whether IRS-proteins transduce distinct downstream signals in response to IFNs or insulin/insulin-like growth factor (IGF)-1-mediated activation. Our data show that in response to IFN-alpha treatment, IRS-1 functions selectively as a docking protein for the SH2 domains of the p85 subunit of the PI 3'-kinase, but not the SH2 domain of Grb-2 which is engaged during insulin/IGF-1 signaling. In studies with THP-1 human myelomonocytic cells and 32D mouse myeloid cells, which are IRS-defective, we found that the IFN-alpha-regulated activation of Stat-1, Stat-2, and Stat-3 does not require the function of the IRS-system. Furthermore, THP-1 cells are responsive to the protective effect of IFN-alpha against vesicular stomatitis virus. Both 32D and THP-1 cells were resistant to the growth inhibitory effect of IFN-alpha, but this effect was not reversible by expression of IRS-1 or IRS-2 alone in 32D cells. Taken altogether these data show that: (1) The IRS-system transduces common and distinct signals in response to IFN-alpha or insulin/lGF-1 stimulation of hematopoietic cells. (2) The IRS-pathway operates separately from the Stat-pathway, and its function is not essential for the generation of the antiviral effect of IFN-alpha. (3) Neither the IRS- nor the Stat-pathways alone are sufficient to mediate the antiproliferative effects of IFN-alpha in hematopoietic cells, and additional signaling elements are required. AD - Department of Medicine, University of Illinois at Chicago and West Side Veterans Affairs Hospital, 60607-7173, USA. FAU - Uddin, S AU - Uddin S FAU - Fish, E N AU - Fish EN FAU - Sher, D AU - Sher D FAU - Gardziola, C AU - Gardziola C FAU - Colamonici, O R AU - Colamonici OR FAU - Kellum, M AU - Kellum M FAU - Pitha, P M AU - Pitha PM FAU - White, M F AU - White MF FAU - Platanias, L C AU - Platanias LC LA - eng GR - CA73381/CA/NCI GR - DK38712/DK/NIDDK GR - DK43808/DK/NIDDK GR - etc. PT - Journal Article PL - UNITED STATES TA - Blood JID - 7603509 RN - 0 (DNA-Binding Proteins) RN - 0 (Interferon-alpha) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Interferon) RN - 0 (Stat1 protein) RN - 0 (Stat2 protein) RN - 0 (Stat3 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 0 (interferon alpha receptor) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Animals MH - Burkitt Lymphoma/pathology MH - Comparative Study MH - DNA-Binding Proteins/*physiology MH - Hematopoietic Stem Cells/cytology/*metabolism MH - Humans MH - Insulin/pharmacology MH - Insulin-Like Growth Factor I/pharmacology MH - Interferon-alpha/pharmacology MH - Leukemia, Myelomonocytic, Acute/pathology MH - Leukemia, T-Cell, Acute/pathology MH - Mice MH - Multiple Myeloma/pathology MH - Neoplasm Proteins/physiology MH - Phosphoproteins/*physiology MH - Receptor, Insulin/drug effects/*physiology MH - Receptors, Interferon/drug effects/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/*physiology MH - Trans-Activators/*physiology MH - Tumor Cells, Cultured MH - src Homology Domains EDAT- 1997/11/05 MHDA- 1997/11/05 00:01 PST - ppublish SO - Blood 1997 Oct 1;90(7):2574-82. -------------------------------------------------------------------------------- 220: Schneller M et al. Alphavbeta3 integrin associat...[PMID: 9312019] Related Articles, Cited in PMC, Books, LinkOut PMID- 9312019 OWN - NLM STAT- MEDLINE DA - 19971114 DCOM- 19971114 LR - 20041117 PUBM- Print IS - 0261-4189 VI - 16 IP - 18 DP - 1997 Sep 15 TI - Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. PG - 5600-7 AB - Integrin-mediated cell attachment modulates growth responses and growth factors regulate cell attachment. Moreover, both cell attachment to extracellular matrix and mitogenic signaling by growth factors are necessary for the proliferation of most types of normal cells, suggesting that integrin and growth factor receptor signaling pathways meet at some downstream point. We report here that a small, highly tyrosine-phosphorylated fraction of PDGFbeta and insulin receptors co-immunoprecipitates with the alphavbeta3 integrin from cells. The integrin association requires growth factor stimulation of the receptors. Several signaling molecules that are known to be associated with activated growth factor receptors were present in the alphavbeta3 integrin complexes. Mitogenicity and chemotaxis induced by PDGF-BB were enhanced in cells plated on the alphavbeta3 ligand vitronectin compared with cells plated on the beta1 integrin ligand collagen. Thus, the engagement of the alphavbeta3 integrin in cell-matrix interactions appears to coordinate an intense response to growth factors, helping to explain the importance of this integrin for tissue regeneration, angiogenesis and tumor metastasis. AD - La Jolla Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. FAU - Schneller, M AU - Schneller M FAU - Vuori, K AU - Vuori K FAU - Ruoslahti, E AU - Ruoslahti E LA - eng GR - CA30199/CA/NCI GR - CA67224/CA/NCI GR - CA71560/CA/NCI PT - Journal Article PL - ENGLAND TA - EMBO J JID - 8208664 RN - 0 (Antibodies) RN - 0 (Antibodies, Monoclonal) RN - 0 (Platelet-Derived Growth Factor) RN - 0 (Receptors, Vitronectin) RN - 0 (platelet-derived growth factor BB) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (Receptor, Platelet-Derived Growth Factor beta) RN - EC 2.7.1.112 (Receptors, Platelet-Derived Growth Factor) SB - IM MH - 3T3 Cells MH - Animals MH - Antibodies/pharmacology MH - Antibodies, Monoclonal/pharmacology MH - Cell Adhesion/drug effects/physiology MH - Cell Division/drug effects MH - Cell Line MH - Cells, Cultured MH - Chemotaxis/drug effects/physiology MH - Extracellular Matrix/physiology MH - Humans MH - Male MH - Mice MH - Platelet-Derived Growth Factor/*pharmacology MH - Rats MH - Receptor, Insulin/*physiology MH - Receptor, Platelet-Derived Growth Factor beta MH - Receptors, Platelet-Derived Growth Factor/immunology/*physiology MH - Receptors, Vitronectin/immunology/*physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Skin EDAT- 1997/10/06 MHDA- 1997/10/06 00:01 AID - 10.1093/emboj/16.18.5600 [doi] PST - ppublish SO - EMBO J 1997 Sep 15;16(18):5600-7. -------------------------------------------------------------------------------- 221: Tanaka S et al. Biological effects of human i...[PMID: 9303488] Related Articles, Books, LinkOut PMID- 9303488 OWN - NLM STAT- MEDLINE DA - 19971008 DCOM- 19971008 LR - 20041117 PUBM- Print IS - 0270-9139 VI - 26 IP - 3 DP - 1997 Sep TI - Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. PG - 598-604 AB - The human insulin receptor substrate-1 (hIRS-1) is a key intracellular protein involved in various cytokine signaling pathways associated with cell growth. We have previously demonstrated that stable transfection and overexpression of hIRS-1 in human hepatoblastoma cells in vitro leads to the constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. In this setting, hIRS-1 acts as a dominant oncogene and will induce neoplastic transformation of NIH 3T3 cells. In the present study, the biologic effects of hIRS-1 overexpression in the liver was analyzed using both clinical tumor samples and a newly developed transgenic mouse model. We have found that approximately 40% of 22 human hepatocellular carcinoma (HCC) tumors had enhanced (>200%) hIRS-1 gene expression compared with adjacent non-involved liver tissue. There was a significant relationship between the level of hIRS-1 overexpression and the tumor size; this finding suggests a possible role for hIRS-1 in tumor progression. To determine if downstream signal transduction cascades were activated by overexpression of hIRS-1 in hepatocytes, we established a transgenic mouse model using an hIRS-1 construct driven by an albumin promoter/enhancer element to direct liver specific expression. The overexpressed hIRS-1 protein was found to be tyrosyl phosphorylated and interacted with downstream SH2-containing molecules such as the p85 subunit of phosphatidylinositol-3 kinase (PI3K), Grb2 adaptor, and SHP2 phosphatase proteins. The functional consequences of hIRS-1 overexpression were reflected by constitutive activation of both the MAPK and PI3K signal transduction cascades. More important, overexpression of hIRS-1 in the transgenic liver led to increased hepatocyte DNA synthesis. Our findings indicate that hIRS-1 overexpression induces downstream signaling molecules associated with hepatocyte growth and may potentially enhance tumor progression of HCC. AD - Molecular Hepatology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown 02129, USA. FAU - Tanaka, S AU - Tanaka S FAU - Mohr, L AU - Mohr L FAU - Schmidt, E V AU - Schmidt EV FAU - Sugimachi, K AU - Sugimachi K FAU - Wands, J R AU - Wands JR LA - eng GR - AA-02666/AA/NIAAA GR - AA-08169/AA/NIAAA GR - CA-35711/CA/NCI PT - Journal Article PL - UNITED STATES TA - Hepatology JID - 8302946 RN - 0 (Phosphoproteins) RN - 0 (Recombinant Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - 3T3 Cells MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/*metabolism MH - Carcinoma, Hepatocellular/*metabolism MH - Humans MH - Kidney/metabolism MH - Liver/*metabolism MH - Liver Neoplasms/*metabolism MH - Lung/metabolism MH - Mice MH - Mice, Transgenic MH - Muscle, Skeletal/metabolism MH - Myocardium/metabolism MH - Phosphoproteins/biosynthesis/genetics/*physiology MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - Polymerase Chain Reaction MH - Recombinant Proteins/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Spleen/metabolism EDAT- 1997/09/26 MHDA- 1997/09/26 00:01 AID - S0270913997003881 [pii] AID - 10.1002/hep.510260310 [doi] PST - ppublish SO - Hepatology 1997 Sep;26(3):598-604. -------------------------------------------------------------------------------- 222: Nolan MK et al. Differential roles of IRS-1 a...[PMID: 9311601] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9311601 OWN - NLM STAT- MEDLINE DA - 19971031 DCOM- 19971031 LR - 20041117 PUBM- Print IS - 0020-7136 VI - 72 IP - 5 DP - 1997 Sep 4 TI - Differential roles of IRS-1 and SHC signaling pathways in breast cancer cells. PG - 828-34 AB - Several polypeptide growth factors stimulate breast cancer growth and may be involved in tumor progression. However, the relative importance of diverse growth factor signaling pathways in the development and maintenance of the neoplastic phenotype is largely unknown. The activation of such growth factor receptors as the insulin-like growth factor I receptor (IGF-I R), erbB-type receptors (erbB Rs) and FGF receptors (FGF Rs) controls the phenotype of a model breast cancer cell line MCF-7. To evaluate the function of 2 post-receptor signaling molecules, insulin receptor substrate-1 (IRS-1) (a major substrate of the IGF-IR) and SHC (a common substrate of tyrosine kinase receptors), we developed several MCF-7-derived cell clones in which the synthesis of either IRS-1 or SHC was blocked by antisense RNA. In MCF-7 cells, down-regulation of IRS-1 by 80-85% strongly suppressed anchorage-dependent and -independent growth and induced apoptotic cell death under growth factor- and estrogen-reduced conditions. The reduction of SHC levels by approximately 50% resulted in the inhibition of monolayer and anchorage-independent growth but did not decrease cell survival. Importantly, cell aggregation and the ability of cells to survive on the extracellular matrix were inhibited in MCF-7/anti-SHC clones, but not in MCF-7/anti-IRS-1 clones. Cell motility toward IGF was not attenuated in any of the tested cell lines, but motility toward EGF was decreased in MCF-7/anti-SHC clones. Our results suggest that in MCF-7 cells: 1) both IRS-1 and SHC are implicated in the control of monolayer and anchorage-independent growth; 2) IRS-1 is critical to support cell survival; 3) SHC is involved in EGF-dependent motility; and 4) normal levels of SHC, but not IRS-1, are necessary for the formation and maintenance of cell-cell interactions. AD - Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Nolan, M K AU - Nolan MK FAU - Jankowska, L AU - Jankowska L FAU - Prisco, M AU - Prisco M FAU - Xu, S AU - Xu S FAU - Guvakova, M A AU - Guvakova MA FAU - Surmacz, E AU - Surmacz E LA - eng GR - DK48969/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Int J Cancer JID - 0042124 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (RNA, Antisense) RN - 0 (Somatomedins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (insulin receptor substrate-1 protein) RN - 62229-50-9 (Epidermal Growth Factor) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Apoptosis MH - Blotting, Western MH - Breast Neoplasms/*pathology MH - Cell Adhesion/drug effects MH - Cell Aggregation/drug effects MH - Cell Division/drug effects MH - Cell Movement/drug effects MH - Cell Survival/drug effects MH - Cell Transformation, Neoplastic/drug effects MH - Epidermal Growth Factor/pharmacology MH - Female MH - Humans MH - Phosphoproteins/genetics/*physiology MH - Proteins/genetics/*physiology MH - RNA, Antisense/pharmacology MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Somatomedins/pharmacology MH - Tumor Cells, Cultured EDAT- 1997/09/25 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1097-0215(19970904)72:5<828::AID-IJC20>3.0.CO;2-3 [pii] PST - ppublish SO - Int J Cancer 1997 Sep 4;72(5):828-34. -------------------------------------------------------------------------------- 223: Kowalski-Chauvel A et al. Tyrosine phosphorylation of i...[PMID: 9245714] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9245714 OWN - NLM STAT- MEDLINE DA - 19970915 DCOM- 19970915 LR - 20041117 PUBM- Print IS - 0006-291X VI - 236 IP - 3 DP - 1997 Jul 30 TI - Tyrosine phosphorylation of insulin receptor substrate-1 and activation of the PI-3-kinase pathway by glycine-extended gastrin precursors. PG - 687-92 AB - Glycine-extended gastrin precursors (G-Gly) were considered as processing intermediates devoid of biological activity. However, we have recently identified selective receptors for G-Gly which mediate the proliferative effects of this precursor. Little is known about the signaling pathways activated by G-Gly. In the present study, we demonstrate that PI-3-kinase is rapidly and transiently activated by G-Gly. We also observed a rapid increase in the tyrosine phosphorylation of IRS-1 and an activation of the PI-3-kinase in anti-IRS-1 immunoprecipitates, suggesting that PI-3-kinase may be activated by association with tyrosine phosphorylated IRS-1. We also demonstrated that gastrin precursors activate the serine/threonine kinase, p70 kDa S6 kinase (p70S6K), through a wortmannin sensitive pathway. AD - INSERM U.151, Groupe de Recherche de Biologie et Pathologie digestive, Institut Louis Bugnard, CHU Rangueil, Toulouse, France. FAU - Kowalski-Chauvel, A AU - Kowalski-Chauvel A FAU - Pradayrol, L AU - Pradayrol L FAU - Vaysse, N AU - Vaysse N FAU - Seva, C AU - Seva C LA - eng PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (Androstadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (Gastrins) RN - 0 (Phosphoproteins) RN - 0 (Protein Precursors) RN - 0 (insulin receptor substrate-1 protein) RN - 19545-26-7 (wortmannin) RN - 21820-51-9 (Phosphotyrosine) RN - 56-40-6 (Glycine) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Androstadienes/pharmacology MH - Animals MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Gastrins/*pharmacology MH - Glycine/*pharmacology MH - Kinetics MH - Pancreatic Neoplasms MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors/*metabolism MH - Phosphotyrosine/*metabolism MH - Protein Precursors/*pharmacology MH - Protein-Serine-Threonine Kinases/metabolism MH - Rats MH - Research Support, Non-U.S. Gov't MH - Tumor Cells, Cultured EDAT- 1997/07/30 MHDA- 1997/07/30 00:01 AID - S0006291X97969758 [pii] PST - ppublish SO - Biochem Biophys Res Commun 1997 Jul 30;236(3):687-92. -------------------------------------------------------------------------------- 224: Ish-Shalom D et al. Mitogenic properties of insul...[PMID: 9248698] Related Articles, Substance via MeSH, Books, LinkOut PMID- 9248698 OWN - NLM STAT- MEDLINE DA - 19971128 DCOM- 19971128 LR - 20031114 PUBM- Print IS - 0012-186X VI - 40 Suppl 2 DP - 1997 Jul TI - Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. PG - S25-31 AB - Insulin has traditionally been considered as a hormone essential for metabolic regulation, while the insulin-like growth factors (IGF-I and IGF-II) are postulated to be more specifically involved in growth regulation. The conventional wisdom is that they share each other's effects only at high concentrations, due to their weak affinity for the heterologous receptor. We discuss here the evidence that in the proper cellular context, insulin can be mitogenic at physiologic concentrations through its own receptor. We studied the insulin and IGF-I binding characteristics of a new model suitable for analysing insulin receptor mediated mitogenesis; that is, a T-cell lymphoma line that depends on insulin for growth, but is unresponsive to IGFs. The cells showed no specific binding of 125I-IGF-I and furthermore, no IGF-I receptor mRNA was detected by RNAse protection assay in the LB cells, in contrast with mouse brain and thymus. The cells bound at saturation about 3000 insulin molecules to receptors that had normal characteristics in terms of affinity, kinetics, pH dependence and negative co-operativity. A series of insulin analogues competed for 125I-insulin binding with relative potencies comparable to those observed in other insulin target cells. The full sequence of the insulin receptor cDNA was determined and found to be identical to the published sequence of the murine insulin receptor cDNA. The LB cell line is therefore an ideal model with which to investigate insulin mitogenic signalling without interference from the IGF-I receptor. Using this model, we have started approaching the molecular basis of insulin-induced mitogenesis, in particular the role of signalling kinetics in choosing between mitogenic and metabolic pathways. AD - Lautenberg Center for General and Tumour Immunology, Hebrew University, Hadassah Medical School, Jerusalem, Israel. FAU - Ish-Shalom, D AU - Ish-Shalom D FAU - Christoffersen, C T AU - Christoffersen CT FAU - Vorwerk, P AU - Vorwerk P FAU - Sacerdoti-Sierra, N AU - Sacerdoti-Sierra N FAU - Shymko, R M AU - Shymko RM FAU - Naor, D AU - Naor D FAU - De Meyts, P AU - De Meyts P LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - GERMANY TA - Diabetologia JID - 0006777 RN - 0 (Mitogens) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Insulin/*analogs & derivatives/metabolism/*physiology MH - Insulin-Like Growth Factor I/metabolism/*physiology MH - Lymphoma, T-Cell MH - Mice MH - Mitogens/metabolism/*physiology MH - Receptor, Insulin/*metabolism MH - Tumor Cells, Cultured RF - 45 EDAT- 1997/07/01 MHDA- 1997/07/01 00:01 PST - ppublish SO - Diabetologia 1997 Jul;40 Suppl 2:S25-31. -------------------------------------------------------------------------------- 225: Esposito DL et al. Tyrosine residues in the C-te...[PMID: 9202243] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9202243 OWN - NLM STAT- MEDLINE DA - 19970724 DCOM- 19970724 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 138 IP - 7 DP - 1997 Jul TI - Tyrosine residues in the C-terminal domain of the insulin-like growth factor-I receptor mediate mitogenic and tumorigenic signals. PG - 2979-88 AB - We investigated cellular proliferation, the transforming activity, and activation of known signal transduction pathways in NIH-3T3 cells stably expressing insulin-like growth factor-I receptors (IGF-IRs) with amino acid substitutions in the carboxy(C)-terminal domain. The mutant receptors contained substitutions of both tyrosines 1250 and 1251 with phenylalanine and histidine (amino acids present in the analogous positions in the insulin receptor), as well as phenylalanine 1310 replaced by tyrosine (IsY clones) to resemble the placement of tyrosine residues in the C-terminal domain of the insulin receptor. As a control for the IsY clones, a second mutant receptor was expressed with a substitution of phenylalanine 1310 with tyrosine only (DBY clones). Clones expressing IGF-IRs with the IsY substitutions had a significantly slower rate of growth compared with cells expressing an equivalent number of wild-type IGF-IRs (NWT). In contrast, the DBY clones showed relatively normal growth rates. Cells with wild-type IGF-IR demonstrated a transformed phenotype in soft agar assays. The IsY clones lost the transforming ability of the wild type IGF-IR, whereas DBY clones formed colonies. IGF-I-stimulated autophosphorylation of the IGF-IR and tyrosine phosphorylation of IRS-1 and SHC, known substrates in the IGF-IR signal transduction pathway, were studied. Mutated IGF-IRs (IsY and DBY) did not alter the IGF-I-induced tyrosine phosphorylation of these proteins. Furthermore, the mutated IGF-IRs did not alter Grb2 association with phosphorylated IRS-1 and SHC. IGF-I stimulation of Crk-II phosphorylation, a novel substrate of the IGF-IR, was similar in cells expressing mutated and wild-type IGF-IRs. IGF-I-induced activation of phosphatidylinositol (PI) 3'-kinase was equivalent in cells expressing either mutant or wild-type IGF-IRs. These data suggest that the IGF-IR mediates, at least in part, cellular proliferation and increased transforming ability through its C-terminal domain. The exact postreceptor signaling pathway(s) involved have yet to be fully elucidated. AD - Diabetes Branch, NIDDK, NIH, Bethesda, Maryland 20892-1770, USA. FAU - Esposito, D L AU - Esposito DL FAU - Blakesley, V A AU - Blakesley VA FAU - Koval, A P AU - Koval AP FAU - Scrimgeour, A G AU - Scrimgeour AG FAU - LeRoith, D AU - LeRoith D LA - eng PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (proto-oncogene protein c-crk) RN - 55520-40-6 (Tyrosine) RN - 63-91-2 (Phenylalanine) RN - 71-00-1 (Histidine) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein Kinases) SB - AIM SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - 3T3 Cells MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cell Division MH - *Cell Transformation, Neoplastic MH - Clone Cells/metabolism MH - Histidine/metabolism MH - Humans MH - Mice MH - *Mitosis MH - Phenylalanine/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Protein Kinases/metabolism MH - *Proto-Oncogene Proteins MH - Receptor, IGF Type 1/*metabolism MH - Research Support, Non-U.S. Gov't MH - Structure-Activity Relationship MH - Tyrosine/*metabolism MH - src Homology Domains EDAT- 1997/07/01 MHDA- 1997/07/01 00:01 PST - ppublish SO - Endocrinology 1997 Jul;138(7):2979-88. -------------------------------------------------------------------------------- 226: Valentinis B et al. Insulin-like growth factor I ...[PMID: 9199308] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 9199308 OWN - NLM STAT- MEDLINE DA - 19970724 DCOM- 19970724 LR - 20050209 PUBM- Print IS - 0270-7306 VI - 17 IP - 7 DP - 1997 Jul TI - Insulin-like growth factor I receptor signaling in transformation by src oncogenes. PG - 3744-54 AB - R- cells, a line of mouse embryo fibroblasts with a targeted disruption of the insulin-like growth factor I (IGF-I) receptor genes, are refractory to transformation by several viral and cellular oncogenes. Using colony formation in soft agar as a measure of full transformation, we report here that R- cells can be transformed by v-src, although they still cannot be transformed by the activated c-src527 (mutation at tyrosine 527 to phenylalanine), which readily transforms mouse embryo cells with a wild-type number of IGF-I receptors (W cells). Although v-src is a more potent inducer of tyrosine phosphorylation than c-src527, the extent of phosphorylation of either insulin receptor substrate 1 or Shc, two of the major substrates of the IGF-I receptor, does not seem sufficiently different to explain the qualitative difference in soft agar growth. v-src, however, is considerably more efficient than c-src527 in its ability to tyrosyl phosphorylate, in R- cells, the focal adhesion kinase, Stat1, and p130cas. These results indicate that v-src, but not c-src527, can bypass the requirement for a functional IGF-I receptor in the full transformation of mouse embryo fibroblasts and suggest that qualitative and quantitative differences between the two oncogenes can be used to identify some of the signals relevant to the mechanism(s) of transformation. AD - Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Valentinis, B AU - Valentinis B FAU - Morrione, A AU - Morrione A FAU - Taylor, S J AU - Taylor SJ FAU - Baserga, R AU - Baserga R LA - eng GR - CA 53484/CA/NCI PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Cell Adhesion Molecules) RN - 0 (DNA-Binding Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (Stat1 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 21820-51-9 (Phosphotyrosine) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - 3T3 Cells MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Animals MH - Cell Adhesion Molecules/metabolism MH - Cell Division MH - *Cell Transformation, Neoplastic MH - Cells, Cultured MH - DNA-Binding Proteins/metabolism MH - Epidermal Growth Factor/pharmacology MH - *Genes, src MH - Mice MH - *Oncogenes MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Protein-Tyrosine Kinase/metabolism MH - Proteins/metabolism MH - Receptor, IGF Type 1/*physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Trans-Activators/metabolism MH - Transfection EDAT- 1997/07/01 MHDA- 1997/07/01 00:01 PST - ppublish SO - Mol Cell Biol 1997 Jul;17(7):3744-54. -------------------------------------------------------------------------------- 227: Mooney RA et al. The protein tyrosine phosphat...[PMID: 9207225] Related Articles, Substance via MeSH, Books, LinkOut PMID- 9207225 OWN - NLM STAT- MEDLINE DA - 19970724 DCOM- 19970724 LR - 20041117 PUBM- Print IS - 0006-291X VI - 235 IP - 3 DP - 1997 Jun 27 TI - The protein tyrosine phosphatase LAR has a major impact on insulin receptor dephosphorylation. PG - 709-12 AB - Transmembrane protein tyrosine phosphatases (PTPases) may act as regulators of the insulin receptor. Supporting this hypothesis, antisense suppression of the PTPase LAR in McA-RH7777 hepatoma cells increased insulin receptor signaling (Kulas et. al., J. Biol. Chem. (1996) 271, 748-754). The effects of decreased LAR expression may be mediated by decreased dephosphorylation of the insulin receptor. The rate of insulin receptor dephosphorylation was examined in situ, following elution of surface bound insulin at pH 4.0. In LAR antisense cells, dephosphorylation was prolonged by 2.6-fold with a t(1/2) of 87+/-11 sec compared to a t(1/2) of 34+/-6 sec in control cells. EGF receptor dephosphorylation was also prolonged in LAR antisense cells. These results are further evidence that LAR is a physiological regulator of the insulin receptor and is consistent with its direct interaction with the tyrosine phosphorylated insulin receptor. AD - Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, New York 14642, USA. FAU - Mooney, R A AU - Mooney RA FAU - Kulas, D T AU - Kulas DT FAU - Bleyle, L A AU - Bleyle LA FAU - Novak, J S AU - Novak JS LA - eng GR - R01-DK38138/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (DNA, Antisense) RN - 0 (Receptors, Cell Surface) RN - 0 (Recombinant Proteins) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.1.3.48 (leukocyte common antigen-related phosphatase) SB - IM MH - Animals MH - DNA, Antisense MH - Insulin/pharmacology MH - Kinetics MH - Liver Neoplasms, Experimental MH - Phosphorylation MH - Protein-Tyrosine-Phosphatase/biosynthesis/*metabolism MH - Rats MH - Receptor, Epidermal Growth Factor/*metabolism MH - Receptor, Insulin/*physiology MH - *Receptors, Cell Surface MH - Recombinant Proteins/biosynthesis/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/*physiology MH - Transfection MH - Tumor Cells, Cultured EDAT- 1997/06/27 MHDA- 1997/06/27 00:01 AID - S0006291X97968893 [pii] PST - ppublish SO - Biochem Biophys Res Commun 1997 Jun 27;235(3):709-12. -------------------------------------------------------------------------------- 228: Chuang LM et al. Novel pathway of insulin sign...[PMID: 9199189] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9199189 OWN - NLM STAT- MEDLINE DA - 19970724 DCOM- 19970724 LR - 20041117 PUBM- Print IS - 0006-291X VI - 235 IP - 2 DP - 1997 Jun 18 TI - Novel pathway of insulin signaling involving Stat1alpha in Hep3B cells. PG - 317-20 AB - STAT proteins are important transcription factors that regulate cell growth and differentiation. To elucidate the molecular mechanisms of insulin actions, we have studied how insulin activates STAT proteins in Hep3B cells. Insulin rapidly phosphorylated Stat1alpha at tyrosine residues and increased its specific binding activities to a GAS/ISRE consensus oligonucleotide. IL-4 also phosphorylated Stat1alpha and increased DNA binding activities to the same Stat1alpha responsive element. There was no increase in tyrosine phosphorylation of JAK family of kinases following insulin stimulation. In contrast, IL-4 stimulated tyrosine phosphorylation of JAK1, JAK2 and tyk2 in this cell line. These data indicate that insulin receptor signaling can activate the transcriptional regulatory function of STAT protein, and that insulin actions on Stat1alpha are mediated through signaling pathways independent of JAK family of kinases. AD - Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei. FAU - Chuang, L M AU - Chuang LM FAU - Wang, P H AU - Wang PH FAU - Chang, H M AU - Chang HM FAU - Lee, S C AU - Lee SC LA - eng GR - HL-55533/HL/NHLBI PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (DNA-Binding Proteins) RN - 0 (Deoxyribonucleotides) RN - 0 (Nuclear Proteins) RN - 0 (Transcription Factors) RN - 0 (gamma interferon activation factor) RN - 11061-68-0 (Insulin) RN - 207137-56-2 (Interleukin-4) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/metabolism MH - DNA-Binding Proteins/metabolism MH - Deoxyribonucleotides/metabolism MH - Immunoblotting MH - Insulin/metabolism/*pharmacology MH - Interleukin-4/pharmacology MH - Nuclear Proteins/analysis/metabolism MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Precipitin Tests MH - Protein-Tyrosine Kinase/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction MH - Transcription Factors/*metabolism MH - Tumor Cells, Cultured EDAT- 1997/06/18 MHDA- 1997/06/18 00:01 AID - S0006291X97967711 [pii] PST - ppublish SO - Biochem Biophys Res Commun 1997 Jun 18;235(2):317-20. -------------------------------------------------------------------------------- 229: Yamamoto H et al. alpha2,6-Sialyltransferase ge...[PMID: 9166754] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9166754 OWN - NLM STAT- MEDLINE DA - 19970617 DCOM- 19970617 LR - 20050209 PUBM- Print IS - 0022-3042 VI - 68 IP - 6 DP - 1997 Jun TI - alpha2,6-Sialyltransferase gene transfection into a human glioma cell line (U373 MG) results in decreased invasivity. PG - 2566-76 AB - Glycosyltransferase gene transfection into cell lines has been an approach used successfully to elucidate the functional role of cell surface glycoconjugates. We have transfected the rat CMP-NeuAc:Galbeta1,4GlcNAc alpha2,6-sialyltransferase (EC 2.4.99.1) gene into a human, tumorigenic, glioma cell line, U373 MG. This transfection led to a marked inhibition of invasivity, alterations in adhesivity to fibronectin and collagen matrices, and inappropriately sialylated alpha3beta1 integrin. Adhesion-mediated protein tyrosine phosphorylation was reduced in the transfectants despite increased expression of focal adhesion kinase, p125fak. Furthermore, the transfectants showed a distinct cell morphology, an increased number of focal adhesion sites, and different sensitivity to cytochalasin D treatment than control U373 MG cells. These results suggest that inappropriate sialylation of cell surface glycoconjugates, such as integrins, can change focal adhesion as well as adhesion-mediated signal transduction and block glioma cell invasivity in vitro. AD - Chicago Institute for Neurosurgery and Neuroresearch, Illinois, U.S.A. FAU - Yamamoto, H AU - Yamamoto H FAU - Kaneko, Y AU - Kaneko Y FAU - Rebbaa, A AU - Rebbaa A FAU - Bremer, E G AU - Bremer EG FAU - Moskal, J R AU - Moskal JR LA - eng GR - NS33383/NS/NINDS PT - Journal Article PL - UNITED STATES TA - J Neurochem JID - 2985190R RN - 0 (Antigens, CD) RN - 0 (Cell Adhesion Molecules) RN - 0 (Fibronectins) RN - 0 (Integrin alpha3beta1) RN - 0 (Integrins) RN - 0 (Receptors, Laminin) RN - 0 (Sialic Acids) RN - 55520-40-6 (Tyrosine) RN - 9007-34-5 (Collagen) RN - EC 2.4.99.- (Sialyltransferases) RN - EC 2.4.99.1 (beta-D-galactoside alpha 2-6-sialyltransferase) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - Animals MH - Antigens, CD/genetics/metabolism MH - Cell Adhesion/physiology MH - Cell Adhesion Molecules/metabolism MH - Cloning, Molecular MH - Collagen/metabolism MH - Cytoskeleton/metabolism MH - Fibronectins/metabolism MH - Glioma MH - Humans MH - Integrin alpha3beta1 MH - Integrins/metabolism MH - Neoplasm Invasiveness/*physiopathology MH - Phosphorylation MH - Protein-Tyrosine Kinase/metabolism MH - Rats MH - Receptor, Insulin/metabolism MH - Receptors, Laminin/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Sialic Acids/metabolism MH - Sialyltransferases/genetics/*metabolism MH - Signal Transduction/physiology MH - Transfection MH - Tumor Cells, Cultured/chemistry/enzymology MH - Tyrosine/metabolism EDAT- 1997/06/01 MHDA- 1997/06/01 00:01 PST - ppublish SO - J Neurochem 1997 Jun;68(6):2566-76. -------------------------------------------------------------------------------- 230: Mohammadi M et al. Structures of the tyrosine ki...[PMID: 9139660] Related Articles, Compound via MeSH, Substance via MeSH, Protein, Structure, 3D Domains, Cited in PMC, Books, LinkOut PMID- 9139660 OWN - NLM STAT- MEDLINE DA - 19970523 DCOM- 19970523 LR - 20041117 PUBM- Print IS - 0036-8075 VI - 276 IP - 5314 DP - 1997 May 9 TI - Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. PG - 955-60 AB - A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis. AD - Department of Pharmacology, New York University Medical Center, New York, NY 10016, USA. FAU - Mohammadi, M AU - Mohammadi M FAU - McMahon, G AU - McMahon G FAU - Sun, L AU - Sun L FAU - Tang, C AU - Tang C FAU - Hirth, P AU - Hirth P FAU - Yeh, B K AU - Yeh BK FAU - Hubbard, S R AU - Hubbard SR FAU - Schlessinger, J AU - Schlessinger J LA - eng SI - PDB/1AGW SI - PDB/1FGI PT - Journal Article PL - UNITED STATES TA - Science JID - 0404511 RN - 0 (Enzyme Inhibitors) RN - 0 (Piperazines) RN - 0 (Pyrroles) RN - 0 (Receptors, Fibroblast Growth Factor) RN - 0 (SU 4984) RN - 0 (SU 5402) RN - 21820-51-9 (Phosphotyrosine) RN - 56-65-5 (Adenosine Triphosphate) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (Receptors, Platelet-Derived Growth Factor) RN - EC 2.7.1.112 (fibroblast growth factor receptor 1) SB - IM MH - 3T3 Cells MH - Adenosine Triphosphate/metabolism MH - Amino Acid Sequence MH - Animals MH - Crystallography, X-Ray MH - Enzyme Inhibitors/chemistry/*metabolism/pharmacology MH - Hydrogen Bonding MH - Mice MH - Models, Molecular MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Piperazines/chemistry/*metabolism/pharmacology MH - Protein-Tyrosine Kinase/antagonists & inhibitors/*chemistry/metabolism MH - Pyrroles/chemistry/*metabolism/pharmacology MH - *Receptor Protein-Tyrosine Kinases MH - Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism MH - Receptor, Insulin/antagonists & inhibitors/metabolism MH - Receptors, Fibroblast Growth Factor/antagonists & inhibitors/*chemistry/metabolism MH - Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors/metabolism MH - Research Support, Non-U.S. Gov't EDAT- 1997/05/09 MHDA- 1997/05/09 00:01 PST - ppublish SO - Science 1997 May 9;276(5314):955-60. -------------------------------------------------------------------------------- 231: Garrouste FL et al. Up-regulation of insulin/insu...[PMID: 9112401] Related Articles, Substance via MeSH, Books, LinkOut PMID- 9112401 OWN - NLM STAT- MEDLINE DA - 19970509 DCOM- 19970509 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 138 IP - 5 DP - 1997 May TI - Up-regulation of insulin/insulin-like growth factor-I hybrid receptors during differentiation of HT29-D4 human colonic carcinoma cells. PG - 2021-32 AB - To assess the autocrine function of insulin-like growth factor II (IGF-II) in the balance of proliferation and differentiation in HT29-D4 human colonic cancer cells, we studied the expression of IGF-I receptors (IGF-IR) and insulin receptors (IR) in relation to the state of cell differentiation. IGF-IR and IR were expressed in both undifferentiated and enterocyte-like differentiated HT29-D4 cells. IGF-IR had two isoforms with a 97-kDa and a 102-kDa beta-subunit. In addition, HT29-D4 cells expressed hybrid receptors (HR) formed by the association of two alphabeta heterodimers from both IR and IGF-IR. HR were evidenced through 1) inhibition of IGF-I binding by the B6 anti-IR antibody and 2) immunoprecipitation with the alpha-IR3 anti-IGF-IR antibody, which revealed an additional 95-kDa IR beta-subunit that disappeared when the heterotetrameric receptor was dissociated by disulfide reduction into alphabeta heterodimers before immunoprecipitation. Like IGF-IR, HR had a high affinity for IGF-I (Kd, approximately 1.5 nM), but did not bind insulin significantly; the latter interacted with the native IR only (Kd, approximately 4 nM). In the differentiated HT29-D4 cell monolayer, all receptor species were strongly polarized (>97%) toward the basolateral membrane. Moreover, HT29-D4 cell differentiation was accompanied by an approximately 2-fold increase in the number of IR, whereas the number of IGF-I-binding sites was unaltered. However, in differentiated HT29-D4 cells, approximately 55% of the latter were involved in HR vs. approximately 20% in undifferentiated HT29-D4 cells. Thus, HT29-D4 cell differentiation is characterized by an up-regulation (approximately 3-fold) of the level of HR coupled to a down-regulation (approximately 40%) of the level of native tetrameric IGF-IR. Alterations were induced early during the cell differentiation process, i.e. 5 days postconfluence, and remained unchanged for at least 21 days. Taken together, these results suggest that the IGF-II autocrine loop in HT29-D4 cells may trigger distinct signaling pathways if it activates native IGF-IR, which predominate in undifferentiated cells, or if it activates HR, which are up-regulated in differentiated cells. AD - Unite Interactions entre Systemes Proteiques et Differenciation dans la Cellule Tumorale, CNRS URA 1924, Faculte de Medecine, Marseille, France. FAU - Garrouste, F L AU - Garrouste FL FAU - Remacle-Bonnet, M M AU - Remacle-Bonnet MM FAU - Lehmann, M M AU - Lehmann MM FAU - Marvaldi, J L AU - Marvaldi JL FAU - Pommier, G J AU - Pommier GJ LA - eng PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (Cross-Linking Reagents) RN - 0 (Iodine Radioisotopes) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Binding, Competitive MH - *Cell Differentiation MH - Cross-Linking Reagents MH - Flow Cytometry MH - HT29 Cells MH - Humans MH - Immunosorbent Techniques MH - Insulin/metabolism MH - Insulin-Like Growth Factor I/metabolism MH - Iodine Radioisotopes MH - Receptor, IGF Type 1/*metabolism MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't EDAT- 1997/05/01 MHDA- 1997/05/01 00:01 PST - ppublish SO - Endocrinology 1997 May;138(5):2021-32. -------------------------------------------------------------------------------- 232: Guvakova MA et al. Overexpressed IGF-I receptors...[PMID: 9056422] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9056422 OWN - NLM STAT- MEDLINE DA - 19970320 DCOM- 19970320 LR - 20041117 PUBM- Print IS - 0014-4827 VI - 231 IP - 1 DP - 1997 Feb 25 TI - Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells. PG - 149-62 AB - The insulin-like growth factor I receptor (IGF-IR) paracrine or autocrine loop plays an important role in the maintenance of breast cancer growth. Cancer cells contain several-fold higher levels of the IGF-IR than normal breast tissue; however, it is still not clear whether abnormally high activation of IGF-IR signaling may induce progression of the disease. To address this question, we have established several MCF-7-derived clones (MCF-7/IGF-IR cells) overexpressing the IGF-IR. We report here that overexpression of the IGF-IR did not modify sensitivity of cells to IGF-I; however, responsiveness to the ligand was moderately enhanced in most of the MCF-7/IGF-IR clones (measured by [3H]thymidine incorporation into DNA). All MCF-7/IGF-IR clones responded to the synergistic action of 1 nM estradiol (E2) and small amounts of IGF-I (up to 0.8 ng/ml). Exposure of cells to higher concentrations of IGF-I abolished estrogen requirements for stimulation of DNA synthesis in all MCF-7/IGF-IR clones, but not in the parental cells. The most important finding of this work was that the amplification of the IGF-IR induced cell-cell adhesion in MCF-7 cells. High levels of the IGF-IR promoted cell aggregation on Matrigel, allowed proliferation of cells within the aggregates, and protected clustered cells from death. In both MCF-7 and MCF-7/IGF-IR cells, IGF-I stimulated aggregation, whereas an anti-E cadherin antibody blocked cell-cell adhesion. Furthermore, immunofluorescence staining with specific antibodies revealed co-localization of the IGF-IR and E-cadherin at the points of cell-cell contacts. Moreover, the IGF-IR and its two substrates, insulin receptor substrate 1 and SHC, were contained within the E-cadherin complexes. Our results suggest that overexpressed IGF-IRs, by promoting the aggregation, growth, and survival of breast cancer cells, may accelerate the increase of tumor mass and may also prevent cell scattering. AD - Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania, 19107, USA. FAU - Guvakova, M A AU - Guvakova MA FAU - Surmacz, E AU - Surmacz E LA - eng GR - DK48969/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Exp Cell Res JID - 0373226 RN - 0 (Cadherins) RN - 0 (Drug Combinations) RN - 0 (Laminin) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Proteoglycans) RN - 0 (insulin receptor substrate-1 protein) RN - 119978-18-6 (matrigel) RN - 21820-51-9 (Phosphotyrosine) RN - 50-28-2 (Estradiol) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9007-34-5 (Collagen) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Breast Neoplasms/metabolism/*pathology MH - Cadherins/analysis/*physiology MH - *Cell Adhesion MH - Cell Aggregation/drug effects MH - Cell Division MH - Cell Survival MH - Collagen MH - Drug Combinations MH - Estradiol/*pharmacology MH - Extracellular Matrix MH - Fluorescent Antibody Technique MH - Humans MH - Insulin-Like Growth Factor I/pharmacology MH - Laminin MH - Neoplasm Invasiveness MH - Phosphoproteins/analysis MH - Phosphorylation MH - Phosphotyrosine/metabolism MH - Proteins/analysis MH - Proteoglycans MH - Receptor, IGF Type 1/analysis/genetics/*metabolism MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Transfection MH - Tumor Cells, Cultured EDAT- 1997/02/25 MHDA- 1997/02/25 00:01 AID - S0014482796934576 [pii] PST - ppublish SO - Exp Cell Res 1997 Feb 25;231(1):149-62. -------------------------------------------------------------------------------- 233: Wang HY et al. The IL-4-induced tyrosine pho...[PMID: 9013940] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9013940 OWN - NLM STAT- MEDLINE DA - 19970219 DCOM- 19970219 LR - 20041217 PUBM- Print IS - 0022-1767 VI - 158 IP - 3 DP - 1997 Feb 1 TI - The IL-4-induced tyrosine phosphorylation of the insulin receptor substrate is dependent on JAK1 expression in human fibrosarcoma cells. PG - 1037-40 AB - It has been shown that IL-4 induces the tyrosine phosphorylation of JAK1 and JAK3 in the majority of hemopoietic cell types, and JAK2 and TYK2 in several other types. However, the significance of this tyrosine phosphorylation in regulating IL-4 signaling has not been shown. To determine whether JAKs play a role in activating a signal transduction pathway different from the classical JAK/STAT pathway, we analyzed the ability of huIL-4 to stimulate the tyrosine phosphorylation of one of its major cellular substrates, the insulin receptor substrate (IRS). Using human fibrosarcoma cell lines with mutations in JAK1, JAK2, and TYK2, we found that expression of functional JAK1, but not TYK2 or JAK2, is essential for IL-4-induced tyrosine phosphorylation of IRS. We also provide evidence that the IRS pathway is independent of STAT-6, showing that JAK1 is essential for activating a STAT-independent pathway. AD - Immunology Department, Jerome Holland Laboratories, American Red Cross, Rockville, MD 20855, USA. FAU - Wang, H Y AU - Wang HY FAU - Zamorano, J AU - Zamorano J FAU - Yoerkie, J L AU - Yoerkie JL FAU - Paul, W E AU - Paul WE FAU - Keegan, A D AU - Keegan AD LA - eng GR - AI-38985/AI/NIAID PT - Journal Article PL - UNITED STATES TA - J Immunol JID - 2985117R RN - 0 (Phosphoproteins) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 207137-56-2 (Interleukin-4) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.1.112 (Janus kinase 1) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) SB - AIM SB - IM MH - Fibrosarcoma/metabolism MH - Humans MH - Interleukin-4/*physiology MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Phosphotyrosine/*metabolism MH - Protein-Tyrosine Kinase/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Trans-Activators/physiology MH - Tumor Cells, Cultured EDAT- 1997/02/01 MHDA- 1997/02/01 00:01 PST - ppublish SO - J Immunol 1997 Feb 1;158(3):1037-40. -------------------------------------------------------------------------------- 234: Murata T et al. Human ovarian-carcinoma cell ...[PMID: 9009165] Related Articles, Substance via MeSH, Books, LinkOut PMID- 9009165 OWN - NLM STAT- MEDLINE DA - 19970220 DCOM- 19970220 LR - 20050126 PUBM- Print IS - 0020-7136 VI - 70 IP - 2 DP - 1997 Jan 17 TI - Human ovarian-carcinoma cell lines express IL-4 and IL-13 receptors: comparison between IL-4- and IL-13-induced signal transduction. PG - 230-40 AB - We have reported that human ovarian-carcinoma cell lines express high-affinity IL-4 receptor. Since IL-4R has been hypothesized to share a chain with IL-13R, we investigated whether ovarian cancer cells express IL-13 receptor. In the present study, we report that the ovarian-carcinoma cell lines IGROV-1 and PA-1 express varying numbers of high-affinity IL-13 receptors. Furthermore, IL-13 inhibited the binding of IL-4 on both ovarian-carcinoma cell lines, while IL-4 did not inhibit IL-13 binding on IGROV-1 cell line. IL-13 and IL-4 induced the phosphorylation of JAK1, JAK2 and Tyk2 Janus kinases in PA-1 cells. In contrast, JAK3 tyrosine kinase was expressed in PA-1 cells, but IL-4 or IL-13 did not augment its phosphorylation. In IGROV-1 cells, Tyk2 was constitutively phosphorylated and this phosphorylation was augmented by IL-4 or IL-13. JAK1 and JAK2 but not JAK3 were expressed but only JAK2 was faintly phosphorylated in response to either IL-13 or IL-4 respectively. IRS (insulin-receptor substrate)-1 and IRS-2 were also phosphorylated constitutively in both ovarian cancer cell lines examined, but only the phosphorylation of IRS-1 was augmented in response to IL-4 or IL-13. STAT6 was phosphorylated and activated in response to IL-4 and IL-13 in all cell lines examined. Our results demonstrate that ovarian cancer cell lines may express 2 types of IL-13R and the IL-13- or IL-4-induced signaling patterns may be slightly different in each type of receptor. AD - Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. FAU - Murata, T AU - Murata T FAU - Obiri, N I AU - Obiri NI FAU - Puri, R K AU - Puri RK LA - eng PT - Journal Article PL - UNITED STATES TA - Int J Cancer JID - 0042124 RN - 0 (Antigens, CD) RN - 0 (Interleukin-13) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Interleukin) RN - 0 (Receptors, Interleukin-4) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 0 (interleukin-13 receptor) RN - 207137-56-2 (Interleukin-4) RN - EC 2.7.1.112 (Janus kinase 1) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Janus kinase 3) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) SB - IM MH - Adenocarcinoma/genetics/metabolism/*pathology MH - Antigens, CD/*biosynthesis/genetics MH - Comparative Study MH - Female MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - Interleukin-13/*pharmacology MH - Interleukin-4/*pharmacology MH - Neoplasm Proteins/*biosynthesis/genetics MH - Ovarian Neoplasms/genetics/metabolism/*pathology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Processing, Post-Translational/*drug effects MH - Protein-Tyrosine Kinase/metabolism MH - *Proto-Oncogene Proteins MH - Receptors, Interleukin/*biosynthesis/genetics MH - Receptors, Interleukin-4 MH - Signal Transduction/*drug effects MH - Teratocarcinoma/genetics/metabolism/*pathology MH - Trans-Activators/metabolism MH - Transcription Factors/metabolism MH - Tumor Cells, Cultured/drug effects EDAT- 1997/01/17 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1097-0215(19970117)70:2<230::AID-IJC15>3.0.CO;2-M [pii] PST - ppublish SO - Int J Cancer 1997 Jan 17;70(2):230-40. -------------------------------------------------------------------------------- 235: Murata T et al. Comparison of IL-13- and IL-4...[PMID: 9015186] Related Articles, Substance via MeSH, Books, LinkOut PMID- 9015186 OWN - NLM STAT- MEDLINE DA - 19970220 DCOM- 19970220 LR - 20050126 PUBM- Print IS - 0008-8749 VI - 175 IP - 1 DP - 1997 Jan 10 TI - Comparison of IL-13- and IL-4-induced signaling in EBV-immortalized human B cells. PG - 33-40 AB - Interleukin 4 (IL-4) and Interleukin 13 (IL-13) have been shown to have numerous similar effects on human B cells; however, the mechanism of signal transduction is not known. We have examined IL-4- and IL-13-induced signal transduction in Epstein-Barr virus (EBV)-immortalized B cells. We demonstrate that Janus kinase 3 (JAK3) and Tyk2 but not JAK1 and JAK2 tyrosine kinases were constitutively phosphorylated in three EBV B cell lines. The phosphorylation level of Tyk2 was augmented at a low level in response to IL-13 and IL-4 in two of three cell lines; however, IL-13 did not induce or augment phosphorylation of the other JAK kinases. On the other hand, IL-4 further augmented phosphorylation of JAK3 and induced the phosphorylation of JAK1 kinases. IL-4 receptor p140 protein was also constitutively phosphorylated in two of three EBV B cell lines examined and both IL-4 and IL-13 further augmented its phosphorylation. Insulin receptor substrate (IRS)-1 or IRS-2 proteins were not constitutively phosphorylated nor did IL-13 and IL-4 induce phosphorylation of these proteins. In contrast to JAKs, IL-4-specific signal transducer and activator of transcription (STAT6) was not constitutively phosphorylated or activated in these cell lines, but both IL-4 and IL-13 induced their phosphorylation and activation. These findings suggest that in EBV-immortalized B cells JAK3 and Tyk2 proteins were constitutively phosphorylated but STAT6 protein was not constitutively phosphorylated. In addition, despite major similarities in biological effects between IL-4 and IL-13, phosphorylation patterns of JAK kinases in response to IL-13 in EBV-immortalized B cells appear to be different from those of IL-4. AD - Laboratory of Molecular Tumor Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. FAU - Murata, T AU - Murata T FAU - Puri, R K AU - Puri RK LA - eng PT - Journal Article PL - UNITED STATES TA - Cell Immunol JID - 1246405 RN - 0 (Antigens, CD) RN - 0 (DNA Probes) RN - 0 (Interleukin-13) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Receptors, Interleukin) RN - 0 (Receptors, Interleukin-4) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 207137-56-2 (Interleukin-4) RN - EC 2.7.1.112 (Janus kinase 3) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (TYK2 protein, human) SB - IM MH - Animals MH - Antigens, CD/metabolism MH - B-Lymphocytes/*immunology/metabolism MH - Base Sequence MH - COS Cells MH - Cell Line MH - Cell Transformation, Viral MH - Comparative Study MH - DNA Probes/genetics MH - Herpesvirus 4, Human MH - Humans MH - Interleukin-13/*pharmacology/physiology MH - Interleukin-4/*pharmacology/physiology MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein Binding MH - Protein-Tyrosine Kinase/metabolism MH - Proteins/metabolism MH - Receptors, Interleukin/metabolism MH - Receptors, Interleukin-4 MH - Signal Transduction MH - Trans-Activators/metabolism EDAT- 1997/01/10 MHDA- 1997/01/10 00:01 AID - S0008874996910515 [pii] PST - ppublish SO - Cell Immunol 1997 Jan 10;175(1):33-40. -------------------------------------------------------------------------------- 236: Chan JL et al. Effect of dimerization on sig...[PMID: 8995240] Related Articles, Books, LinkOut PMID- 8995240 OWN - NLM STAT- MEDLINE DA - 19970218 DCOM- 19970218 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 272 IP - 1 DP - 1997 Jan 3 TI - Effect of dimerization on signal transduction and biological function of oncogenic Ros, insulin, and insulin-like growth factor I receptors. PG - 146-53 AB - The avian sarcoma virus UR2 codes for an oncogenic Gag-Ros fusion protein-tyrosine kinase (PTK). We have previously derived two retroviruses, T6 and NM1, coding for oncogenic Gag-insulin receptor and Gag-insulin-like growth factor I receptor (IGFR) fusion proteins, respectively. The Gag-IGFR fusion protein dimerizes, whereas Gag-Ros does not. To identify sequences affecting dimerization and the effect of dimerization on signaling and biological functions, we generated recombinants exchanging the extracellular and transmembrane sequences among the three fusion receptors. The presence of multiple cysteines in the Gag sequence appears to preclude dimerization, since deletion of the 3' cysteine residue allows for dimerization. Most of the chimeric receptors retain high PTK activity and induce transformation regardless of their configuration on the cell surface. UT, a UR2/T6 chimera, retained mitogenic activity but has a markedly reduced transforming ability, while UN7, a UR2/NM1 recombinant, which also harbors Y950F and F951S mutations in IGFR, exhibits dramatic reductions in both activities. All of the fusion receptors can phosphorylate insulin receptor substrate 1 and activate PI 3-kinase. UT protein induces Shc phosphorylation, whereas UN7 protein does not, but both are unable to activate mitogen-activated protein kinase. Our results show that overexpressed oncogenic Gag-fusion receptors do not require dimerization for their signaling and transforming functions and that the extracellular and transmembrane sequences of a receptor PTK can affect its specific substrate interactions. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. FAU - Chan, J L AU - Chan JL FAU - Lai, M AU - Lai M FAU - Wang, L H AU - Wang LH LA - eng GR - CA55054/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Bacterial Proteins) RN - 0 (Chimeric Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Repressor Proteins) RN - 0 (Ros protein, bacteria) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Animals MH - *Bacterial Proteins MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - *Cell Transformation, Neoplastic MH - Chick Embryo MH - Chimeric Proteins MH - DNA-Binding Proteins/*chemistry MH - Dimerization MH - Glycosylation MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Protein Binding MH - Proteins/metabolism MH - Receptor Protein-Tyrosine Kinases/*chemistry MH - Receptor, IGF Type 1/*chemistry MH - Receptor, Insulin/*chemistry MH - Repressor Proteins/*chemistry MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Structure-Activity Relationship EDAT- 1997/01/03 MHDA- 2000/02/26 09:00 PST - ppublish SO - J Biol Chem 1997 Jan 3;272(1):146-53. -------------------------------------------------------------------------------- 237: Ahmad F et al. Effect of tumor necrosis fact...[PMID: 9015760] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9015760 OWN - NLM STAT- MEDLINE DA - 19970512 DCOM- 19970512 LR - 20050317 PUBM- Print IS - 0730-2312 VI - 64 IP - 1 DP - 1997 Jan TI - Effect of tumor necrosis factor-alpha on the phosphorylation of tyrosine kinase receptors is associated with dynamic alterations in specific protein-tyrosine phosphatases. PG - 117-27 AB - Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. Overall PTPase activity in the cytosol fraction did not change with TNF-alpha treatment, and PTPase activity in the particulate fraction was decreased by 55-66%, demonstrating that increases in total cellular PTPase activity did not account for the observed alterations in receptor signalling. However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. These data suggest that at least part of the TNF-alpha effect on pathways of reversible tyrosine phosphorylation may be exerted through the dynamic modulation of the expression of specific PTPases. Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited. AD - Dorrance H. Hamilton Research Laboratories, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Ahmad, F AU - Ahmad F FAU - Goldstein, B J AU - Goldstein BJ LA - eng GR - R01 DK43396/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Cell Biochem JID - 8205768 RN - 0 (Phosphoproteins) RN - 0 (Receptors, Cell Surface) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.1.3.48 (leukocyte common antigen-related phosphatase) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/drug therapy/metabolism/pathology MH - Cell Differentiation/drug effects MH - Cell Division/drug effects MH - Drug Resistance, Neoplasm MH - Immunoblotting MH - Insulin/pharmacology MH - Phosphoproteins/drug effects/metabolism MH - Phosphorylation/drug effects MH - Protein-Tyrosine-Phosphatase/drug effects/*metabolism MH - Rats MH - Receptor Protein-Tyrosine Kinases/drug effects/*metabolism MH - Receptor, Epidermal Growth Factor/drug effects/metabolism MH - Receptor, Insulin/drug effects/metabolism MH - *Receptors, Cell Surface MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Subcellular Fractions MH - Tumor Cells, Cultured MH - Tumor Necrosis Factor-alpha/*pharmacology EDAT- 1997/01/01 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1097-4644(199701)64:1<117::AID-JCB14>3.0.CO;2-I [pii] PST - ppublish SO - J Cell Biochem 1997 Jan;64(1):117-27. -------------------------------------------------------------------------------- 238: Lee AV et al. Activation of estrogen recept...[PMID: 9014838] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9014838 OWN - NLM STAT- MEDLINE DA - 19970220 DCOM- 19970220 LR - 20041117 PUBM- Print IS - 0022-0795 VI - 152 IP - 1 DP - 1997 Jan TI - Activation of estrogen receptor-mediated gene transcription by IGF-I in human breast cancer cells. PG - 39-47 AB - Estrogen and IGF-I are potent mitogens for most breast cancer cell lines, and although their signaling pathways contrast, there is considerable interaction between them. Recent evidence indicating that IGF-I can alter estrogen receptor (ER) action led us to investigate whether an inhibitor of IGF-I action. IGF-binding protein-1 (IGFBP-1), could affect transcriptional activation of ER. First, we confirmed that tamoxifen (TAM) could inhibit IGF-I-mediated proliferation of MCF-7 cells. Although TAM can increase IGFBP-3 expression in MCF-7 cells, and this binding protein has been shown to be able to inhibit IGF action, TAM had no effect on IGF-I-stimulated tyrosine phosphorylation of IGF-I receptor or the downstream signaling molecule, insulin receptor substrate-1. Therefore, to confirm that IGF-I was affecting transcriptional activation of ER, we utilized a gene reporter assay using a single consensus estrogen response element (ERE-tk-luc) upstream of luciferase. As expected, estradiol (E2; 1nM) increased transcriptional activation three- to fivefold from the ERE in three ER-positive breast cancer cell lines (MCF-7, ZR-75 and T47D). A 2.5-to 4-fold increase was also seen with IGF-I (5 nM). TAM (1 microM) effectively blocked activation by E2 and IGF-I, indicating disruption of ER-mediated transcription. As expected, human recombinant IGFBP-1 (80 nM) completely inhibited IGF-I-mediated activation of ER, however, IGFBP-1 also caused a significant decrease in E2-mediated activation. We also noticed that IGF-I increased the activity of all plasmids that we cotransfected including TATA-luc, SV40-luc and pGL Basic. This effect was post-transcriptional, as it was not affected by actinomycin D (2 micrograms/ml), while we were able to completely inhibit E2-mediated transcriptional activation of ERE-tk-luc. Unlike the complete inhibition of ER-mediated transcriptional activation by actinomycin D, IGF-I-mediated transactivation was reduced by only 50%, indicating that the activation by IGF-I represented both transcriptional and post-transcriptional effects. This study confirmed that IGF-I can cause transcriptional activation of endogenous ER in human breast cancel cells, and inhibition of ER action by IGFBP-1 suggests that IGF-1 signaling may be necessary for maximal ER activation. AD - Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7884, USA. FAU - Lee, A V AU - Lee AV FAU - Weng, C N AU - Weng CN FAU - Jackson, J G AU - Jackson JG FAU - Yee, D AU - Yee D LA - eng GR - KO4CA01670/CA/NCI GR - P30CA54174/CA/NCI GR - PO1CA30195/CA/NCI PT - Journal Article PL - ENGLAND TA - J Endocrinol JID - 0375363 RN - 0 (Estrogen Antagonists) RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 0 (Plasmids) RN - 0 (Protein Synthesis Inhibitors) RN - 0 (Receptors, Estrogen) RN - 0 (Recombinant Proteins) RN - 10540-29-1 (Tamoxifen) RN - 50-28-2 (Estradiol) RN - 50-76-0 (Dactinomycin) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Breast Neoplasms/*genetics/pathology MH - Cell Division/drug effects MH - Dactinomycin/pharmacology MH - Estradiol/pharmacology MH - Estrogen Antagonists/pharmacology MH - Female MH - Humans MH - Insulin-Like Growth Factor Binding Protein 1/pharmacology MH - Insulin-Like Growth Factor I/antagonists & inhibitors/*pharmacology MH - Plasmids MH - Protein Synthesis Inhibitors/pharmacology MH - Receptors, Estrogen/*genetics MH - Recombinant Proteins/pharmacology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tamoxifen/pharmacology MH - Trans-Activation (Genetics)/*drug effects MH - Tumor Cells, Cultured EDAT- 1997/01/01 MHDA- 1997/01/01 00:01 PST - ppublish SO - J Endocrinol 1997 Jan;152(1):39-47. -------------------------------------------------------------------------------- 239: deVente JE et al. Transcriptional regulation of...[PMID: 8943287] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8943287 OWN - NLM STAT- MEDLINE DA - 19970117 DCOM- 19970117 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 271 IP - 50 DP - 1996 Dec 13 TI - Transcriptional regulation of insulin receptor substrate 1 by protein kinase C. PG - 32276-80 AB - Insulin receptor substrate-1 (IRS-1) is involved in insulin signal transduction distal to receptor occupation. Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. Using the MCF-7 breast cancer cell, a role for PKC in regulating IRS-1 expression was examined. In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. This decrease in IRS-1 content was associated with a 30-fold reduction in IRS-1 transcription. In parental MCF-7 cells, PKC inhibitors (GF109203X (bisindolylmaleimide I) and staurosporine) reduced IRS-1 content. Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA; >8 h) reduced IRS-1 content and down-regulated the novel PKC-delta isoform. Bryostatin 1 inhibited TPA-induced depletion of both IRS-1 and PKC-delta expression in MCF-7 cells. Associated with TPA-induced reduction in IRS-1 content was a reduction in IRS-1 transcription. These data demonstrate that PKC can modulate IRS-1 content and suggest a potential role for PKC-delta in positively regulating IRS-1 expression. AD - Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA. FAU - deVente, J E AU - deVente JE FAU - Carey, J O AU - Carey JO FAU - Bryant, W O AU - Bryant WO FAU - Pettit, G J AU - Pettit GJ FAU - Ways, D K AU - Ways DK LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Antineoplastic Agents) RN - 0 (Isoenzymes) RN - 0 (Lactones) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 16561-29-8 (Tetradecanoylphorbol Acetate) RN - 83314-01-6 (bryostatin 1) RN - EC 2.7.1.- (protein kinase C-delta) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology MH - Down-Regulation MH - Enzyme Activation MH - Female MH - Humans MH - Insulin Resistance MH - Isoenzymes/metabolism MH - Lactones/pharmacology MH - Mice MH - Phosphoproteins/*metabolism MH - Protein Kinase C/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tetradecanoylphorbol Acetate/pharmacology MH - *Transcription, Genetic MH - Tumor Cells, Cultured EDAT- 1996/12/13 MHDA- 1996/12/13 00:01 PST - ppublish SO - J Biol Chem 1996 Dec 13;271(50):32276-80. -------------------------------------------------------------------------------- 240: Corleta HE et al. Insulin receptor tyrosine kin...[PMID: 9222417] Related Articles, Books, LinkOut PMID- 9222417 OWN - NLM STAT- MEDLINE DA - 19971009 DCOM- 19971009 LR - 20041117 PUBM- Print IS - 0100-879X VI - 29 IP - 12 DP - 1996 Dec TI - Insulin receptor tyrosine kinase activity in colon carcinoma. PG - 1593-7 AB - Colon carcinoma is the most common tumor of the gastrointestinal tract. According to some investigators, insulin, epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) man be involved in the neoplastic proliferation. Insulin-binding and receptor tyrosine kinase activity were investigated in colon carcinomas and in normal colons. The insulin receptor concentration, as shown by binding assays, was 17.4 +/- 4.3 fmol/micrograms in normal colon and 29.69 +/- 9.4 fmol/micrograms in colon carcinoma. Nevertheless, the insulin affinity of the receptor was similar in both groups (Kd identical to 1 nM). Both normal and neoplastic colon showed phosphorylation of the insulin receptor. The electrophoretic migration of the beta-subunit of the insulin receptors purified from colon carcinomas was similar to that of normal colon and both tissues demonstrated an insulin-dependent autophosphorylation. The receptor tyrosine kinase activity was measured by the incorporation of [gamma 32P]ATP into the beta-subunit. The basal and the insulin-stimulated tyrosine kinase activities were significantly higher in colon carcinomas compared to normal colon tissues (2.2 and 1.6 times, respectively). Understanding the metabolism of neoplastic cells may contribute to the development of prevention strategies as well as new therapies. It is now necessary to study other steps of the insulin signal transduction pathway, such as insulin receptor substrate 1 phosphorylation. AD - Departamento de Cirurgia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil. FAU - Corleta, H E AU - Corleta HE FAU - Capp, E AU - Capp E FAU - Corleta, O C AU - Corleta OC LA - eng PT - Journal Article PL - BRAZIL TA - Braz J Med Biol Res JID - 8112917 RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Colonic Neoplasms/*enzymology MH - Humans MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't EDAT- 1996/12/01 MHDA- 1996/12/01 00:01 PST - ppublish SO - Braz J Med Biol Res 1996 Dec;29(12):1593-7. -------------------------------------------------------------------------------- 241: Li PM et al. Suppression of insulin recept...[PMID: 9023010] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9023010 OWN - NLM STAT- MEDLINE DA - 19970417 DCOM- 19970417 LR - 20041117 PUBM- Print IS - 0898-6568 VI - 8 IP - 7 DP - 1996 Nov TI - Suppression of insulin receptor activation by overexpression of the protein-tyrosine phosphatase LAR in hepatoma cells. PG - 467-73 AB - Protein-tyrosine phosphatases (PTPases) play an essential role in the regulation of reversible tyrosine phosphorylation of cellular proteins that mediate insulin action. In order to explore the potential role of the transmembrane PTPase (LAR) in insulin receptor signal transduction, we overexpressed the full-length LAR protein in McA-RH7777 rat hepatoma cells and found that modest increases in the abundance of LAR protein expression downregulated a number of insulin-stimulated cellular responses closely related to the activation of the receptor kinase. An increase in LAR protein of 2.4-fold over the level in control cells caused a 40% reduction in insulin receptor autophosphorylation in intact cells, without an alteration in insulin receptor mass or a change in the insulin-stimulated receptor kinase activity measured with partially purified receptors in vitro. In addition, insulin-stimulated tyrosine phosphorylation of the endogenous insulin receptor substrates IRS-1 and Shc were decreased to 57% and 73% of control, respectively, and IRS-1 associated phosphatidylinositol 3'-kinase activity was reduced to 47% of control of the cells overexpressing LAR. The present results, taken with our recent data demonstrating that reducing the abundance of LAR by expression of antisense mRNA enhances insulin receptor signal transduction (Kulas D. T., et al. J. Biol. Chem. 270:2435, 1995), supports the hypothesis that LAR acts as a physiological modulator of insulin action in insulin-sensitive hepatoma cells. AD - Dorrance H. Hamilton Research Laboratories, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA. FAU - Li, P M AU - Li PM FAU - Zhang, W R AU - Zhang WR FAU - Goldstein, B J AU - Goldstein BJ LA - eng GR - R01-DK43396/DK/NIDDK PT - Journal Article PT - Review PT - Review, Tutorial PL - ENGLAND TA - Cell Signal JID - 8904683 RN - 0 (Phosphoproteins) RN - 0 (Receptors, Cell Surface) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) RN - EC 3.1.3.48 (leukocyte common antigen-related phosphatase) SB - IM MH - Animals MH - Carcinoma, Hepatocellular MH - Down-Regulation MH - Insulin/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Protein-Tyrosine-Phosphatase/genetics/*metabolism MH - Rabbits MH - Rats MH - Receptor, Insulin/*metabolism MH - *Receptors, Cell Surface MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Transfection MH - Tumor Cells, Cultured MH - src Homology Domains RF - 35 EDAT- 1996/11/01 MHDA- 1996/11/01 00:01 AID - S0898656896001015 [pii] PST - ppublish SO - Cell Signal 1996 Nov;8(7):467-73. -------------------------------------------------------------------------------- 242: Tanaka S et al. A carboxy-terminal truncated ...[PMID: 8903330] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 8903330 OWN - NLM STAT- MEDLINE DA - 19970103 DCOM- 19970103 LR - 20041117 PUBM- Print IS - 0021-9738 VI - 98 IP - 9 DP - 1996 Nov 1 TI - A carboxy-terminal truncated insulin receptor substrate-1 dominant negative protein reverses the human hepatocellular carcinoma malignant phenotype. PG - 2100-8 AB - Insulin receptor substrate-1 (IRS-1), a substrate of various receptor tyrosine kinases transmits mitogenic signals initiated by extracellular ligands. This protein is involved in normal hepatocyte growth and has been found to be overexpressed in human hepatocellular carcinoma. Expression of a carboxy-terminal truncated IRS-1 molecule containing the pleckstrin homology and phosphotyrosine-binding domains associates with the insulin receptor and prevents tyrosyl phosphorylation of endogenous IRS-1 and Shc proteins. Thus, subsequent activation of downstream signaling molecules induced by insulin and IGF-1 such as phosphatidylinositol-3 kinase and mitogen activated protein kinase is inhibited. The morphologic features of transformed human hepatocellular carcinoma cells change to a differentiated hepatocyte appearance and characteristics of the malignant phenotype as manifested by anchorage independent cell growth and tumor formation in nude mice are lost. These studies demonstrate that signal transduction pathways mediated through or by IRS-1 are important in hepatocyte and human hepatocellular carcinoma cell growth. AD - Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown 02129, USA. FAU - Tanaka, S AU - Tanaka S FAU - Wands, J R AU - Wands JR LA - eng GR - AA-02666/AA/NIAAA GR - CA-35711/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Clin Invest JID - 7802877 RN - 0 (Blood Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (platelet protein P47) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Animals MH - Blood Proteins/chemistry MH - Carcinoma, Hepatocellular/*pathology MH - Humans MH - Liver Neoplasms/*pathology MH - Mice MH - Mice, Nude MH - Neoplasm Proteins/metabolism MH - Neoplasm Transplantation MH - Phosphoproteins/*chemistry/metabolism MH - Phosphotyrosine/metabolism MH - Receptor, IGF Type 1/metabolism MH - Receptor, Insulin/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Deletion MH - Signal Transduction MH - Structure-Activity Relationship MH - Transplantation, Heterologous MH - Tumor Cells, Cultured EDAT- 1996/11/01 MHDA- 1996/11/01 00:01 PST - ppublish SO - J Clin Invest 1996 Nov 1;98(9):2100-8. -------------------------------------------------------------------------------- 243: Tachibana I et al. A 100-kDa protein tyrosine ph...[PMID: 8831561] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8831561 OWN - NLM STAT- MEDLINE DA - 19961105 DCOM- 19961105 LR - 20050209 PUBM- Print IS - 0014-4827 VI - 227 IP - 2 DP - 1996 Sep 15 TI - A 100-kDa protein tyrosine phosphorylation is concurrent with beta 1 integrin-mediated morphological differentiation in neuroblastoma and small cell lung cancer cells. PG - 230-9 AB - IMR32, a neuroblastoma cell line, and CADO LC6, a small cell lung cancer (SCLC) cell line, extended neurite-like processes when cultured on fibronectin (FN)-coated surfaces or cultured in a serum-free medium. Monoclonal antibodies against the integrin beta 1 subunit inhibited this process formation, suggesting that their morphological change is initiated by beta 1 integrin-dependent signal transduction to the cell interior. Anti-phosphorylation level of a 100-kDa protein, but not 125-kDa focal adhesion kindase, correlated well with the morphological change in both cell lines. This 100-kDa protein phosphorylation did not accompany FN-induced morphological changes in NIH 3T3 fibroblasts or A549 adenocarcinoma cells. These findings suggest that neuroblastoma and SCLC may share beta 1 integrin-mediated signaling events distinct from nonneuronal cells. AD - Department of Medicine III, Osaka University Medical School, Japan. FAU - Tachibana, I AU - Tachibana I FAU - Mori, M AU - Mori M FAU - Tanio, Y AU - Tanio Y FAU - Hosoe, S AU - Hosoe S FAU - Sakuma, T AU - Sakuma T FAU - Osaki, T AU - Osaki T FAU - Ueno, K AU - Ueno K FAU - Kumagai, T AU - Kumagai T FAU - Kijima, T AU - Kijima T FAU - Kishimoto, T AU - Kishimoto T LA - eng PT - Journal Article PL - UNITED STATES TA - Exp Cell Res JID - 0373226 RN - 0 (Antigens, CD29) RN - 0 (Cell Adhesion Molecules) RN - 0 (Enzyme Inhibitors) RN - 0 (Quinones) RN - 55520-40-6 (Tyrosine) RN - 70563-58-5 (herbimycin) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - Adenocarcinoma MH - Antigens, CD29/*pharmacology MH - Blotting, Western MH - Carcinoma, Small Cell/*pathology MH - Cell Adhesion/physiology MH - Cell Adhesion Molecules/metabolism MH - Cell Differentiation/physiology MH - Enzyme Inhibitors/pharmacology MH - Flow Cytometry MH - Humans MH - Lung Neoplasms MH - *Neuroblastoma/*pathology MH - Phosphorylation MH - Protein-Tyrosine Kinase/metabolism MH - Quinones/pharmacology MH - Receptor, Insulin/metabolism MH - Signal Transduction/*physiology MH - Tumor Cells, Cultured/cytology/drug effects/enzymology MH - Tyrosine/*metabolism EDAT- 1996/09/15 MHDA- 1996/09/15 00:01 AID - S0014482796902724 [pii] PST - ppublish SO - Exp Cell Res 1996 Sep 15;227(2):230-9. -------------------------------------------------------------------------------- 244: Xu G et al. Insulin and secretagogues dif...[PMID: 8809056] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8809056 OWN - NLM STAT- MEDLINE DA - 19961113 DCOM- 19961113 LR - 20041117 PUBM- Print IS - 0264-6021 VI - 318 ( Pt 2) DP - 1996 Sep 1 TI - Insulin and secretagogues differentially regulate fluid-phase pinocytosis in insulin-secreting beta-cells. PG - 623-9 AB - The physiological role of the beta-cell insulin receptor is unknown. To evaluate a candidate function, the insulin regulation of fluid-phase pinocytosis was investigated in a clonal insulinoma cell line (beta TC6-F7) and, for comparison, also in Chinese hamster ovary cells transfected with the human insulin receptor (CHO-T cells). In CHO-T cells, the net rate of fluid-phase pinocytosis was rapidly increased 3-4-fold over the basal rate by 100 nM insulin, with half-maximal stimulation at 2 nM insulin, as assayed by cellular uptake of horseradish peroxidase from the medium. Wortmannin, an inhibitor of phosphatidylinositol (PI)-3-kinase, blocked insulin-stimulated pinocytosis with an IC50 of 7.5 nM without affecting the basal rate of pinocytosis. In insulin-secreting beta TC6-F7 cells, the secretagogues glucose and carbachol (at maximally effective concentrations of 15 mM and 0.5 mM respectively) augmented fluid-phase pinocytosis 1.65-fold over the basal rate. Wortmannin also inhibited secretagogue-stimulated pinocytosis in these beta-cells with an IC50 of 7 nM but did not affect the basal rate of pinocytosis measured in the absence of secretagogues. Wortmannin did not influence either basal or secretagogue-induced insulin secretion. Although these beta TC6-F7 cells have cell-surface insulin receptors, adding exogenous insulin or insulin-like growth factor 1 did not affect their rate of fluid-phase pinocytosis, either in the absence or presence of secretagogues. From these observations, we conclude that: (1) in both insulin-secreting beta-cells and in conventional, insulin-responsive CHO-T cells, a common, wortmannin-sensitive reaction, which probably involves PI-3-kinase, regulates fluid-phase pinocytosis; (2) the insulin-receptor signal transduction pathway is dissociated from the regulation of fluid-phase pinocytosis in the insulin-secreting beta-cell line we studied; and (3) the enhancement of fluid-phase pinocytosis associated with secretagogue-induced insulin release in beta TC6-F7 cells is not attributable to autocrine activation of beta-cell surface insulin receptors. AD - Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, U.S.A. FAU - Xu, G AU - Xu G FAU - Howland, J AU - Howland J FAU - Rothenberg, P L AU - Rothenberg PL LA - eng GR - DK45308/DK/NIDDK PT - Journal Article PL - ENGLAND TA - Biochem J JID - 2984726R RN - 0 (Androstadienes) RN - 0 (Insulin Antagonists) RN - 0 (Recombinant Proteins) RN - 11061-68-0 (Insulin) RN - 19545-26-7 (wortmannin) RN - 50-99-7 (Glucose) RN - 51-83-2 (Carbachol) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Androstadienes/pharmacology MH - Animals MH - CHO Cells MH - Carbachol/pharmacology MH - Clone Cells MH - Glucose/pharmacology MH - Hamsters MH - Humans MH - Insulin/*pharmacology/*secretion MH - Insulin Antagonists/pharmacology MH - Insulinoma MH - Islets of Langerhans/drug effects/*physiology/secretion MH - Kinetics MH - Pancreatic Neoplasms MH - Pinocytosis/drug effects/*physiology MH - Receptor, Insulin/biosynthesis/*physiology MH - Recombinant Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Transfection EDAT- 1996/09/01 MHDA- 1996/09/01 00:01 PST - ppublish SO - Biochem J 1996 Sep 1;318 ( Pt 2):623-9. -------------------------------------------------------------------------------- 245: Tanaka S et al. Insulin receptor substrate 1 ...[PMID: 8758899] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8758899 OWN - NLM STAT- MEDLINE DA - 19960930 DCOM- 19960930 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 56 IP - 15 DP - 1996 Aug 1 TI - Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. PG - 3391-4 AB - Insulin-like growth factors initiate tyrosyl phosphorylation of the insulin receptor substrate I (IRS-I) protein and activate multiple signaling pathways essential for liver growth. This gene has been found to be up-regulated in human hepatocellular carcinomas (HCCs), and overexpression of IRS-1 in NIH 3T3 cells leads to malignant transformation with activation of the mitogen-activated protein kinase cascade. To explore another possible role of IRS-I in hepatocarcinogenesis, we examined the capability of transforming growth factor beta1 (TGF-beta1), a known negative regulator of hepatocyte growth, to induce programmed cell death in the context of IRS-I overexpression. Hep3B HCC cells were stably transfected with a retroviral vector containing the IRS-I gene. The overexpressed IRS-I protein was highly tyrosyl phosphorylated following insulin/insulin- like growth factor I stimulation and led to constitutive activation of downstream signal transduction molecules such as phosphatidylinositol-3 kinase and mitogen-activated protein kinase. Although parental Hep3B cells were sensitive to apoptosis, the Hep3B-IRS-I-transfected cells acquired resistance to TGF-beta1-induced programmed cell death. Our investigations suggest that IRS-I-mediated signals may act as survival factors and protect against TGF-beta1-induced apoptosis in HCC; this phenomenon may contribute to hepatic oncogenesis. AD - Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Charlestown 02129, USA. FAU - Tanaka, S AU - Tanaka S FAU - Wands, J R AU - Wands JR LA - eng GR - AA02666/AA/NIAAA GR - CA35711/CA/NCI PT - Journal Article PL - UNITED STATES TA - Cancer Res JID - 2984705R RN - 0 (Phosphoproteins) RN - 0 (Transforming Growth Factor beta) RN - 0 (insulin receptor substrate-1 protein) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Apoptosis/*physiology MH - Base Sequence MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Carcinoma, Hepatocellular/*metabolism/pathology MH - Enzyme Activation MH - Humans MH - Liver Neoplasms/*metabolism/pathology MH - Molecular Sequence Data MH - Phosphoproteins/*biosynthesis/metabolism MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/physiology MH - Transforming Growth Factor beta/*physiology MH - Tumor Cells, Cultured MH - Tyrosine/metabolism EDAT- 1996/08/01 MHDA- 1996/08/01 00:01 PST - ppublish SO - Cancer Res 1996 Aug 1;56(15):3391-4. -------------------------------------------------------------------------------- 246: Batty IH et al. Thrombin receptors modulate i...[PMID: 8713057] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8713057 OWN - NLM STAT- MEDLINE DA - 19960912 DCOM- 19960912 LR - 20041117 PUBM- Print IS - 0264-6021 VI - 317 ( Pt 2) DP - 1996 Jul 15 TI - Thrombin receptors modulate insulin-stimulated phosphatidylinositol 3,4,5-trisphosphate accumulation in 1321N1 astrocytoma cells. PG - 347-51 AB - Thrombin and insulin receptor signaling via phosphoinositide (PI)-specific phospholipase C (PLC) and PI 3-kinase was studied in [3H]inositol-labelled 1321N1 cells. Thrombin stimulated a dramatic, transient activation of PLC which is probably mediated via receptors of the 'tethered-ligand' type, since it was both reproduced by, and abolished following, pretreatment of cells with a synthetic peptide (SFLLRN) corresponding to the ligand domain of the human thrombin receptor. However, neither thrombin nor SFLLRN stimulated PI 3-kinase. By contrast, insulin did not influence [3H]InsP3 concentration but stimulated accumulation of [3H]PtdIns(3,4,5)P3 and [3H]PtdIns(3,4)P2, the relative steady-state concentrations of which may indicate degradation of [3H]PtdIns(3,4,5)P3 by 5- and 3-phosphatases. The independent coupling of thrombin and insulin receptors to PLC and PI 3-kinase respectively in 1321N1 cells allowed interactions between these systems to be examined. Thus insulin-stimulated [3H]PtdIns(3,4,5)P3 accumulation was attenuated on co-stimulation of the thrombin receptor, whereas concentrations of [3H]PtdIns(3,4)P2 were transiently enhanced but then reduced. These results indicate that thrombin receptors in 1321N1 cells do not activate PI 3-kinase, but can modulate signalling by this enzyme. AD - Department of Biochemistry, University of Dundee, Scotland, UK. FAU - Batty, I H AU - Batty IH FAU - Downes, C P AU - Downes CP LA - eng PT - Journal Article PL - ENGLAND TA - Biochem J JID - 2984726R RN - 0 (Peptide Fragments) RN - 0 (Phosphatidylinositol Phosphates) RN - 0 (Receptors, Thrombin) RN - 0 (phosphatidylinositol 3,4,5-triphosphate) RN - 0 (phosphatidylinositol 3,4-diphosphate) RN - 0 (thrombin receptor peptide (42-47)) RN - 11061-68-0 (Insulin) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.4.3 (Phospholipase C) RN - EC 3.4.21.5 (Thrombin) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Amino Acid Sequence MH - Astrocytoma MH - Comparative Study MH - Enzyme Activation/drug effects MH - Humans MH - Insulin/*pharmacology MH - Molecular Sequence Data MH - Peptide Fragments/pharmacology MH - Phosphatidylinositol Phosphates/*biosynthesis MH - Phospholipase C/metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Receptors, Thrombin/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/drug effects MH - Thrombin/*pharmacology MH - Tumor Cells, Cultured EDAT- 1996/07/15 MHDA- 1996/07/15 00:01 PST - ppublish SO - Biochem J 1996 Jul 15;317 ( Pt 2):347-51. -------------------------------------------------------------------------------- 247: Zhang-Sun G et al. A 60-kilodalton protein in ra...[PMID: 8770882] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8770882 OWN - NLM STAT- MEDLINE DA - 19961010 DCOM- 19961010 LR - 20050317 PUBM- Print IS - 0013-7227 VI - 137 IP - 7 DP - 1996 Jul TI - A 60-kilodalton protein in rat hepatoma cells overexpressing insulin receptor was tyrosine phosphorylated and associated with Syp, phophatidylinositol 3-kinase, and Grb2 in an insulin-dependent manner. PG - 2649-58 AB - Tyrosine phosphorylation of cellular proteins is an early and key step after activation of the insulin receptor kinase (IRK). The study of the properties of these proteins should contribute to our understanding of insulin action. In rat hepatoma cells overexpressing human insulin receptors (HTC-IR), insulin treatment resulted in rapid tyrosine phosphorylation of proteins of 180, 94, 68, and 60 kDa. When lysates from insulin-treated cells were immunoprecipitated with anti-Syp antibody, subsequent immunoblotting identified p65 and p68, which reacted with anti-Syp, and p6O and p68, which reacted with antiphosphotyrosine antibody. Thus, insulin treatment yielded tyrosine phosphorylation of both Syp and a Syp-associated p6O molecule. When lysates from insulin-treated cells were adsorbed with a glutathione S-transferase (GST)-Syp-Src homology-2 (SH2) fusion protein, tyrosine- phosphorylated p6O was sequestered. After subjecting lysates to SDS-PAGE, the GST-SypSH2 fusion protein was found to bind to p18O, p94, and p6O. Thus, Syp associates directly with a 60-kDa IRK substrate via its SH2 domains. Syp-associated p6O differed from the 60- to 62-kDa proteins, associating with ras guanosine triphosphatase-activating protein, which also underwent modest tyrosine phosphorylation in response to insulin. Preadsorption of cell lystates with antibody against the 85-kDa subunit (p85) of phosphatidylinositol 3-kinase substantially reduced the amount of p60 subsequently immunoprecipitated by anti-Syp. Thus, p60 associates with both Syp and p85. The amount of tyrosine-phosphorylated p60 exceeded that of p180 in anti-Syp immunoprecipitates, whereas their proportion was comparable in anti-p85 immunoprecipitates. Grb2 was also observed in the anti-Syp immunoprecipitates. When lysates from insulin-treated cells were adsorbed with GST-p85SH2 domains or GST-Grb2, the subsequent eluates contained tyrosine-phosphorylated p60, as determined by immunoblotting with antiphosphotyrosine. Membrane binding assays using GST fusion proteins showed that these associations were direct. Studies in rat liver, muscle, and adipose tissue identified insulin-dependent association of Syp, Grb2, and p85 with tyrosine-phosphorylated p60 in adipose tissue only. We conclude that insulin treatment of HTC-IR cells and rat adipose tissue results in the tyrosine phosphorylation of p60, which might participate in the recruitment of downstream effectors involved in insulin signal transduction. AD - The Protein and Polypeptide Hormone Laboratory, McGill University, Montreal, Quebec, Canada. FAU - Zhang-Sun, G AU - Zhang-Sun G FAU - Yang, C AU - Yang C FAU - Viallet, J AU - Viallet J FAU - Feng, G AU - Feng G FAU - Bergeron, J J AU - Bergeron JJ FAU - Posner, B I AU - Posner BI LA - eng PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.5.1.18 (Glutathione Transferase) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - AIM SB - IM CIN - Endocrinology. 1996 Jul;137(7):2647-8. PMID: 8770881 MH - 1-Phosphatidylinositol 3-Kinase MH - *Adaptor Proteins, Signal Transducing MH - Adipose Tissue/metabolism MH - Animals MH - Blotting, Western MH - Electrophoresis, Polyacrylamide Gel MH - Female MH - Glutathione Transferase/biosynthesis MH - Humans MH - Insulin/*pharmacology MH - Kinetics MH - Liver/metabolism MH - Liver Neoplasms, Experimental MH - Male MH - Molecular Weight MH - Muscle, Skeletal/metabolism MH - Organ Specificity MH - Phosphoproteins/analysis/metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - Phosphotyrosine/metabolism MH - Protein-Tyrosine-Phosphatase/analysis/*metabolism MH - Proteins/analysis/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, Epidermal Growth Factor/metabolism MH - Receptor, Insulin/biosynthesis/*metabolism/*physiology MH - Recombinant Fusion Proteins/biosynthesis MH - Transfection EDAT- 1996/07/01 MHDA- 1996/07/01 00:01 PST - ppublish SO - Endocrinology 1996 Jul;137(7):2649-58. -------------------------------------------------------------------------------- 248: Schaller MD. The focal adhesion kinase....[PMID: 8708550] Related Articles, Books, LinkOut PMID- 8708550 OWN - NLM STAT- MEDLINE DA - 19960910 DCOM- 19960910 LR - 20050209 PUBM- Print IS - 0022-0795 VI - 150 IP - 1 DP - 1996 Jul TI - The focal adhesion kinase. PG - 1-7 AD - Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill 27599, USA. FAU - Schaller, M D AU - Schaller MD LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - ENGLAND TA - J Endocrinol JID - 0375363 RN - 0 (Cell Adhesion Molecules) RN - 0 (Integrins) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - Animals MH - Cell Adhesion Molecules/*metabolism MH - Integrins/*metabolism MH - Neoplasms/*metabolism MH - Protein-Tyrosine Kinase/*metabolism MH - Receptor, Insulin/*metabolism MH - Signal Transduction/*physiology RF - 88 EDAT- 1996/07/01 MHDA- 1996/07/01 00:01 PST - ppublish SO - J Endocrinol 1996 Jul;150(1):1-7. -------------------------------------------------------------------------------- 249: Tanaka S et al. Neoplastic transformation ind...[PMID: 8662827] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8662827 OWN - NLM STAT- MEDLINE DA - 19960820 DCOM- 19960820 LR - 20050317 PUBM- Print IS - 0021-9258 VI - 271 IP - 24 DP - 1996 Jun 14 TI - Neoplastic transformation induced by insulin receptor substrate-1 overexpression requires an interaction with both Grb2 and Syp signaling molecules. PG - 14610-6 AB - The insulin receptor substrate-1 (IRS-1) is the major intracellular substrate of insulin and insulin-like growth factor-I (IGF-I) receptor tyrosine kinase activity, and this protein has been found to be overexpressed in human hepatocellular carcinomas. IRS-1 contains several src homology 2 (SH2) binding motifs that interact following tyrosyl phosphorylation with SH2-containing proteins, and this interaction may be essential for transmitting the growth signal from the cell surface to the nucleus. We have previously reported that overexpression of IRS-1 may induce neoplastic transformation of NIH 3T3 cells. This study examines the role of two SH2-containing molecules, namely the Grb2 adapter and Syp tyrosine phosphatase proteins as important components of the cellular transforming activity of IRS-1. Mutations of tyrosine 897 in the YVNI motif (Y897F) and of tyrosine 1180 in the YIDL motif (Y1180F) reduced the intracellular interaction of IRS-1 with Grb2 and Syp proteins, respectively. Furthermore, a single mutation at either Phe-897 or Phe-1180 substantially but not completely reduced IGF-I-dependent transforming activity of IRS-1, whereas creation of a double mutation of both tyrosine residues (Y897F/Y1180F) strikingly attenuated the transforming activity of IRS-1. Stable expression of the IRS-1 mutant constructs in NIH 3T3 cells was associated with a lower level of activation of the mitogen-activated protein kinase kinase (MAPKK)/MAPK cascade following IGF-I stimulation compared with cells stably transfected with the "wild-type" IRS-1 gene. These results suggest that IRS-1-induced cellular transformation requires an interaction with both Grb2 and Syp signal transduction molecules since neither interaction alone appears to be required, and this event subsequently leads to activation of the MAPKK/MAPK cascade. AD - Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. FAU - Tanaka, S AU - Tanaka S FAU - Ito, T AU - Ito T FAU - Wands, J R AU - Wands JR LA - eng GR - AA-02666/AA/NIAAA GR - AA-08169/AA/NIAAA GR - CA-35711/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Oligodeoxyribonucleotides) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Recombinant Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase Kinases) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.37 (Protein Kinases) RN - EC 3.1.3- (SH protein-tyrosine phosphatase) RN - EC 3.1.3.- (SHP-1 protein-tyrosine phosphatase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - 3T3 Cells MH - *Adaptor Proteins, Signal Transducing MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - Binding Sites MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Carcinoma, Hepatocellular MH - Cell Adhesion/drug effects MH - Cell Division/drug effects MH - *Cell Transformation, Neoplastic MH - Enzyme Activation MH - Gene Expression MH - Humans MH - Insulin-Like Growth Factor I/*pharmacology MH - Liver Neoplasms MH - Mice MH - Mitogen-Activated Protein Kinase Kinases MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - Oligodeoxyribonucleotides MH - Phosphoproteins/*biosynthesis MH - Protein Kinases/metabolism MH - Protein-Tyrosine-Phosphatase/*metabolism MH - Proteins/*metabolism MH - Receptor, Epidermal Growth Factor/biosynthesis MH - Recombinant Proteins/biosynthesis MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Transfection MH - Tumor Cells, Cultured MH - src Homology Domains EDAT- 1996/06/14 MHDA- 1996/06/14 00:01 PST - ppublish SO - J Biol Chem 1996 Jun 14;271(24):14610-6. -------------------------------------------------------------------------------- 250: Li PM et al. Differential regulation of in...[PMID: 8660383] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8660383 OWN - NLM STAT- MEDLINE DA - 19960801 DCOM- 19960801 LR - 20041117 PUBM- Print IS - 0006-291X VI - 223 IP - 1 DP - 1996 Jun 5 TI - Differential regulation of insulin-stimulated tyrosine phosphorylation of IRS-1 and SHC by Wortmannin in intact cells. PG - 80-4 AB - Wortmannin is an inhibitor of phosphatidylinositol (PI) 3'-kinase, a cellular kinase activated by docking to phosphotyrosyl residues of insulin receptor substrate-1 (IRS-1) that can also phosphorylate serine residues on IRS-1 in vitro. After treatment of hepatoma cells with 100 nM wortmannin, the tyrosine phosphorylation of IRS-1 in response to insulin was increased by 38.3 +/- 3.3% while its phosphoserine/threonine content was reduced by 19%. Treatment with 1 microM wortmannin further increased IRS-1 tyrosine phosphorylation to 180% of control, while under these conditions, tyrosine phosphorylation of the IR substrate p52 Shc was reduced to less than 50% of control. Thus, alteration of the serine phosphorylation of IR substrates by a wortmannin-sensitive kinase may regulate post-insulin receptor signaling pathways by differential modulation of their insulin-stimulated tyrosine phosphorylation. AD - Dorrance H. Hamilton Research Laboratories, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Li, P M AU - Li PM FAU - Goldstein, B J AU - Goldstein BJ LA - eng GR - R01-DK43396/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (Androstadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphates) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 1114-81-4 (Phosphothreonine) RN - 17885-08-4 (Phosphoserine) RN - 19545-26-7 (wortmannin) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Androstadienes/*pharmacology MH - Animals MH - Cell Line MH - Enzyme Inhibitors/*pharmacology MH - Insulin/*pharmacology MH - Kinetics MH - Liver Neoplasms, Experimental MH - Phosphates/metabolism MH - Phosphoproteins/isolation & purification/*metabolism MH - Phosphorylation MH - Phosphoserine/metabolism MH - Phosphothreonine/metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors MH - Phosphotyrosine/analysis/metabolism MH - Rats MH - Receptor, Insulin/isolation & purification/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - Tyrosine/*metabolism EDAT- 1996/06/05 MHDA- 1996/06/05 00:01 AID - S0006291X96908499 [pii] PST - ppublish SO - Biochem Biophys Res Commun 1996 Jun 5;223(1):80-4. -------------------------------------------------------------------------------- 251: Sachs M et al. Motogenic and morphogenic act...[PMID: 8655582] Related Articles, Cited in PMC, Books, LinkOut PMID- 8655582 OWN - NLM STAT- MEDLINE DA - 19960801 DCOM- 19960801 LR - 20041117 PUBM- Print IS - 0021-9525 VI - 133 IP - 5 DP - 1996 Jun TI - Motogenic and morphogenic activity of epithelial receptor tyrosine kinases. PG - 1095-1107 AB - Receptor tyrosine kinases play essential roles in morphogenesis and differentiation of epithelia. Here we examined various tyrosine kinase receptors, which are preferentially expressed in epithelia (c-met, c-ros, c-neu, and the keratin growth factor [KGF] receptor), for their capacity to induce cell motility and branching morphogenesis of epithelial cells. We exchanged the ligand-binding domain of these receptors by the ectodomain of trkA and could thus control signaling by the new ligand, NGF. We demonstrate here that the tyrosine kinases of c-met, c-ros, c-neu, the KGF receptor, and trkA, but not the insulin receptor, induced scattering and increased motility of kidney epithelial cells in tissue culture. Mutational analysis suggests that SHC binding is essential for scattering and increased cell motility induced by trkA. The induction of motility in epithelial cells is thus an important feature of various receptor tyrosine kinases, which in vivo play a role in embryogenesis and metastasis. In contrast, only the c-met receptor promoted branching morphogenesis of kidney epithelial cells in three-dimensional matrices, which resemble the formation of tubular epithelia in development. Interestingly, the ability of c-met to induce morphogenesis could be transferred to trkA, when in a novel receptor hybrid COOH-terminal sequences of c-met (including Y14 to Y16) were fused to the trkA kinase domain. These data demonstrate that tubulogenesis of epithelia is a restricted activity of tyrosine kinases, as yet only demonstrated for the c-met receptor. We predict the existence of specific substrates that mediate this morphogenesis signal. AD - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. FAU - Sachs, M AU - Sachs M FAU - Weidner, K M AU - Weidner KM FAU - Brinkmann, V AU - Brinkmann V FAU - Walther, I AU - Walther I FAU - Obermeier, A AU - Obermeier A FAU - Ullrich, A AU - Ullrich A FAU - Birchmeier, W AU - Birchmeier W LA - eng PT - Journal Article PL - UNITED STATES TA - J Cell Biol JID - 0375356 RN - 0 (DNA Primers) RN - 0 (DNA, Recombinant) RN - 0 (Nerve Growth Factors) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Nerve Growth Factor) RN - 0 (Recombinant Fusion Proteins) RN - EC 2.7.1.112 (Proto-Oncogene Protein c-met) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, trkA) SB - IM MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - Cell Line MH - Cell Movement/drug effects/*physiology MH - DNA Primers/genetics MH - DNA, Recombinant/genetics MH - Dogs MH - Epithelial Cells MH - Epithelium/drug effects/enzymology MH - Humans MH - Molecular Sequence Data MH - Molecular Structure MH - Morphogenesis/drug effects/*physiology MH - Nerve Growth Factors/pharmacology MH - Proto-Oncogene Protein c-met MH - Proto-Oncogene Proteins/chemistry/genetics/physiology MH - Receptor Protein-Tyrosine Kinases/chemistry/genetics/*physiology MH - Receptor, trkA MH - Receptors, Nerve Growth Factor/chemistry/genetics/physiology MH - Recombinant Fusion Proteins/chemistry/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Transfection EDAT- 1996/06/01 MHDA- 1996/06/01 00:01 PST - ppublish SO - J Cell Biol 1996 Jun;133(5):1095-1107. -------------------------------------------------------------------------------- 252: Durick K et al. Mitogenic signaling by Ret/pt...[PMID: 8662982] Related Articles, Cited in PMC, Cited in Books, Books, LinkOut PMID- 8662982 OWN - NLM STAT- MEDLINE DA - 19960815 DCOM- 19960815 LR - 20041203 PUBM- Print IS - 0021-9258 VI - 271 IP - 22 DP - 1996 May 31 TI - Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM domain. PG - 12691-4 AB - The ret/ptc2 papillary thyroid cancer oncogene, an oncogenic form of the c-Ret receptor tyrosine kinase, is the product of a somatic crossover event fusing the dimerization domain of the type Ialpha regulatory subunit of cyclic AMP-dependent protein kinase (RI) with the tyrosine kinase domain of c-Ret. Mitogenic activity of Ret/ptc2 required dimerization via the N terminus of RI and a tyrosine residue located C-terminal to the kinase core of Ret, Tyr-586 (Durick, K., Yao, V. J., Borrello, M. G., Bongarzone, I., Pierotti, M. A. and Taylor, S. S. (1995) J. Biol. Chem. 270, 24642-24645). Using the yeast two-hybrid system, Ret/ptc2 binding proteins were identified, and the sites of interaction with Ret/ptc2 were mapped. The SH2 domains of phospholipase Cgamma and Grb10 were both identified, and binding depended on phosphorylation of Tyr-539 and Tyr-429, respectively. These interactions, however, were not required for mitogenic signaling. The second of the three LIM domains in Enigma (Wu, R. Y., and Gill, G. N. (1994) J. Biol. Chem. 269, 25085-25090) was also identified as a Ret/ptc2 binding domain. Enigma, a 455-residue protein, was discovered based on its interaction with the insulin receptor through the C-terminal LIM domain. Although the association with Enigma required Tyr-586 of Ret/ptc2, the interaction was phosphorylation-independent. In contrast to the SH2 interactions, disruption of the interaction with Enigma abolished Ret/ptc2 mitogenic signaling, suggesting that LIM domain recognition of an unphosphorylated tyrosine-based motif is required for Ret signal transduction. AD - Department of Chemistry, University of California, San Diego, La Jolla, California 92093-0654, USA. FAU - Durick, K AU - Durick K FAU - Wu, R Y AU - Wu RY FAU - Gill, G N AU - Gill GN FAU - Taylor, S S AU - Taylor SS LA - eng GR - DK13149/DK/NIDDK GR - T32 CA09523/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Carrier Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Mitogens) RN - 0 (Oncogene Proteins) RN - 0 (PDLIM7 protein, human) RN - 0 (Pdlim7 protein, mouse) RN - 0 (RET protein, human) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) SB - IM MH - 3T3 Cells MH - Animals MH - Carrier Proteins/*metabolism MH - *Intracellular Signaling Peptides and Proteins MH - Mice MH - Mitogens/*metabolism MH - Oncogene Proteins/genetics/*metabolism MH - Protein Binding MH - Receptor Protein-Tyrosine Kinases/genetics/*metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Saccharomyces cerevisiae/genetics MH - *Signal Transduction MH - src Homology Domains EDAT- 1996/05/31 MHDA- 1996/05/31 00:01 PST - ppublish SO - J Biol Chem 1996 May 31;271(22):12691-4. -------------------------------------------------------------------------------- 253: Patrone C et al. Cross-coupling between insuli...[PMID: 8732681] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8732681 OWN - NLM STAT- MEDLINE DA - 19961010 DCOM- 19961010 LR - 20041117 PUBM- Print IS - 0888-8809 VI - 10 IP - 5 DP - 1996 May TI - Cross-coupling between insulin and estrogen receptor in human neuroblastoma cells. PG - 499-507 AB - Insulin is a well known mitotic agent for neuroblastoma cells. Human SK-N-BE neuroblastoma cells stably transfected with the estrogen receptor, however, undergo growth arrest and differentiation when treated with insulin. These effects were shown to be due to an insulin-dependent activation of the unliganded estrogen receptor. Here, we demonstrate that this activation involves the AF-2 COOH-terminal domain of the estrogen receptor and that the communication between estrogen and insulin receptor systems occurs via selected and specific transduction signals. In fact, by the use of dominant negative and dominant positive mutants we demonstrate that p21ras is essential for insulin and estrogen receptor coupling. With pharmacological tools, we prove that PI 3'kinase does not contribute to this cross-talk and that protein kinase C triggers transduction signals that act in synergism with p21ras. These results prove the intricacy of all these intracellular paths of communication. The finding that, in neuroblastoma cells, selected signal transduction systems are involved in the insulin-dependent activation of estrogen receptor is of particular interest considering that estrogen receptor might restrict the role played by insulin during the differentiation of neural cells and interfere with its proliferative potential while allowing its regulation of other functions related to cell survival. AD - Milano Molecular Pharmacology Laboratory, Institute of Pharmacological Sciences, University of Milan, Italy. FAU - Patrone, C AU - Patrone C FAU - Ma, Z Q AU - Ma ZQ FAU - Pollio, G AU - Pollio G FAU - Agrati, P AU - Agrati P FAU - Parker, M G AU - Parker MG FAU - Maggi, A AU - Maggi A LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Receptors, Estrogen) RN - 11061-68-0 (Insulin) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Cell Differentiation/drug effects MH - Cell Division/drug effects MH - Enzyme Activation MH - Genes, ras/physiology MH - Humans MH - Insulin/*pharmacology MH - Neuroblastoma/*metabolism/pathology MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Protein Kinase C/metabolism MH - Receptor, Insulin/*physiology MH - Receptors, Estrogen/genetics/*physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Transcription, Genetic/drug effects MH - Transfection MH - Tumor Cells, Cultured EDAT- 1996/05/01 MHDA- 1996/05/01 00:01 PST - ppublish SO - Mol Endocrinol 1996 May;10(5):499-507. -------------------------------------------------------------------------------- 254: Kanety H et al. Sphingomyelinase and ceramide...[PMID: 8626623] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8626623 OWN - NLM STAT- MEDLINE DA - 19960621 DCOM- 19960621 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 271 IP - 17 DP - 1996 Apr 26 TI - Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. PG - 9895-7 AB - The sphingomyelin pathway is a newly described signal transduction pathway mediating the action of several cytokines including tumor necrosis factor-alpha (TNF). TNF was recently shown to interfere with insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1). In this work we examined the possible effect of direct activation of the sphingomyelin pathway on insulin-induced tyrosine phosphorylation of IRS-1. Incubation of the insulin-sensitive rat hepatoma Fao cells with bacterial sphingomyelinase (SMase) that causes membrane hydrolysis of sphingomyelin led to a time- and dose-dependent decrease in insulin-induced tyrosine phosphorylation of IRS-1. The effect was apparent after 10 min of incubation and with a dose of 10 milliunits/ml SMase. It was not associated with a decrease in insulin receptor autophosphorylation. In addition, SMase treatment interrupted the association of the 85-kDa catalytic subunit of phosphatidylinositol 3-kinase with IRS-1. A similar impact on IRS-1 tyrosine phosphorylation was observed after addition of cell-permeable ceramide analogs (C2 and C6). Comparable changes in IRS-1 tyrosine phosphorylation and electrophoretic mobility were found after exposure of cells to either TNF, SMase, or ceramide. Our findings suggest that TNF may utilize the sphingomyelin pathway in its effect on the insulin-stimulated tyrosine phosphorylation of IRS-1. AD - Institute of Endocrinology and the Department of Surgery, Sheba Medical Center, Tel Hashomer, Israel 52621, USA. FAU - Kanety, H AU - Kanety H FAU - Hemi, R AU - Hemi R FAU - Papa, M Z AU - Papa MZ FAU - Karasik, A AU - Karasik A LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Ceramides) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoproteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase) SB - IM MH - Animals MH - Ceramides/*pharmacology MH - Enzyme Inhibitors/pharmacology MH - Insulin/*pharmacology MH - Liver Neoplasms, Experimental MH - Phosphoproteins/*metabolism MH - Phosphotyrosine/metabolism MH - Rats MH - Receptor, Insulin/*metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Sphingomyelin Phosphodiesterase/*metabolism MH - Tumor Cells, Cultured MH - Tumor Necrosis Factor-alpha/physiology EDAT- 1996/04/26 MHDA- 1996/04/26 00:01 PST - ppublish SO - J Biol Chem 1996 Apr 26;271(17):9895-7. -------------------------------------------------------------------------------- 255: Li PM et al. Cell density-dependent change...[PMID: 8726353] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8726353 OWN - NLM STAT- MEDLINE DA - 19961015 DCOM- 19961015 LR - 20041117 PUBM- Print IS - 0730-2312 VI - 61 IP - 1 DP - 1996 Apr TI - Cell density-dependent changes in the insulin action pathway: evidence for involvement of protein-tyrosine phosphatases. PG - 31-8 AB - In order to examine alterations in the phosphorylation state of proteins involved in insulin action that might accompany the reduced growth state of density-arrested cells, we measured the insulin-stimulated phosphorylation of the receptor and high M(r) cellular substrates of the receptor kinase in rat hepatoma cells at different cell densities. As cell density increased from 2 x 10(5) to 3.2 x 10(6) per 35-mm well, the rate of DNA synthesis fell to 22% of control, while insulin-stimulated tyrosine phosphorylation of high M(r) receptor substrates ("pp185") was enhanced to 198% of control, without a change in the abundance of insulin receptor substrate (IRS)-1 protein. In anti-IRS-1 immunoprecipitates, tyrosine phosphorylation was increased by only 30%, suggesting that increased tyrosine phosphorylation of additional high M(r) proteins (e.g., IRS-2) accounted for much of the observed increase in tyrosine phosphorylation of the receptor substrates. In spite of increased tyrosine phosphorylation of IRS-1 and total pp185-related proteins, however, cells studied at high growth density exhibited a 25% decrease in IRS-1-associated phosphatidylinositol 3'-kinase activity and only a 39% increase in phosphatidylinositol 3'-kinase activity in antiphosphotyrosine immunoprecipitates. To explore the potential role of hepatic protein-tyrosine phosphatases (PTPases) in the hyperphosphorylation of pp185 proteins, we found by immunoblotting that at high cell density the intracellular PTPase PTP1B and the transmembrane PTPase LAR were reduced in abundance by 49% and 55%, respectively, while the abundance of the SH2-domain containing PTPase SH-PTP2 was increased by 48%. These data demonstrate that the attenuation of post-receptor signaling by insulin in hepatoma cells at increasing growth density involves changes in endogenous substrate phosphorylation which may result from alterations in specific PTPases implicated in the regulation of the insulin action pathway. AD - Dorrance H. Hamilton Research Laboratories, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Li, P M AU - Li PM FAU - Goldstein, B J AU - Goldstein BJ LA - eng GR - R01-DK43396/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Cell Biochem JID - 8205768 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (insulin receptor substrate-2 protein) RN - 11061-68-0 (Insulin) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Animals MH - Cell Count MH - Cell Division MH - Insulin/*pharmacology MH - Liver Neoplasms, Experimental MH - Phosphoproteins/biosynthesis MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Protein-Tyrosine Kinase/*metabolism MH - Protein-Tyrosine-Phosphatase/*metabolism MH - Rats MH - Receptor, Insulin/analysis MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 1996/04/01 MHDA- 2000/06/20 09:00 AID - 10.1002/(SICI)1097-4644(19960401)61:1<31::AID-JCB5>3.0.CO;2-3 [pii] PST - ppublish SO - J Cell Biochem 1996 Apr;61(1):31-8. -------------------------------------------------------------------------------- 256: Samel D et al. The effect of purified extrac...[PMID: 8657738] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8657738 OWN - NLM STAT- MEDLINE DA - 19960731 DCOM- 19960731 LR - 20041117 PUBM- Print IS - 0032-0943 VI - 62 IP - 2 DP - 1996 Apr TI - The effect of purified extract of Fagopyrum esculentum (buckwheat) on protein kinases involved in signal transduction pathways. PG - 106-10 AB - The effect of a purified extract of the flowering herb of Fagopyrum esculentum (buckwheat) on various protein kinases involved in signal transduction was examined. We observed that buckwheat contains red fluorescent compounds having photosensitizing properties. Spectrophotometric analysis of the extract has indicated structural similarity to hypericin. Dose- and light-dependent inhibition of various protein kinases was observed. The purified buckwheat extract strongly inhibited two receptor-associated protein tyrosine kinases (EGF-R and Ins-R) and a Ser/Thr kinase (PK-C) at an ng/ml concentration range. Selectivity was exhibited as a decreased sensitivity to cytosolic PTKs and protein kinase CK-2. The protein kinases are important components of the signal transduction pathway. Aberration of signal transduction is a hallmark of several proliferative diseases. Our results indicate that photosensitizing compounds in buckwheat are potential antiproliferative agents. AD - Laboratorium voor Farmaceutische Biologie, Faculteit Farmaceutische Wetenschappen, Leuven, Belgium. FAU - Samel, D AU - Samel D FAU - Donnella-Deana, A AU - Donnella-Deana A FAU - de Witte, P AU - de Witte P LA - eng PT - Journal Article PL - GERMANY TA - Planta Med JID - 0066751 RN - 0 (Enzyme Inhibitors) RN - 0 (Plant Extracts) RN - 0 (Protein Kinase Inhibitors) RN - 198-55-0 (Perylene) RN - 548-04-9 (hypericin) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM SB - S MH - 3T3 Cells MH - Animals MH - Carcinoma, Squamous Cell MH - Cell Line MH - *Cereals MH - Enzyme Inhibitors/*pharmacology MH - Humans MH - Mice MH - Perylene/analogs & derivatives MH - Plant Extracts/*pharmacology MH - Protein Kinase C/antagonists & inhibitors MH - *Protein Kinase Inhibitors MH - Protein-Tyrosine Kinase/*antagonists & inhibitors MH - Receptor, Epidermal Growth Factor/antagonists & inhibitors MH - Receptor, Insulin/antagonists & inhibitors MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1996/04/01 MHDA- 1996/04/01 00:01 PST - ppublish SO - Planta Med 1996 Apr;62(2):106-10. -------------------------------------------------------------------------------- 257: Bergmann U et al. Increased expression of insul...[PMID: 8607861] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8607861 OWN - NLM STAT- MEDLINE DA - 19960520 DCOM- 19960520 LR - 20041117 PUBM- Print IS - 0006-291X VI - 220 IP - 3 DP - 1996 Mar 27 TI - Increased expression of insulin receptor substrate-1 in human pancreatic cancer. PG - 886-90 AB - Insulin receptor substrate-1 (IRS-1) is a multisite docking protein implicated in mitogenic signaling following activation of the insulin and insulin-like growth factor I receptors. In the present study we characterized IRS-1 expression in human pancreatic cancer. Northern blot analysis revealed high levels of IRS-1 mRNA transcripts in ASPC-1 and MIA PaCa-2 human pancreatic cancer cell lines, and lower levels in COLO-357, PANC-1, and T3M4 cells. Immunoblotting with anti-IRS-1 antibodies indicated that IRS-1 protein levels paralleled IRS-1 mRNA levels. Analysis of RNA isolated from normal and cancerous human pancreatic tissues indicated that 7 of 16 pancreatic cancer samples overexpressed IRS-1 mRNA transcripts by comparison with the normal pancreas and that insulin mRNA levels were abundant in many tumors. These data suggest that IRS-1 contributes to the signaling pathways that lead to excessive growth stimulation in human pancreatic cancer. AD - Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine 92717, USA. FAU - Bergmann, U AU - Bergmann U FAU - Funatomi, H AU - Funatomi H FAU - Kornmann, M AU - Kornmann M FAU - Beger, H G AU - Beger HG FAU - Korc, M AU - Korc M LA - eng GR - CA-40162/CA/NCI GR - DK-44948/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Biochem Biophys Res Commun JID - 0372516 RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) SB - IM MH - Blotting, Northern MH - Cell Line MH - Colonic Neoplasms MH - Comparative Study MH - *Gene Expression/drug effects MH - Humans MH - Insulin/biosynthesis/pharmacology MH - Pancreas/*metabolism MH - Pancreatic Neoplasms/*metabolism MH - Phosphoproteins/*biosynthesis/isolation & purification MH - RNA, Messenger/analysis/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - *Transcription, Genetic MH - Tumor Cells, Cultured EDAT- 1996/03/27 MHDA- 1996/03/27 00:01 AID - S0006291X96905008 [pii] PST - ppublish SO - Biochem Biophys Res Commun 1996 Mar 27;220(3):886-90. -------------------------------------------------------------------------------- 258: Ito T et al. Overexpression of human insul...[PMID: 8622697] Related Articles, Free in PMC, Books, LinkOut PMID- 8622697 OWN - NLM STAT- MEDLINE DA - 19960618 DCOM- 19960618 LR - 20041117 PUBM- Print IS - 0270-7306 VI - 16 IP - 3 DP - 1996 Mar TI - Overexpression of human insulin receptor substrate 1 induces cellular transformation with activation of mitogen-activated protein kinases. PG - 943-51 AB - The receptor insulin substrate 1 protein (IRS-1) is a specific substrate for insulin receptor tyrosine kinase. Expression and tyrosyl phosphorylation of IRS-1 play an important role during normal hepatocyte growth, and the gene is overexpressed in hepatocellular carcinoma tissue. We determined if IRS-1 overexpression directly contributes to cellular transformation. The human IRS-1 gene was subcloned into a mammalian expression vector driven by the cytomegalovirus early promoter. NIH 3T3 cells transiently transfected with this vector subsequently developed transformed foci. Several stably transfected cell lines were established, and they grew efficiently under low-serum conditions and formed colonies when plated in soft agar. Cell lines overexpressing IRS-1 displayed increased tyrosyl phosphorylation of IRS-1 and association with Grb2 but not with the p85 subunit of phosphatidylinositol 3' kinase. Since Grb2 is a component of the son-of-sevenless-Ras pathway and upstream in the mitogen-activated protein kinase (MAPK) cascade, enzymatic activities of the major components of this cascade, such as MAPK kinase and MAPK were evaluated and found to be substantially increased in three independent cell lines with IRS-1 protein overexpression. Such cells, when injected into nude mice, were highly tumorigenic, and there may be a correlation between the degree of MAPK activation and tumor growth rate. This report describes the generation of a transformed phenotype by overexpression of a molecule without a catalytic domain far upstream in the signal transduction cascade and suggests that prolonged activation of MAPKs by this mechanism may be one of the molecular events related to hepatocellular transformation. AD - Molecular Hepatology Laboratory, MGH Cancer Center, Charlestown, Massachusetts, USA. FAU - Ito, T AU - Ito T FAU - Sasaki, Y AU - Sasaki Y FAU - Wands, J R AU - Wands JR LA - eng GR - AA-02666/AA/NIAAA GR - AA-08169/AA/NIAAA GR - CA-35711/CA/NCI PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) SB - IM MH - 3T3 Cells MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/*metabolism MH - Cell Division MH - Cell Transformation, Neoplastic/genetics/*metabolism/pathology MH - Enzyme Activation MH - Gene Transfer Techniques MH - Humans MH - Mice MH - Phosphoproteins/*biosynthesis/genetics MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction EDAT- 1996/03/01 MHDA- 1996/03/01 00:01 PST - ppublish SO - Mol Cell Biol 1996 Mar;16(3):943-51. -------------------------------------------------------------------------------- 259: Giuliano M et al. Role of insulin-like growth f...[PMID: 8612625] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8612625 OWN - NLM STAT- MEDLINE DA - 19960603 DCOM- 19960603 LR - 20041117 PUBM- Print IS - 0014-2956 VI - 236 IP - 2 DP - 1996 Mar 1 TI - Role of insulin-like growth factors in autocrine growth of human retinoblastoma Y79 cells. PG - 523-32 AB - In this study, we have demonstrated that human retinoblastoma Y79 cells produce insulin-like growth factors (IGFs) type I and type II and release them into the medium. We have also ascertained, by means of competitive studies and cross-linking procedure, that Y79 cells contain the type-I IGF receptor (IGF-IR). Furthermore, surface-bound IGF-I is internalised by the receptor, then degraded to amino acids. Insulin, IGF-I and IGF-II caused down-regulation of IGF-IR; the effect is concentration and time dependent. Scatchard analysis demonstrated that incubation with insulin markedly decreased the binding capacity measured for IGF-I while the apparent Kd value calculated for IGF-I binding was not significantly modified. IGF-I, IGF-II and insulin induced tyrosine phosphorylation of IGF-IR. Tyrosine phosphorylation of this receptor with, however, a less strong signal, was detectable even in cells cultured in serum-free medium without the addition of any exogenous growth factor. Similar results have been found concerning the tyrosine phosphorylation of insulin receptor substrate-1 (IRS 1). Tyrosine phosphorylation of both IGF-IR and IRS 1, either under basal conditions or after stimulation with growth factors, was strongly inhibited when alpha-IR3, a monoclonal antibody to IGF-IR, was added to the culture. IGF-I was capable of inducing Y79 cell proliferation and its effect was entirely inhibited by the addition of alpha-IR3. This antibody also markedly reduced the proliferation of Y79 cells cultured in serum-free medium not supplemented with stimulatory factors. Our results indicate that IGF-I and IGF-IR mediate an autocrine growth mechanism in Y79 cells. AD - Institute of Biological Chemistry, University of Palermo, Italy. FAU - Giuliano, M AU - Giuliano M FAU - Vento, R AU - Vento R FAU - Lauricella, M AU - Lauricella M FAU - Calvaruso, G AU - Calvaruso G FAU - Carabillo, M AU - Carabillo M FAU - Tesoriere, G AU - Tesoriere G LA - eng PT - Journal Article PL - GERMANY TA - Eur J Biochem JID - 0107600 RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Binding, Competitive MH - Cell Division/drug effects MH - Humans MH - Insulin/pharmacology MH - Insulin-Like Growth Factor I/*physiology MH - Insulin-Like Growth Factor II/*physiology MH - Phosphoproteins/metabolism MH - Phosphotyrosine/metabolism MH - Receptor, IGF Type 1/*physiology MH - Research Support, Non-U.S. Gov't MH - Retinoblastoma/*pathology MH - Signal Transduction EDAT- 1996/03/01 MHDA- 1996/03/01 00:01 PST - ppublish SO - Eur J Biochem 1996 Mar 1;236(2):523-32. -------------------------------------------------------------------------------- 260: Holgado-Madruga M et al. A Grb2-associated docking pro...[PMID: 8596638] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, OMIM, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 8596638 OWN - NLM STAT- MEDLINE DA - 19960417 DCOM- 19960417 LR - 20041118 PUBM- Print IS - 0028-0836 VI - 379 IP - 6565 DP - 1996 Feb 8 TI - A Grb2-associated docking protein in EGF- and insulin-receptor signalling. PG - 560-4 AB - The protein Grb2 plays a central role in signalling by receptor protein-tyrosine kinases, where its SH2 domain binds to the receptor and its two SH3 domains link to effectors. One target effector is Sos, so Grb2 links receptor protein-tyrosine kinases with the Ras signalling pathway. The SH3 domains can also couple to other signalling proteins, including Vav, c-Abl and dynamin. We have identified several bands in glial and medulloblastoma tumours that are recognized by Grb2 but these did not correspond to any known protein. Here we use recombinant Grb2 to isolate a complementary DNA called Gab1 (for Grb2-associated binder-1). Gab1 shares amino-acid homology and several structural features with IRS-1 (insulin-receptor substrate-1; refs 6,7), is a substrate of the EGF and insulin receptors, and can act as a docking protein for several SH2-containing proteins. Over-expression of Gab1 enhances cell growth and results in transformation. We conclude that Gab1 is a new protein in EGF and insulin receptor signalling which could integrate signals from different systems. AD - Department of Microbiology & Immunology, Jefferson Cancer Institute, Philadelphia, Pennsylvania 19107, USA. FAU - Holgado-Madruga, M AU - Holgado-Madruga M FAU - Emlet, D R AU - Emlet DR FAU - Moscatello, D K AU - Moscatello DK FAU - Godwin, A K AU - Godwin AK FAU - Wong, A J AU - Wong AJ LA - eng SI - GENBANK/U43885 PT - Journal Article PL - ENGLAND TA - Nature JID - 0410462 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (DNA, Complementary) RN - 0 (GAB1 protein, human) RN - 0 (Gab1 protein, mouse) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Recombinant Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - 3T3 Cells MH - *Adaptor Proteins, Signal Transducing MH - Amino Acid Sequence MH - Animals MH - Blotting, Northern MH - Blotting, Western MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cell Division MH - Cell Transformation, Neoplastic MH - DNA, Complementary MH - Enzyme Activation MH - Humans MH - Mice MH - Molecular Sequence Data MH - Phosphoproteins/genetics/*metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Proteins/*metabolism MH - Receptor, Epidermal Growth Factor/*metabolism MH - Receptor, Insulin/*metabolism MH - Recombinant Proteins/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Homology, Amino Acid MH - *Signal Transduction MH - Tumor Cells, Cultured MH - src Homology Domains/genetics EDAT- 1996/02/08 MHDA- 1996/02/08 00:01 PST - ppublish SO - Nature 1996 Feb 8;379(6565):560-4. -------------------------------------------------------------------------------- 261: Blakesley VA et al. Tumorigenic and mitogenic cap...[PMID: 8593783] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8593783 OWN - NLM STAT- MEDLINE DA - 19960409 DCOM- 19960409 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 137 IP - 2 DP - 1996 Feb TI - Tumorigenic and mitogenic capacities are reduced in transfected fibroblasts expressing mutant insulin-like growth factor (IGF)-I receptors. The role of tyrosine residues 1250, 1251, and 1316 in the carboxy-terminus of the IGF-I receptor. PG - 410-7 AB - Regulation of ligand-mediated signal transduction through transmembrane tyrosine kinase growth factor receptors involves phosphorylation of tyrosine residues in the intracellular domain of the receptor. The insulin-like growth factor-I (IGF-I) receptor contains three tyrosine residues in the carboxy-terminal domain at positions 1250, 1251, and 1316. Of these, only the tyrosine at position 1316 is conserved in the homologous position of the insulin receptor. Mutational analysis was used to study the role of these tyrosines in specific outcomes of IGF-I-mediated signal transduction. Mutations in the human IGF-I receptor were either replacement of tyrosines 1250 and 1251 with phenylalanine and histidine (yyFH), respectively, or replacement of the conserved distal tyrosine (position 1316) with phenylalanine (yCF). The yyFH mutation results in an IGF-I receptor with the amino acids found in the homologous position of the human insulin receptor. Cells overexpressing mutated IGF-I receptors were compared with cells expressing only endogenous IGF-I receptors or overexpressing wild-type IGF-I receptors. The ability of yyFH mutant IGF-I receptors to autophosphorylate the beta-subunit or phosphorylate insulin receptor substrate-1 was not significantly different from wild-type type IGF-I receptors. However, one or both of the proximal tyrosine residues (positions 1250 and 1251) in the carboxy-terminus of the IGF-I receptor are essential for IGF-I-stimulation of mitogenic and tumorigenic pathways. IGF-I-induced mitogenesis, measured as thymidine incorporation and cellular proliferation, was abrogated in cells overexpressing mutant IGF-I receptors with replacement of the proximal double tyrosines (positions 1250 and 1251). Fibroblasts expressing this mutant IGF-I receptor formed fewer tumors than the negative control cells, whereas cells expressing wild-type IGF-I receptors formed large tumors in all recipient mice injected. Conversely, cells expressing mutant IGF-I receptors with only the conserved distal tyrosine (position 1316) replaced had slightly reduced IGF-I-stimulated beta-subunit autophosphorylation, thymidine incorporation, and cellular proliferation when compared with cells expressing wild-type receptors. Phosphorylation of insulin receptor substrate-1 by the yCF mutant receptors was not impaired. Despite the ability of these mutant receptors to stimulate mitogenic growth, fibroblasts expressing this mutant receptor were also incapable of forming tumors in recipient nude mice. The distal tyrosine (position 1316) of the IGF-I receptor is crucial for tumor formation but is not essential for IGF-I stimulated mitogenesis. Thus, the tyrosine moieties in the carboxy-terminus of the IGF-I receptor participate in the signal transduction pathways that affect the mitogenic and tumorigenic potentials of cells expressing mutant IGF-I receptors. AD - Section on Molecular and Cellular Physiology, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA. FAU - Blakesley, V A AU - Blakesley VA FAU - Kalebic, T AU - Kalebic T FAU - Helman, L J AU - Helman LJ FAU - Stannard, B AU - Stannard B FAU - Faria, T N AU - Faria TN FAU - Roberts, C T Jr AU - Roberts CT Jr FAU - LeRoith, D AU - LeRoith D LA - eng PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (Peptide Fragments) RN - 0 (Receptors, Somatomedin) RN - 50-89-5 (Thymidine) RN - 55520-40-6 (Tyrosine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) SB - AIM SB - IM MH - 3T3 Cells/physiology MH - Animals MH - Base Sequence MH - Fibroblasts/cytology/metabolism/physiology MH - Humans MH - Insulin-Like Growth Factor I/*metabolism MH - Mice MH - Mice, Nude MH - Mitosis MH - Molecular Sequence Data MH - *Mutation MH - Neoplasms, Experimental/*etiology MH - Peptide Fragments/physiology MH - Phosphorylation MH - Protein-Tyrosine Kinase/metabolism MH - Receptors, Somatomedin/*genetics/*metabolism MH - Thymidine/metabolism MH - Transfection MH - Tyrosine/*physiology EDAT- 1996/02/01 MHDA- 2001/03/28 10:01 PST - ppublish SO - Endocrinology 1996 Feb;137(2):410-7. -------------------------------------------------------------------------------- 262: Kulas DT et al. The transmembrane protein-tyr...[PMID: 8557682] Related Articles, Cited in PMC, Books, LinkOut PMID- 8557682 OWN - NLM STAT- MEDLINE DA - 19960226 DCOM- 19960226 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 271 IP - 2 DP - 1996 Jan 12 TI - The transmembrane protein-tyrosine phosphatase LAR modulates signaling by multiple receptor tyrosine kinases. PG - 748-54 AB - Antisense-mediated suppression of the transmembrane protein-tyrosine phosphatase (PTPase) LAR has been shown previously to increase insulin-dependent phosphatidylinositol 3-kinase (PI 3-kinase) activation by greater than 300% in the rat hepatoma cell line McA-RH7777. Here, insulin-dependent insulin receptor tyrosine kinase activation was examined with recombinant insulin receptor substrate 1 (IRS-1) as the substrate and shown to be 3-fold greater in cells with suppressed LAR levels. Consistent with a receptor level effect, in vivo insulin-dependent tyrosine phosphorylation of both IRS-1 and Shc was increased by a similar 3-fold with LAR suppression. These increases in IRS-1 and Shc phosphorylation were paralleled by increases in insulin-dependent PI 3-kinase association with IRS-1 and activation of the MAP kinase pathway. Reduced LAR levels also resulted in increases of over 300% and 250% in epidermal growth factor (EGF)- and hepatocyte growth factor (HGF)-dependent receptor autophosphorylation, respectively, as well as a severalfold increase in substrate tyrosine phosphorylation. In a post-receptor response, EGF- and HGF-dependent MAP kinase activation was increased by 300% and 350%, respectively, with LAR suppression. Similarly, growth factor-dependent PI 3-kinase activation was increased in LAR antisense expressing cells when compared to null vector expressing cells. These results demonstrate that the transmembrane PTPase LAR modulates ligand-dependent activation of at least three receptor tyrosine kinases. AD - Department of Pathology, University of Rochester School of Medicine and Dentistry, New York 14642, USA. FAU - Kulas, D T AU - Kulas DT FAU - Goldstein, B J AU - Goldstein BJ FAU - Mooney, R A AU - Mooney RA LA - eng GR - R01-DK38138/DK/NIDDK GR - R01-DK43396/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Phosphoproteins) RN - 0 (Recombinant Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/*enzymology MH - Phosphoproteins/*metabolism MH - Phosphorylation MH - Protein-Tyrosine-Phosphatase/*metabolism MH - Rats MH - Receptor Protein-Tyrosine Kinases/*metabolism MH - Receptor, Insulin/*metabolism MH - Recombinant Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1996/01/12 MHDA- 1996/01/12 00:01 PST - ppublish SO - J Biol Chem 1996 Jan 12;271(2):748-54. -------------------------------------------------------------------------------- 263: Jiang Y et al. Effect of tyrosine mutations ...[PMID: 8550552] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8550552 OWN - NLM STAT- MEDLINE DA - 19960220 DCOM- 19960220 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 271 IP - 1 DP - 1996 Jan 5 TI - Effect of tyrosine mutations on the kinase activity and transforming potential of an oncogenic human insulin-like growth factor I receptor. PG - 160-7 AB - The tyrosines in the cytoplasmic domain of an oncogenic human insulin-like growth factor I receptor (gag-IGFR) were systematically mutated to phenylalanines to investigate the role of those tyrosines in the enzymatic and biological function of the gag-IGFR. Our results indicate that tyrosines 1131, 1135, 1136, and 1221 are important for the receptor protein-tyrosine kinase (PTK) activity. However, mutation of Tyr-1136 only slightly affects the kinase activity but dramatically reduces the transforming ability and overall substrate phosphorylation, in particular, annexin II, which is strongly phosphorylated by the gag-IGFR but not by the Phe-1136 mutant. Single mutation of either Tyr-943 or Tyr-950 resulted in significantly reduced phosphorylation of the receptor but not on its PTK activity or transforming ability. Tyr-950 together with its surrounding sequence is involved in mediating the interaction between the gag-IGFR and insulin receptor substrate 1. Our data also suggest that Tyr-1316 is involved in phosphorylation of phospholipase C-gamma, which is, however, not important for cell transforming activity. Overall, our study has identified several tyrosine residues of IGFR important for its PTK activity and substrate interaction. The transforming potential of the gag-IGFR correlates well with its ability to phosphorylate overall cellular substrates and to activate phosphatidylinositol 3-kinase via insulin receptor substrate 1. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA. FAU - Jiang, Y AU - Jiang Y FAU - Chan, J L AU - Chan JL FAU - Zong, C S AU - Zong CS FAU - Wang, L H AU - Wang LH LA - eng GR - CA55054/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Isoenzymes) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 55520-40-6 (Tyrosine) RN - 63-91-2 (Phenylalanine) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 3.1.4.- (phospholipase C gamma) RN - EC 3.1.4.3 (Phospholipase C) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Animals MH - Cell Transformation, Neoplastic/*genetics MH - Chick Embryo MH - Humans MH - Isoenzymes/metabolism MH - Mutagenesis, Site-Directed MH - *Mutation MH - Phenylalanine/genetics MH - Phospholipase C/metabolism MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Protein-Tyrosine Kinase/*metabolism MH - Receptor, IGF Type 1/genetics/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Tyrosine/*genetics EDAT- 1996/01/05 MHDA- 1996/01/05 00:01 PST - ppublish SO - J Biol Chem 1996 Jan 5;271(1):160-7. -------------------------------------------------------------------------------- 264: Melmed S et al. IGF-I receptor signalling: le...[PMID: 8701079] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8701079 OWN - NLM STAT- MEDLINE DA - 19960905 DCOM- 19960905 LR - 20041117 PUBM- Print IS - 0079-9963 VI - 51 DP - 1996 TI - IGF-I receptor signalling: lessons from the somatotroph. PG - 189-215; discussion 215-6 AB - Insulin-like growth factor 1 (IGF-I) is a major feedback regulator of pituitary GH secretion, with defined actions occurring at both the hypothalamus and pituitary. The IGF-I gene is expressed in the anterior pituitary in a GH-dependent manner thus providing for both endocrine-as well as autocrine-mediated GH regulation. In turn, IGF-I selectively and specifically inhibits GH gene transcription and secretion, its attenuating effects on nascent GH mRNA synthesis being demonstrable within 1 h. Binding of IGF-I to its pituitary cell surface receptor is followed by rapid activation of the intrinsic tyrosine kinase activity of the receptor beta-subunit and phosphorylation of insulin receptor substrate 1 (IRS-1). Structure-function studies of the human IGF-I receptor were performed in stable, GH-secreting transfectants expressing either the cDNA encoding the wild-type (WT) human IGF receptor and exhibiting enhanced IGF-I responsiveness, or cDNAs encoding IGF-I receptor mutants and a truncated, kinase-deficient receptor (952STOP). 950Tyr situated on the submembrane receptor domain was found to be critical for transducing the IGF-I signal to the GH gene. IGF-I failed to suppress GH secretion by signalling endogenous rat IGF-I receptors when hybrid receptors were formed with kinase-deficient human receptors and rat hemi-receptors. This dominant negative effect on hormone secretion was also evidenced when mitogenic IGF-I signals were blocked in vitro and in vivo by these hybrid receptors. Using similar doses of IGF-I, the IGF-I receptor cell transfectants also demonstrated ligand-dependent activation of ERKs in pituitary cells. In conclusion, the pituitary IGF-I receptor mediates the negative feedback regulation of GH. Thus, IGF-I receptor mass may determine GH responses to malnutrition, pregnancy, and refeeding. IGF-I receptor mutations may also prove useful to abrogate the growth of IGF-I-dependent tumors. These structure-function studies of the human IGF-I receptor provide mechanistic insights into both metabolic control of the GH axis, as well as target tissue proliferative characteristics. AD - Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine 90048, USA. FAU - Melmed, S AU - Melmed S FAU - Yamashita, S AU - Yamashita S FAU - Yamasaki, H AU - Yamasaki H FAU - Fagin, J AU - Fagin J FAU - Namba, H AU - Namba H FAU - Yamamoto, H AU - Yamamoto H FAU - Weber, M AU - Weber M FAU - Morita, S AU - Morita S FAU - Webster, J AU - Webster J FAU - Prager, D AU - Prager D LA - eng PT - Journal Article PT - Review PL - UNITED STATES TA - Recent Prog Horm Res JID - 0404471 RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9002-72-6 (Growth Hormone) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Animals MH - Female MH - Gene Expression MH - Growth Hormone/genetics/*secretion MH - Humans MH - Insulin-Like Growth Factor I/pharmacology MH - Mutation MH - Pituitary Gland/*metabolism MH - Pregnancy MH - Receptor, IGF Type 1/genetics/*physiology MH - *Signal Transduction MH - Transfection RF - 65 EDAT- 1996/01/01 MHDA- 1996/01/01 00:01 PST - ppublish SO - Recent Prog Horm Res 1996;51:189-215; discussion 215-6. -------------------------------------------------------------------------------- 265: Murata T et al. Receptors for interleukin (IL...[PMID: 8530527] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 8530527 OWN - NLM STAT- MEDLINE DA - 19960130 DCOM- 19960130 LR - 20041217 PUBM- Print IS - 0021-9258 VI - 270 IP - 51 DP - 1995 Dec 22 TI - Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. PG - 30829-36 AB - We have previously reported on the expression of interleukin-4 receptors (IL-4R) on many human epithelial cancer cells; however, the binding characteristics, structure, function, and signal transduction through the IL-4R in cancer cells is not known. IL-4 binding characteristics were determined in human colon carcinoma cell lines by a 125I-IL-4 binding assay, which demonstrated that the HT-29 and WiDr colon cancer cell lines expressed high affinity IL-4R (Kd = 200 pM). Cross-linking experiments revealed a major band of 140 kDa and a broad band at 70 kDa. While the common gamma chain of IL-2R is associated with IL-4R in immune cells and is similar in size to the 70-kDa protein, this chain was not expressed in these colon cancer cells. Interestingly, IL-13, which has many functions similar to IL-4, inhibited 125I-IL-4 binding to both the 140- and 70-kDa molecules. Next, we investigated the mechanism of IL-4-induced signal transduction in colon cancer cells. After stimulation with IL-4, a 170-kDa band was primarily phosphorylated within 1 min of exposure and was identified as insulin receptor substrate-1. In addition, by immunoprecipitation assay, three other phosphorylated bands were identified as JAK1, JAK2, and Tyk2 tyrosine kinases. The phosphorylation of JAK1 and JAK2 was induced by IL-4 stimulation; however, Tyk2 was constitutively phosphorylated, and IL-4 treatment further augmented this phosphorylation. The kinetics and in vitro kinase assays demonstrated that JAK1, JAK2, and Tyk2 were phosphorylated within minutes and that JAK1 and JAK2 were activated after IL-4 exposure. Contrary to observations in immune cells. JAK3 mRNA was neither detected in colon cancer cells nor did IL-4 treatment cause phosphorylation of JAK3. These data indicate that in colon carcinoma cells JAK1, JAK2, Tyk2, and insulin receptor substrate-1 are phosphorylated after IL-4 stimulation. In addition, as is the case in lymphoid cells, IL-4 activated and phosphorylated signal transducers and activators of transcription (IL-4-STAT or STAT-6) protein in both colon cancer cell lines. These results indicate that the IL-4R complex is composed of different subunits in different tissues and shares a component with the IL-13R complex. In addition, we demonstrate for the first time that like its family members (e.g. IL-3 and GM-CSF), IL-4 can phosphorylate and activate JAK-2 kinase. AD - Laboratory of Molecular Tumor Biology, Food and Drug Administration, Bethesda, Maryland 20892, USA. FAU - Murata, T AU - Murata T FAU - Noguchi, P D AU - Noguchi PD FAU - Puri, R K AU - Puri RK LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Antigens, CD) RN - 0 (Iodine Radioisotopes) RN - 0 (Macromolecular Substances) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Receptors, Interleukin) RN - 0 (Receptors, Interleukin-4) RN - 0 (Recombinant Proteins) RN - 0 (Stat6 protein) RN - 0 (Trans-Activators) RN - 207137-56-2 (Interleukin-4) RN - 50-89-5 (Thymidine) RN - EC 2.7.1.112 (Janus kinase 1) RN - EC 2.7.1.112 (Janus kinase 2) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) SB - IM MH - Antigens, CD/chemistry/isolation & purification/*metabolism MH - Cell Line MH - Colonic Neoplasms MH - Comparative Study MH - DNA Replication/drug effects MH - Humans MH - Interleukin-4/metabolism/*pharmacology MH - Iodine Radioisotopes MH - Kinetics MH - Macromolecular Substances MH - Models, Structural MH - Phosphorylation MH - Protein-Tyrosine Kinase/*metabolism MH - *Proto-Oncogene Proteins MH - Radioligand Assay MH - Receptors, Interleukin/chemistry/isolation & purification/*metabolism MH - Receptors, Interleukin-4 MH - Recombinant Proteins/metabolism/pharmacology MH - Substrate Specificity MH - Thymidine/metabolism MH - Trans-Activators/metabolism MH - Tumor Cells, Cultured EDAT- 1995/12/22 MHDA- 1995/12/22 00:01 PST - ppublish SO - J Biol Chem 1995 Dec 22;270(51):30829-36. -------------------------------------------------------------------------------- 266: Wang H et al. Unique and selective mitogeni...[PMID: 8927049] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8927049 OWN - NLM STAT- MEDLINE DA - 19961025 DCOM- 19961025 LR - 20041117 PUBM- Print IS - 0300-8177 VI - 153 IP - 1-2 DP - 1995 Dec 6-20 TI - Unique and selective mitogenic effects of vanadate on SV40-transformed cells. PG - 59-67 AB - Vanadate and insulin both function as unique complete mitogens for SV40-transformed 3T3T cells, designated CSV3-1, but not for nontransformed 3T3T cells. The mitogenic effects induced by vanadate and insulin in CSV3-1 cells are mediated by different signaling mechanisms. For example, vanadate does not stimulate the tyrosine phosphorylation of the insulin receptor beta-subunit nor the 170 kDa insulin receptor substrate-1. Instead, vanadate induces a marked increase in tyrosine phosphorylation of 55 and 64 kDa proteins that is not observed in insulin-stimulated CSV3-1 cells. Perhaps most interestingly, vandate-induced mitogenesis is associated with the selective induction of c-jun and junB expression without significantly inducing c-fos or c-myc. Furthermore, treatment of CSV3-1 cells with genistein abolishes the effects of vanadate on protein tyrosine phosphorylation and c-jun induction. These and related data suggest that modulation of protein tyrosine phosphorylation and c-jun and junB expression may serve the critical roles in mediating vandate-induced mitogenesis in SV40-transformed cells. AD - Department of Pathology, The University of Tennessee College of Medicine, Memphis, Tennessee 38163, USA. FAU - Wang, H AU - Wang H FAU - Scott, R E AU - Scott RE LA - eng GR - CA51715/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - NETHERLANDS TA - Mol Cell Biochem JID - 0364456 RN - 0 (Vanadates) SB - IM MH - 3T3 Cells MH - Animals MH - Cell Division/drug effects MH - Cell Line, Transformed MH - Cell Transformation, Viral MH - Mice MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Simian virus 40 MH - Vanadates/*pharmacology RF - 73 EDAT- 1995/12/06 MHDA- 1995/12/06 00:01 PST - ppublish SO - Mol Cell Biochem 1995 Dec 6-20;153(1-2):59-67. -------------------------------------------------------------------------------- 267: Ish-Shalom D et al. Mitogenic potential of insuli...[PMID: 7486686] Related Articles, Substance via MeSH, Books, LinkOut PMID- 7486686 OWN - NLM STAT- MEDLINE DA - 19951206 DCOM- 19951206 LR - 20041117 PUBM- Print IS - 0077-8923 VI - 766 DP - 1995 Sep 7 TI - Mitogenic potential of insulin on lymphoma cells lacking IGF-1 receptor. PG - 409-15 AB - We have characterized an insulin-dependent T-cell lymphoma, LB, devoid of IGF-I receptor, which undergoes insulin stimulation and cell proliferation both in vitro and in vivo. In these cells, the mitogenic response can be evoked only through binding of insulin to its own receptor. This lymphoma is thus a good model for studying the molecular mechanisms involved in insulin mitogenicity. The high level of activated Ras in LB cells, even under nonproliferative conditions, shows that activation of Ras is insufficient for mitogenicity. It has been suggested earlier that separate pathways of signal transduction may emerge from Ras. The decision to activate a certain signaling pathway may depend on the activation state of other signaling routes in the cell. This may be the case in LB cells, where a signaling component activated by insulin works in concert with the Ras signaling pathway to induce mitogenesis. Yet it is still unclear whether activated Ras is a prerequisite for the insulin-induced response in LB cells. AD - Lautenberg Center for General and Tumor Immunology, Hebrew University, Hadassah Medical School, Jerusalem, Israel. FAU - Ish-Shalom, D AU - Ish-Shalom D FAU - Tzivion, G AU - Tzivion G FAU - Christoffersen, C T AU - Christoffersen CT FAU - Urso, B AU - Urso B FAU - De Meyts, P AU - De Meyts P FAU - Naor, D AU - Naor D LA - eng PT - Journal Article PL - UNITED STATES TA - Ann N Y Acad Sci JID - 7506858 RN - 0 (Antibodies) RN - 0 (Mitogens) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Antibodies/pharmacology MH - Cell Division/drug effects MH - Cell Line MH - Humans MH - Insulin/*pharmacology MH - Kinetics MH - Lymphoma, T-Cell/*pathology MH - Mice MH - Mice, Inbred BALB C MH - Mitogens/*pharmacology MH - Receptor, IGF Type 1/genetics/*physiology MH - Receptor, Insulin/immunology/*physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1995/09/07 MHDA- 1995/09/07 00:01 PST - ppublish SO - Ann N Y Acad Sci 1995 Sep 7;766:409-15. -------------------------------------------------------------------------------- 268: Kosaki A et al. The B isoform of the insulin ...[PMID: 7657666] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7657666 OWN - NLM STAT- MEDLINE DA - 19951004 DCOM- 19951004 LR - 20050310 PUBM- Print IS - 0021-9258 VI - 270 IP - 35 DP - 1995 Sep 1 TI - The B isoform of the insulin receptor signals more efficiently than the A isoform in HepG2 cells. PG - 20816-23 AB - We have demonstrated previously that dexamethasone treatment of HepG2 cells caused an enhancement of insulin's metabolic effects (Kosaki, A., and Webster, N. J. (1993) J. Biol. Chem. 268, 21990-21996). This correlated with increased expression of the mRNA encoding the B isoform of the insulin receptor (IR). In the present study, we have demonstrated that dexamethasone treatment caused in addition an enhancement in insulin-stimulated immediate-early gene expression (c-fos and egr-1). Dexamethasone treatment caused an increase in in vivo IR autophosphorylation and insulin receptor substrate-1 (IRS-1) phosphorylation both early events in the insulin signaling pathway. Furthermore, the IRS-1 phosphorylation was distinctly left shifted, although the level of IRS-1 protein was unchanged. Total cellular tyrosine phosphatase activity was unaltered when assayed with 32P-labeled IR and IRS-1. Studies in vitro on wheat-germ agglutinin-purified receptors showed that the B isoform of the IR had increased kinase activity both toward itself and the exogenous substrates poly.glu4:tyr1 and recombinant IRS-1 protein. In addition, two-dimensional tryptic phosphopeptide maps indicated that the B isoform has an additional phosphopeptide that is not seen for the A isoform. In conclusion, it appears that the B isoform of the IR signals more efficiently than the A isoform in HepG2 cells. AD - Department of Medicine, University of California, San Diego, La Jolla 92093, USA. FAU - Kosaki, A AU - Kosaki A FAU - Pillay, T S AU - Pillay TS FAU - Xu, L AU - Xu L FAU - Webster, N J AU - Webster NJ LA - eng GR - DK44643/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (DNA Primers) RN - 0 (DNA-Binding Proteins) RN - 0 (Immediate-Early Proteins) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins c-fos) RN - 0 (Transcription Factors) RN - 0 (early growth response protein 1) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 50-02-2 (Dexamethasone) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM GS - c-fos GS - egr-1 MH - Base Sequence MH - Comparative Study MH - DNA Primers MH - DNA-Binding Proteins/biosynthesis MH - Dexamethasone/*pharmacology MH - Gene Expression/*drug effects MH - Genes, Immediate-Early/*drug effects MH - Genes, fos MH - Hepatoblastoma MH - Humans MH - *Immediate-Early Proteins MH - Insulin/metabolism/*pharmacology MH - Kinetics MH - Liver Neoplasms MH - Molecular Sequence Data MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Polymerase Chain Reaction MH - Protein-Tyrosine-Phosphatase/metabolism MH - Proto-Oncogene Proteins c-fos/biosynthesis MH - Receptor, Insulin/biosynthesis/metabolism/*physiology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction MH - Transcription Factors/biosynthesis MH - Tumor Cells, Cultured MH - Zinc Fingers EDAT- 1995/09/01 MHDA- 1995/09/01 00:01 PST - ppublish SO - J Biol Chem 1995 Sep 1;270(35):20816-23. -------------------------------------------------------------------------------- 269: Ahmad F et al. Osmotic loading of neutralizi...[PMID: 7544790] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 7544790 OWN - NLM STAT- MEDLINE DA - 19951004 DCOM- 19951004 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 270 IP - 35 DP - 1995 Sep 1 TI - Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. PG - 20503-8 AB - Protein-tyrosine phosphatases (PTPases) have been postulated to balance the steady-state phosphorylation and the activation state of the insulin receptor and its substrate proteins. To explore whether PTP1B, a widely expressed, non-receptor-type PTPase, regulates insulin signaling, we used osmotic shock to load rat KRC-7 hepatoma cells with affinity-purified neutralizing antibodies that immunoprecipitate and inactivate the enzymatic activity of recombinant rat PTP1B in vitro. In cells loaded with PTP1B antibody, insulin-stimulated DNA synthesis and phosphatidylinositol 3'-kinase activity were increased by 42% and 38%, respectively, compared with control cells loaded with preimmune IgG (p < 0.005). In order to characterize the potential site(s) of action of PTP1B in insulin signaling, we also determined that insulin-stimulated receptor autophosphorylation and insulin receptor substrate 1 tyrosine phosphorylation were increased 2.2- and 2.0-fold, respectively, and that insulin-stimulated receptor kinase activity toward an exogenous peptide substrate was increased by 57% in the PTP1B antibody-loaded cells. Osmotic loading did not alter the cellular content of PTP1B protein, suggesting that the antibody acts in the cell by sterically blocking catalytic interactions between PTP1B and its physiological substrates. These studies demonstrate that PTP1B has a role in the negative regulation of insulin signaling and acts, at least in part, directly at the level of the insulin receptor. These results also show that insulin signaling can be enhanced by the inhibition of specific PTPases, a maneuver that has potential clinical relevance in the treatment of insulin resistance and Type II diabetes mellitus. AD - Dorrance H. Hamilton Research Laboratories, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Ahmad, F AU - Ahmad F FAU - Li, P M AU - Li PM FAU - Meyerovitch, J AU - Meyerovitch J FAU - Goldstein, B J AU - Goldstein BJ LA - eng GR - DK43396/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Antibodies) RN - 0 (Immunoglobulin G) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.1.3.48 (Protein-Tyrosine-Phosphatase) SB - IM MH - Animals MH - Antibodies/isolation & purification/*pharmacology MH - Antibody Specificity MH - Cell Line MH - Immunoblotting MH - Immunoglobulin G/isolation & purification/pharmacology MH - Insulin/pharmacology MH - Kinetics MH - Liver Neoplasms, Experimental MH - Phosphotyrosine MH - Protein-Tyrosine-Phosphatase/*immunology/*metabolism MH - Rabbits/immunology MH - Rats MH - Receptor, Insulin/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Tyrosine/analogs & derivatives/analysis/metabolism EDAT- 1995/09/01 MHDA- 1995/09/01 00:01 PST - ppublish SO - J Biol Chem 1995 Sep 1;270(35):20503-8. -------------------------------------------------------------------------------- 270: Coffer PJ et al. UV activation of receptor tyr...[PMID: 7543196] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7543196 OWN - NLM STAT- MEDLINE DA - 19950906 DCOM- 19950906 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 11 IP - 3 DP - 1995 Aug 3 TI - UV activation of receptor tyrosine kinase activity. PG - 561-9 AB - The exposure of mammalian cells to ultraviolet radiation (UV) may lead to DNA damage resulting in mutation and thus possibly cancer, while irradiation can further act as a potent tumor promoter. In addition UV induces p21ras-mediated signalling leading to activation of transcription factors such as AP-1 and NF-kappa B, as well as activation of the Src tyrosine kinase. This 'UV-response' has been well studied in mammalian cells and furthermore is conserved in yeast, however the most upstream components of this signal transduction pathway have remained elusive. Here we show that UV rapidly activates both the EGF receptor and insulin receptor, as shown by tyrosine phosphorylation of these receptors. We demonstrate that this activation is due to autophosphorylation as it only occurs in cells containing receptors with a functional kinase domain. We have further analysed the propagation of the UV-induced signal to downstream events such as, IRS-1 and Shc tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, leukotriene synthesis, MAP kinase activation and gene induction all of which are activated by UV irradiation. Importantly, we demonstrate that in cells expressing a 'kinase-dead' receptor mutant the UV-response is inhibited, blocking leukotriene synthesis, MAP kinase activation and transcriptional induction. Furthermore, prior-stimulation of cells with UV appears to reduce further responsiveness to addition of growth factor suggesting a common signaling pathway. These data demonstrate a critical role for receptor-mediated events in regulating the response mammalian cells to UV exposure. AD - Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht. FAU - Coffer, P J AU - Coffer PJ FAU - Burgering, B M AU - Burgering BM FAU - Peppelenbosch, M P AU - Peppelenbosch MP FAU - Bos, J L AU - Bos JL FAU - Kruijer, W AU - Kruijer W LA - eng PT - Journal Article PL - ENGLAND TA - Oncogene JID - 8711562 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Src homology 2 domain-containing, transforming protein 1) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (Proto-Oncogene Proteins c-raf) SB - IM MH - 3T3 Cells MH - *Adaptor Proteins, Signal Transducing MH - *Adaptor Proteins, Vesicular Transport MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Epidermal Growth Factor/pharmacology MH - Insulin/pharmacology MH - Mice MH - Mitogen-Activated Protein Kinase 1 MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotyrosine MH - Protein-Serine-Threonine Kinases/metabolism MH - Proteins/metabolism MH - Proto-Oncogene Proteins/metabolism MH - Proto-Oncogene Proteins c-raf MH - Receptor, Epidermal Growth Factor/metabolism/*radiation effects MH - Receptor, Insulin/metabolism/*radiation effects MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/radiation effects MH - Tyrosine/analogs & derivatives/metabolism MH - Ultraviolet Rays EDAT- 1995/08/03 MHDA- 1995/08/03 00:01 PST - ppublish SO - Oncogene 1995 Aug 3;11(3):561-9. -------------------------------------------------------------------------------- 271: Fei ZL et al. Association of insulin recept...[PMID: 7542742] Related Articles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 7542742 OWN - NLM STAT- MEDLINE DA - 19950829 DCOM- 19950829 LR - 20041117 PUBM- Print IS - 0270-7306 VI - 15 IP - 8 DP - 1995 Aug TI - Association of insulin receptor substrate 1 with simian virus 40 large T antigen. PG - 4232-39 AB - Mouse embryo cells expressing a wild-type number of insulin-like growth factor I receptors (IGF-IR) (W cells) can be transformed either by simian virus 40 large T antigen (SV40 T) or by overexpressed insulin receptor substrate 1 (IRS-1), singly transfected. Neither SV40 T antigen nor IRS-1, individually, can transform mouse embryo cells with a targeted disruption of the IGF-IR genes (R- cells). However, cotransfection of SV40 T antigen and IRS-1 does transform R- cells. In this study, using different antibodies and different cell lines, we found that SV40 T antigen and IRS-1 are coprecipitated from cell lysates in a specific fashion, regardless of whether the lysates are immunoprecipitated with an antibody to SV40 T antigen or an antibody to IRS-1. The same antibody to SV40 T antigen, however, fails to coprecipitate another substrate of IGF-IR, the transforming protein Shc, and two other signal-transducing molecules, Grb2 and Sos. Finally, an SV40 T antigen lacking the amino-terminal 250 amino acids fails to coprecipitate IRS-1 and also fails to transform R- cells overexpressing mouse IRS-1. These experiments indicate that IRS-1 associates with SV40 T antigen and that this association plays a critical role in the combined ability of these proteins to transform R- cells. This finding is discussed in light of the crucial role of the IGF-IR in the establishment and maintenance of the transformed phenotype. AD - Jefferson Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - Fei, Z L AU - Fei ZL FAU - D'Ambrosio, C AU - D'Ambrosio C FAU - Li, S AU - Li S FAU - Surmacz, E AU - Surmacz E FAU - Baserga, R AU - Baserga R LA - eng GR - CA 53484/CA/NCI GR - GM 33694/GM/NIGMS PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Antigens, Viral, Tumor) RN - 0 (Peptide Fragments) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - EC 2.7.1.112 (Proto-Oncogene Protein pp60(c-src)) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - 3T3 Cells MH - Animals MH - Antigens, Viral, Tumor/genetics/*metabolism MH - *Cell Transformation, Neoplastic MH - Mice MH - Mice, Inbred BALB C MH - Peptide Fragments/metabolism MH - Phosphoproteins/immunology/*metabolism MH - Precipitin Tests MH - Protein Binding MH - Proto-Oncogene Protein pp60(c-src)/genetics MH - Receptor, IGF Type 1/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Homology MH - Signal Transduction MH - Simian virus 40/*immunology EDAT- 1995/08/01 MHDA- 1995/08/01 00:01 PST - ppublish SO - Mol Cell Biol 1995 Aug;15(8):4232-39. -------------------------------------------------------------------------------- 272: Sepp-Lorenzino L et al. Herbimycin A induces the 20 S...[PMID: 7622464] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Cited in Books, Books, LinkOut PMID- 7622464 OWN - NLM STAT- MEDLINE DA - 19950825 DCOM- 19950825 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 270 IP - 28 DP - 1995 Jul 14 TI - Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. PG - 16580-7 AB - Herbimycin A is an ansamycin antibiotic isolated as an agent that reverses morphological transformation induced by v-src. Although herbimycin A is widely used as a tool for inhibiting multiple tyrosine protein kinases and tyrosine kinase-activated signal transduction, its mechanism of action is not well defined and includes a decrease in both tyrosine kinase protein levels and activity (Uehara, Y., Murakami, Y., Sugimoto, Y., and Mizuno, S. (1989) Cancer Res. 49, 780-785). We now show that herbimycin A induces a profound decrease in the total cellular activity of transmembrane tyrosine kinase receptors, such as insulin-like growth factor, insulin, and epidermal growth factor receptors. A substantial proportion of the in vivo inhibition could be explained by an increase in the rate of degradation. The enhanced degradation of insulin-like growth factor-insulin receptor was prevented by inhibitors of the 20S proteasome, whereas neither lysosomotropic agents nor general serine- and cysteine-protease inhibitors were active in preventing receptor degradation induced by herbimycin A. Moreover, in a temperature-sensitive mutant cell line defective in the E1-catalyzed activation of ubiquitin, herbimycin A treatment at the restrictive temperature did not result in the degradation of insulin receptor. These results suggest that herbimycin A represents a novel class of drug that targets the degradation of tyrosine kinases by the 20S proteasome. The ubiquitin dependence of this process indicates that this degradation of tyrosine kinases might involve the 20S proteasome as the proteolytic core of the ubiquitin-dependent 26S protease. AD - Cell Biology and Genetics Program, New York, New York 10021, USA. FAU - Sepp-Lorenzino, L AU - Sepp-Lorenzino L FAU - Ma, Z AU - Ma Z FAU - Lebwohl, D E AU - Lebwohl DE FAU - Vinitsky, A AU - Vinitsky A FAU - Rosen, N AU - Rosen N LA - eng GR - CA 58706-01/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Multienzyme Complexes) RN - 0 (Quinones) RN - 0 (Ubiquitins) RN - 70563-58-5 (herbimycin) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 3.4.22 (Cysteine Endopeptidases) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - Amino Acid Sequence MH - Cysteine Endopeptidases/*physiology MH - Dose-Response Relationship, Drug MH - Humans MH - Molecular Sequence Data MH - Multienzyme Complexes/*physiology MH - Proteasome Endopeptidase Complex MH - Protein-Tyrosine Kinase/*antagonists & inhibitors MH - Quinones/*pharmacology MH - Receptor Protein-Tyrosine Kinases/*metabolism MH - Receptor, IGF Type 1/antagonists & inhibitors MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - Ubiquitins/*physiology EDAT- 1995/07/14 MHDA- 1995/07/14 00:01 PST - ppublish SO - J Biol Chem 1995 Jul 14;270(28):16580-7. -------------------------------------------------------------------------------- 273: Lin YL et al. Differential pathways of insu...[PMID: 7789317] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7789317 OWN - NLM STAT- MEDLINE DA - 19950721 DCOM- 19950721 LR - 20050310 PUBM- Print IS - 0013-7227 VI - 136 IP - 7 DP - 1995 Jul TI - Differential pathways of insulin action upon the hepatitis B surface antigen gene expression and cell proliferation in human hepatoma cells. PG - 2922-7 AB - We have shown previously that insulin at the physiological concentration suppresses hepatitis B surface antigen (HBsAg) gene expression in cultured human hepatoma Hep3B cells, and this suppression phenomenon is concomitant with the stimulation of cell proliferation. We have now examined whether these two distinct insulin actions on the Hep3B cells are mediated through the same or different signaling pathways. After prolonged treatment with high concentration of tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA), the protein kinase C-alpha (PKC-alpha) level in the Hep3B cells was diminished and could not be detected by Western blot analysis. Under this condition, TPA treatment has no effect on the number or affinity of the insulin receptor on Hep3B cells. However, insulin-stimulated cell proliferation was completely abolished in the PKC-alpha depleted cells. In contrast, insulin still suppressed HBsAg gene expression with the same ED50 (approximately 0.5 nM) as the control cell. The induction of proto-oncogene egr-1 (early-growth-regulatory-1) by insulin and TPA under similar conditions were also examined. Both insulin and TPA stimulated egr-1 gene expression up to 10-fold in the control cell, but neither of these two agents showed any effect on egr-1 gene expression in the PKC-alpha down-regulated Hep3B cells. These observations indicate that the PKC-alpha may be involved in the insulin induced egr-1 expression and cell proliferation but not in the insulin suppressed HBsAg gene expression in human hepatoma cells. AD - Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan, Republic of China. FAU - Lin, Y L AU - Lin YL FAU - Chen, H C AU - Chen HC FAU - Yeh, S F AU - Yeh SF FAU - Chou, C K AU - Chou CK LA - eng PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (DNA-Binding Proteins) RN - 0 (Hepatitis B Surface Antigens) RN - 0 (Immediate-Early Proteins) RN - 0 (Isoenzymes) RN - 0 (Transcription Factors) RN - 0 (early growth response protein 1) RN - 11061-68-0 (Insulin) RN - 16561-29-8 (Tetradecanoylphorbol Acetate) RN - EC 2.7.1.37 (Protein Kinase C) SB - AIM SB - IM MH - Carcinoma, Hepatocellular/pathology/*virology MH - Cell Division/*drug effects MH - Comparative Study MH - DNA-Binding Proteins/genetics MH - Gene Expression/*drug effects MH - Hepatitis B Surface Antigens/*genetics MH - Humans MH - *Immediate-Early Proteins MH - Insulin/*pharmacology MH - Isoenzymes/metabolism MH - Liver Neoplasms/pathology/*virology MH - Protein Kinase C/metabolism MH - Research Support, Non-U.S. Gov't MH - Tetradecanoylphorbol Acetate/pharmacology MH - Transcription Factors/genetics MH - Tumor Cells, Cultured EDAT- 1995/07/01 MHDA- 1995/07/01 00:01 PST - ppublish SO - Endocrinology 1995 Jul;136(7):2922-7. -------------------------------------------------------------------------------- 274: Scott G et al. pp125FAK in human melanocytes...[PMID: 7543052] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7543052 OWN - NLM STAT- MEDLINE DA - 19950901 DCOM- 19950901 LR - 20050209 PUBM- Print IS - 0014-4827 VI - 219 IP - 1 DP - 1995 Jul TI - pp125FAK in human melanocytes and melanoma: expression and phosphorylation. PG - 197-203 AB - Focal adhesion kinase (pp125FAK) is a nonreceptor tyrosine kinase which colocalizes with integrins to focal contacts, sites where multiple proteins interact to regulate the assembly of the actin cytoskeleton. Autophosphorylation and activation of pp125FAK occur after integrin clustering or cell adhesion to ligands through cognate integrin receptors and are postulated to mediate integrin signaling events. In this report we examined pp125FAK expression and phosphorylation in normal human melanocytes, an adherent human metastatic melanoma cell line (SKMEL28), and a nonadherent human metastatic melanoma cell line (SKMEL1). We show that SKMEL28 cells express constitutively phosphorylated pp125FAK and that pp125FAK phosphorylation in melanocytes is induced by phorbol esters and growth factors present in melanocyte growth medium. Focal adhesion kinase phosphorylation could be enhanced by b1 integrin-activating antibodies in human melanocytes, but not in SKMEL28 cells. In contrast with SKMEL28 cells, constitutive phosphorylation of pp125FAK was not observed in SKMEL1 cells, and incubation with activating b1 integrin antibodies had no effect on pp125FAK phosphorylation. Absence of pp125FAK phosphorylation in SKMEL1 cells was not due to lack of expression of pp125FAK, as shown by immunoprecipitation of the pp125FAK protein from cell lysates. However, b1 integrin expression was significantly less in SKMEL1 cells than in human melanocytes and SKMEL28 cells. This study further supports the importance of integrins in pp125FAK-mediated signaling and indicates that transformation-related changes in pp125FAK phosphorylation exist in human melanocytes and melanoma cells. AD - Department of Dermatology, University of Rochester School of Medicine and Dentistry, New York 14642, USA. FAU - Scott, G AU - Scott G FAU - Liang, H AU - Liang H LA - eng GR - AR-01882-01/AR/NIAMS PT - Journal Article PL - UNITED STATES TA - Exp Cell Res JID - 0373226 RN - 0 (Antibodies) RN - 0 (Antigens, CD29) RN - 0 (Cell Adhesion Molecules) RN - 0 (Integrins) RN - 0 (Macromolecular Substances) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - Antibodies/pharmacology MH - Antigens, CD29 MH - Blotting, Western MH - Cell Adhesion Molecules/biosynthesis/isolation & purification/*metabolism MH - Cell Line MH - Comparative Study MH - Electrophoresis, Polyacrylamide Gel MH - *Gene Expression MH - Humans MH - Integrins/immunology/physiology MH - Macromolecular Substances MH - Melanocytes/*metabolism MH - Melanoma/*metabolism MH - Phosphorylation MH - Phosphotyrosine MH - Protein-Tyrosine Kinase/biosynthesis/isolation & purification/*metabolism MH - Receptor, Insulin/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - Tyrosine/analogs & derivatives/analysis EDAT- 1995/07/01 MHDA- 1995/07/01 00:01 AID - S0014482785712190 [pii] PST - ppublish SO - Exp Cell Res 1995 Jul;219(1):197-203. -------------------------------------------------------------------------------- 275: Milarski KL et al. Detection of a 60 kDa tyrosin...[PMID: 7539611] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7539611 OWN - NLM STAT- MEDLINE DA - 19950705 DCOM- 19950705 LR - 20031114 PUBM- Print IS - 0264-6021 VI - 308 ( Pt 2) DP - 1995 Jun 1 TI - Detection of a 60 kDa tyrosine-phosphorylated protein in insulin-stimulated hepatoma cells that associates with the SH2 domain of phosphatidylinositol 3-kinase. PG - 579-83 AB - Activation of the tyrosine kinase activity of the insulin receptor by autophosphorylation leads to phosphorylation of cellular substrates on tyrosine. Thus far, the best characterized is the insulin receptor substrate (IRS) 1, which has been proposed to serve as a docking protein for other molecules involved in signal transduction. A number of other proteins that become phosphorylated in response to insulin have been identified, some of which are reported to be tissue-specific. A 60 kDa phosphoprotein has been detected in adipocytes after insulin stimulation [Lavan and Lienhard (1993) J. Biol. Chem. 268, 5921-5928]. We have identified a protein of similar molecular mass in rat hepatoma cells transfected with the human insulin receptor. The 60 kDa protein in hepatoma cells is tyrosine-phosphorylated in response to insulin in a dose-dependent manner, with maximal phosphorylation occurring at 50 nM insulin. Although the dose-response of p60 phosphorylation mirrors that of IRS-1, the time course is slightly slower, with maximal phosphorylation observed 5 min after addition of insulin. Like the adipocyte protein, the 60 kDa protein detected in liver cells binds to the SH2 domain of the p85 regulatory subunit of phosphatidylinositol 3-kinase, but not to other SH2 domains. Binding of p60 to p85 is similar to the interaction between p85 and IRS-1 in that a tyrosine-phosphorylated peptide containing the YVXM motif can inhibit the association. The presence of this 60 kDa tyrosine-phosphorylated protein in adipocytes and hepatoma cells suggests that it represents another important intermediate in the insulin-receptor signal-transduction pathway. AD - Department of Signal Transduction, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, MI 48105, USA. FAU - Milarski, K L AU - Milarski KL FAU - Lazar, D F AU - Lazar DF FAU - Wiese, R J AU - Wiese RJ FAU - Saltiel, A R AU - Saltiel AR LA - eng PT - Journal Article PL - ENGLAND TA - Biochem J JID - 2984726R RN - 0 (Peptides) RN - 0 (Phosphoproteins) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Amino Acid Sequence MH - Animals MH - Cells, Cultured MH - Insulin/*pharmacology MH - Liver/*metabolism MH - Liver Neoplasms, Experimental/metabolism MH - Molecular Sequence Data MH - Molecular Weight MH - Peptides/chemistry MH - Phosphoproteins/chemistry/*metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - Phosphotyrosine MH - Protein Binding MH - Rats MH - Receptor, Insulin/*metabolism MH - Signal Transduction MH - Tyrosine/analogs & derivatives/metabolism EDAT- 1995/06/01 MHDA- 1995/06/01 00:01 PST - ppublish SO - Biochem J 1995 Jun 1;308 ( Pt 2):579-83. -------------------------------------------------------------------------------- 276: Welham MJ et al. Interleukin-13 signal transdu...[PMID: 7744881] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7744881 OWN - NLM STAT- MEDLINE DA - 19950612 DCOM- 19950612 LR - 20050126 PUBM- Print IS - 0021-9258 VI - 270 IP - 20 DP - 1995 May 19 TI - Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. PG - 12286-96 AB - Interleukin-13 (IL-13) and interleukin-4 (IL-4) are related in structure and function and are thought to share a common receptor component. We have investigated the signal transduction pathways activated by these two growth factors, as well as insulin, in cell-lines and primary cells of lymphohemopoietic origin. All three factors induced the tyrosine phosphorylation of a protein of 170 kDa (p170), which coimmunoprecipitated with the p85 subunit of P13'-kinase, via high affinity interactions mediated by the SH2 domains of p85. Antibodies raised against the entire insulin-receptor substrate-1 (IRS-1) protein immunoprecipitated p170 much less efficiently than they did IRS-1 from 3T3 cells. However, antibodies directed against the conserved pleckstrin homology domain of IRS-1 immunoprecipitated both p170 and IRS-1 with similar efficiency, suggesting they share structural similarities in this region. In lymphohemopoietic cells, IL-13, IL-4, and insulin failed to induce increased tyrosine phosphorylation of Shc, or its association with grb2, modification of Sos1, or activation of erk-1 and erk-2 mitogen-activated protein kinases, suggesting that p170 mediates downstream pathways distinct from those mediated by IRS-1. Both IL-13 and IL-4 induced low levels of tyrosine phosphorylation of Tyk-2 and Jak-1. IL-4 also activated the Jak-3-kinase, but, despite other similarities, IL-13 did not. Insulin failed to activate any of the known members of the Janus family of kinases. In that Jak-3 is reported to associate with the IL-2 gamma c chain, these data suggest that the IL-13 receptor does not utilize this subunit. However, both IL-13 and IL-4 induced tyrosine phosphorylation of the IL-4-140 kDa receptor chain, suggesting that this is a component of both receptors in these cells and accounts for the similarities in signaling pathways shared by IL-13 and IL-4. AD - Biomedical Research Centre, University of British Columbia, Vancouver, Canada. FAU - Welham, M J AU - Welham MJ FAU - Learmonth, L AU - Learmonth L FAU - Bone, H AU - Bone H FAU - Schrader, J W AU - Schrader JW LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Interleukin-13) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Receptors, Interleukin) RN - 0 (Receptors, Interleukin-4) RN - 0 (Recombinant Fusion Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (interleukin-13 receptor) RN - 11061-68-0 (Insulin) RN - 207137-56-2 (Interleukin-4) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Janus kinase 1) RN - EC 2.7.1.112 (Janus kinase 3) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - 3T3 Cells/metabolism MH - *Adaptor Proteins, Signal Transducing MH - Animals MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cells, Cultured MH - Hematopoietic Stem Cells/*drug effects/physiology MH - Humans MH - Insulin/pharmacology MH - Interleukin-13/*pharmacology MH - Interleukin-4/pharmacology MH - Leukemia, Erythroblastic, Acute/pathology MH - Lymphocyte Subsets/drug effects/physiology MH - Mice MH - Mitogen-Activated Protein Kinase 1 MH - Mitogen-Activated Protein Kinase 3 MH - *Mitogen-Activated Protein Kinases MH - Phosphoproteins/immunology/metabolism/physiology MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/metabolism MH - Plasmacytoma/pathology MH - Protein Processing, Post-Translational/*drug effects MH - Protein-Serine-Threonine Kinases/metabolism MH - Protein-Tyrosine Kinase/metabolism MH - Proteins/genetics/metabolism MH - Receptors, Interleukin/drug effects/physiology MH - Receptors, Interleukin-4 MH - Recombinant Fusion Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*drug effects MH - Tumor Cells, Cultured EDAT- 1995/05/19 MHDA- 1995/05/19 00:01 PST - ppublish SO - J Biol Chem 1995 May 19;270(20):12286-96. -------------------------------------------------------------------------------- 277: D'Ambrosio C et al. Transforming potential of the...[PMID: 7647039] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7647039 OWN - NLM STAT- MEDLINE DA - 19950925 DCOM- 19950925 LR - 20041117 PUBM- Print IS - 1044-9523 VI - 6 IP - 5 DP - 1995 May TI - Transforming potential of the insulin receptor substrate 1. PG - 557-62 AB - The role of the insulin receptor substrate 1 (IRS-1) in cellular transformation was studied in R- cells, which are 3T3-like fibroblasts derived from mouse embryos with a targeted disruption of the insulin-like growth factor I receptor gene. These cells cannot be transformed by oncogenes that readily transform cells originating from wild-type littermate embryos (or other 3T3-like cells). In the present study, we demonstrate that in R- cells, the overexpression of the functional IRS-1 protein was sufficient to induce a mitogenic response to insulin but did not promote transformation, as measured by colony formation in soft agar. The coexpression of IRS-1 and the SV40 T antigen, however, induced transformation. Conversely, expression of an antisense IRS-1 RNA reversed the transformed phenotype in wild-type cells carrying the T antigen. Since the type 1 insulin-like growth factor receptor, by itself, is fully transforming, we propose the hypothesis that the transforming competence of this receptor is based on at least two signaling pathways, one of which is IRS-1-dependent, whereas the other(s) can be substituted with the SV40 T antigen. AD - Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. FAU - D'Ambrosio, C AU - D'Ambrosio C FAU - Keller, S R AU - Keller SR FAU - Morrione, A AU - Morrione A FAU - Lienhard, G E AU - Lienhard GE FAU - Baserga, R AU - Baserga R FAU - Surmacz, E AU - Surmacz E LA - eng GR - CA 53484/CA/NCI GR - DK 42816/DK/NIDDK GR - GM 33694/GM/NIGMS PT - Journal Article PL - UNITED STATES TA - Cell Growth Differ JID - 9100024 RN - 0 (Antigens, Polyomavirus Transforming) RN - 0 (Phosphoproteins) RN - 0 (RNA, Antisense) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) SB - IM MH - Animals MH - Antigens, Polyomavirus Transforming/biosynthesis/genetics MH - Blotting, Western MH - Cell Division/drug effects MH - Cell Transformation, Neoplastic/*drug effects MH - Cells, Cultured MH - Humans MH - Insulin/pharmacology MH - Insulin-Like Growth Factor I/pharmacology MH - Mice MH - Phenotype MH - Phosphoproteins/*biosynthesis/genetics MH - RNA, Antisense/biosynthesis/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/genetics MH - Trans-Activation (Genetics)/*drug effects EDAT- 1995/05/01 MHDA- 1995/05/01 00:01 PST - ppublish SO - Cell Growth Differ 1995 May;6(5):557-62. -------------------------------------------------------------------------------- 278: Sanchez-Margalet V et al. Role of p85 subunit of phosph...[PMID: 7659087] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7659087 OWN - NLM STAT- MEDLINE DA - 19951002 DCOM- 19951002 LR - 20041117 PUBM- Print IS - 0888-8809 VI - 9 IP - 4 DP - 1995 Apr TI - Role of p85 subunit of phosphatidylinositol-3-kinase as an adaptor molecule linking the insulin receptor to insulin receptor substrate 1. PG - 435-42 AB - After insulin stimulation of cells, signaling complexes are formed, containing the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and phosphatidylinositol-3-kinase. To study the nature of these complexes, we employed purified IR, recombinant IRS-1, antibodies to IR and IRS-1, and fusion proteins containing the two SH2 domains of p85. In intact cells, insulin increased tyrosine phosphorylation of both the IR and IRS-1. Both of these proteins were immunoprecipitated with antibodies to p85. Also, fusion proteins containing the two SH2 domains of p85 directly precipitated both the IR and IRS-1. Next, these signaling complexes were reconstituted in vitro with purified IR, recombinant IRS-1, and the two SH2 domains of p85. In the presence of both SH2 domains of p85, the IR associated with IRS-1. Other data, both in intact cells and in vitro, demonstrated that N- and C-terminal SH2 domains of p85 had preferential binding affinities for the IR and IRS-1, respectively. Studies with an IR mutant truncated in the C terminus indicated that the C-terminal phosphotyrosines of the IR play a major role in interacting with the SH2 domains of p85. In conclusion, both in vivo and in vitro data support a role for p85 in directly linking the IR to IRS-1 via its SH2 domains. The formation of these complexes, therefore, may provide a mechanism for the translocation to the plasma membrane of phosphatidylinositol-3-kinase and other molecules that are involved in IR signaling. AD - Department of Medicine, Mount Zion Medical Center/University of California, San Francisco 94115, USA. FAU - Sanchez-Margalet, V AU - Sanchez-Margalet V FAU - Goldfine, I D AU - Goldfine ID FAU - Truitt, K AU - Truitt K FAU - Imboden, J AU - Imboden J FAU - Sung, C K AU - Sung CK LA - eng GR - DK-44884/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Carrier Proteins) RN - 0 (DNA, Complementary) RN - 0 (Macromolecular Substances) RN - 0 (Phosphoproteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (maltose-binding protein) RN - 11061-68-0 (Insulin) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Animals MH - Carrier Proteins/genetics MH - Chromatography, Affinity MH - DNA, Complementary/genetics MH - Humans MH - Insulin/metabolism MH - Liver Neoplasms, Experimental/pathology MH - Macromolecular Substances MH - Mice MH - Phosphoproteins/*chemistry MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/chemistry/genetics/*physiology MH - Protein Conformation MH - Protein Processing, Post-Translational MH - *Protein Structure, Tertiary MH - Rats MH - Receptor, Insulin/*chemistry MH - Recombinant Fusion Proteins/chemistry/isolation & purification MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction MH - Tumor Cells, Cultured EDAT- 1995/04/01 MHDA- 1995/04/01 00:01 PST - ppublish SO - Mol Endocrinol 1995 Apr;9(4):435-42. -------------------------------------------------------------------------------- 279: Bhavani K et al. Effect of ethanol on p36 prot...[PMID: 7542850] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7542850 OWN - NLM STAT- MEDLINE DA - 19950829 DCOM- 19950829 LR - 20041117 PUBM- Print IS - 0145-6008 VI - 19 IP - 2 DP - 1995 Apr TI - Effect of ethanol on p36 protein kinase substrate and insulin receptor substrate 1 expression and tyrosyl phosphorylation in human hepatocellular carcinoma cells. PG - 441-6 AB - Ethanol inhibits insulin (IN) and epidermal growth factor (EGF)-induced hepatocyte DNA synthesis. Growth factor receptor kinases, such as IN and EGF, phosphorylate insulin receptor substrate (IRS-1) and p36 protein kinase substrate, respectively, on tyrosine residues. IRS-1 and p36 are thought to be important intracellular signal transduction molecules involved in the regulation of cell growth. These investigations explored the effect of ethanol additions on the expression and tyrosyl phosphorylation (TP) of p36 and IRS-1 in a human hepatocellular carcinoma cell line (FOCUS) in relationship to cell proliferation induced by IN and serum growth factor stimulation. It was found that p36 was constitutively and highly expressed in serum-starved cells and protein, and mRNA levels did not change with cell proliferation induced by growth factors. However, exposure of FOCUS cells to ethanol additions substantially inhibited TP of p36. The early TP of IRS-1 induced by IN stimulation was also reduced by ethanol additions. Finally, there was a parallel decrease of FOCUS cell proliferation in ethanol-exposed cultures. These studies suggest that one possible mechanism of ethanol inhibitory effect on cell proliferation is through reduced TP of putative intracellular signal transduction molecules, such as p36 and IRS-1. AD - Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, USA. FAU - Bhavani, K AU - Bhavani K FAU - de la Monte, S AU - de la Monte S FAU - Brown, N V AU - Brown NV FAU - Xu, Y Y AU - Xu YY FAU - Sasaki, Y AU - Sasaki Y FAU - Wands, J R AU - Wands JR LA - eng GR - AA-01864/AA/NIAAA GR - AA-02666/AA/NIAAA GR - CA-35711/CA/NCI GR - etc. PT - Journal Article PL - UNITED STATES TA - Alcohol Clin Exp Res JID - 7707242 RN - 0 (Annexin A2) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 0 (insulin receptor substrate-1 protein) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 64-17-5 (Ethanol) SB - IM MH - Annexin A2/*genetics MH - Carcinoma, Hepatocellular MH - Cell Division/drug effects MH - Cell Line MH - DNA Replication/drug effects MH - Ethanol/*pharmacology MH - Gene Expression Regulation, Enzymologic/drug effects MH - Humans MH - Liver Neoplasms MH - Phosphoproteins/*genetics MH - Phosphorylation MH - Phosphotyrosine MH - RNA, Messenger/genetics MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/genetics MH - Tumor Cells, Cultured/*drug effects MH - Tyrosine/*analogs & derivatives/metabolism EDAT- 1995/04/01 MHDA- 1995/04/01 00:01 PST - ppublish SO - Alcohol Clin Exp Res 1995 Apr;19(2):441-6. -------------------------------------------------------------------------------- 280: Uddin S et al. Insulin-dependent tyrosine ph...[PMID: 7535775] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 7535775 OWN - NLM STAT- MEDLINE DA - 19950510 DCOM- 19950510 LR - 20050223 PUBM- Print IS - 0021-9258 VI - 270 IP - 13 DP - 1995 Mar 31 TI - Insulin-dependent tyrosine phosphorylation of the vav protooncogene product in cells of hematopoietic origin. PG - 7712-6 AB - Insulin activates the ras signaling pathway and promotes hematopoietic cell proliferation. One possible mediator in such signaling is the vav proto-oncogene product (p95vav), which is specifically expressed in cells of hematopoietic origin and contains domains typical of guanine nucleotide exchange factors as well as Src homology 2 and Src homology 3 domains. We studied the tyrosine phosphorylation of p95vav in hematopoietic cells expressing insulin receptors. Immunoblotting experiments with an antiphosphotyrosine monoclonal antibody disclosed that insulin induces rapid and transient tyrosine phosphorylation of p95vav in the human U-266 myeloma cell line. These findings were confirmed by immunoprecipitation experiments performed with 32P-labeled cells and phosphoamino acid analysis of the bands corresponding to p95vav. Similarly, insulin-dependent tyrosine phosphorylation of p95vav was observed in the human IM-9 and mouse J558L hematopoietic cell lines. Furthermore, insulin treatment of cells led to the association of the Src homology 2 domain of p95vav with the activated beta-subunit of the insulin receptor in vitro. Altogether, these data suggest that p95vav is a substrate for the insulin receptor tyrosine kinase and may be involved in an insulin signaling pathway linking receptor-generated signals to Ras or other GTP-binding proteins in cells of hematopoietic origin. AD - Division of Hematology-Oncology, Loyola University of Chicago, Maywood, Illinois 60153, USA. FAU - Uddin, S AU - Uddin S FAU - Katzav, S AU - Katzav S FAU - White, M F AU - White MF FAU - Platanias, L C AU - Platanias LC LA - eng GR - DK-38712/DK/NIDDK GR - DK-43808/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Cell Cycle Proteins) RN - 0 (Phosphates) RN - 0 (Phosphorus Radioisotopes) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (proto-oncogene protein c-vav) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 56-65-5 (Adenosine Triphosphate) RN - EC 2.5.1.18 (Glutathione Transferase) RN - EC 2.7.1.37 (Protein Kinases) SB - IM GS - vav MH - Adenosine Triphosphate/metabolism MH - *Cell Cycle Proteins MH - Cell Line MH - Glutathione Transferase/biosynthesis MH - Humans MH - Insulin/*pharmacology MH - Multiple Myeloma MH - Phosphates/metabolism MH - Phosphorus Radioisotopes MH - Phosphorylation MH - Phosphotyrosine MH - Protein Kinases/metabolism MH - Proto-Oncogene Proteins/biosynthesis/isolation & purification/*metabolism MH - *Proto-Oncogenes MH - Recombinant Fusion Proteins/biosynthesis/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured MH - Tyrosine/*analogs & derivatives/analysis/metabolism EDAT- 1995/03/31 MHDA- 1995/03/31 00:01 PST - ppublish SO - J Biol Chem 1995 Mar 31;270(13):7712-6. -------------------------------------------------------------------------------- 281: Buchdunger E et al. Selective inhibition of the p...[PMID: 7708684] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 7708684 OWN - NLM STAT- MEDLINE DA - 19950511 DCOM- 19950511 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 92 IP - 7 DP - 1995 Mar 28 TI - Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. PG - 2558-62 AB - The platelet-derived growth factor (PDGF) receptor is a member of the transmembrane growth factor receptor protein family with intrinsic protein-tyrosine kinase activity. We describe a potent protein-tyrosine kinase inhibitor (CGP 53716) that shows selectivity for the PDGF receptor in vitro and in the cell. The compound shows selectivity for inhibition of PDGF-mediated events such as PDGF receptor autophosphorylation, cellular tyrosine phosphorylation, and c-fos mRNA induction in response to PDGF stimulation of intact cells. In contrast, ligand-induced autophosphorylation of the epidermal growth factor (EGF) receptor, insulin receptor, and the insulin-like growth factor I receptor, as well as c-fos mRNA expression induced by EGF, fibroblast growth factor, and phorbol ester, was insensitive to inhibition by CGP 53716. In antiproliferative assays, the compound was approximately 30-fold more potent in inhibiting PDGF-mediated growth of v-sis-transformed BALB/c 3T3 cells relative to inhibition of EGF-dependent BALB/Mk cells, interleukin-3-dependent FDC-P1 cells, and the T24 bladder carcinoma line. When tested in vivo using highly tumorigenic v-sis- and human c-sis-transformed BALB/c 3T3 cells, CGP 53716 showed antitumor activity at well-tolerated doses. In contrast, CGP 53716 did not show antitumor activity against xenografts of the A431 tumor, which overexpresses the EGF receptor. These findings suggest that CGP 53716 may have therapeutic potential for the treatment of diseases involving abnormal cellular proliferation induced by PDGF receptor activation. AD - CIBA Pharmaceuticals Division, Oncology Research Department, CIBA-Geigy Limited, Basel, Switzerland. FAU - Buchdunger, E AU - Buchdunger E FAU - Zimmermann, J AU - Zimmermann J FAU - Mett, H AU - Mett H FAU - Meyer, T AU - Meyer T FAU - Muller, M AU - Muller M FAU - Regenass, U AU - Regenass U FAU - Lydon, N B AU - Lydon NB LA - eng PT - Journal Article PT - Retracted Publication PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Antineoplastic Agents) RN - 0 (CGP 53716) RN - 0 (Oncogene Proteins v-sis) RN - 0 (Platelet-Derived Growth Factor) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - 0 (Retroviridae Proteins, Oncogenic) RN - 103107-01-3 (Fibroblast Growth Factor 2) RN - 16561-29-8 (Tetradecanoylphorbol Acetate) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptors, Platelet-Derived Growth Factor) SB - IM RIN - Buchdunger E, Trinks U, Mett H, Regenass U, Meyer T, McGlynn E, Pinna LA, Traxler P, Lydon NB, Zimmermann J. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12069. PMID: 9786782 GS - v-sis MH - 3T3 Cells MH - Animals MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Carcinoma, Squamous Cell/drug therapy/*pathology MH - Cell Division/drug effects MH - Cell Line MH - Cell Line, Transformed MH - Epidermal Growth Factor/pharmacology MH - Female MH - Fibroblast Growth Factor 2/pharmacology MH - Humans MH - Kinetics MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Oncogene Proteins v-sis MH - Oncogenes MH - Platelet-Derived Growth Factor/*pharmacology MH - *Protein Kinase Inhibitors MH - Protein-Tyrosine Kinase/*antagonists & inhibitors MH - Pyridines/chemical synthesis/*pharmacology/therapeutic use MH - Pyrimidines/chemical synthesis/*pharmacology/therapeutic use MH - Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors/*physiology MH - Retroviridae Proteins, Oncogenic/antagonists & inhibitors/biosynthesis/genetics MH - Signal Transduction/*drug effects MH - Tetradecanoylphorbol Acetate/pharmacology MH - Transfection MH - Transplantation, Heterologous MH - Tumor Cells, Cultured EDAT- 1995/03/28 MHDA- 1995/03/28 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1995 Mar 28;92(7):2558-62. -------------------------------------------------------------------------------- 282: Taylor IC et al. Mouse mammary tumors express ...[PMID: 7896835] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7896835 OWN - NLM STAT- MEDLINE DA - 19950425 DCOM- 19950425 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 270 IP - 12 DP - 1995 Mar 24 TI - Mouse mammary tumors express elevated levels of RNA encoding the murine homology of SKY, a putative receptor tyrosine kinase. PG - 6872-80 AB - To gain insight into the signal transduction pathways utilized by the Wnt-1-responsive mammary epithelial cell line C57MG, we screened for non-src family member tyrosine kinases expressed in these cells using a polymerase chain reaction-based technique. We identified five cDNA clones encoding receptor tyrosine kinases for which the ligand is known (fibroblast growth factor receptor, platelet-derived growth factor receptor, epithelial growth factor receptor, insulin receptor, and insulin-like growth factor receptor), two putative receptor tyrosine kinases for which the ligand remains to be identified (the products of ryk and the mouse klg homolog), and a novel tyrosine kinase. We cloned cDNAs encoding both the murine and human homologs of this kinase, the sequences of which were subsequently published under the names sky (Ohashi, K., Mizuno, K., Kuma, K., Miyata, T., and Nakamura, T. (1994) Oncogene 9, 699-705) and rse (Mark, M. R., Scadden, D. T., Wang, Z., Gu, Q., Goddard, A., and Godowski, P. J. (1994) J. Biol. Chem. 269, 10720-10728). Mouse sky RNA levels are abundant in mammary tumors derived from transgenic mice that express wnt-1, fgf-3, or both oncogenes in their mammary glands. However, little or no expression of sky is detected in mammary glands from virgin animals or in preneoplastic mammary glands from wnt-1 transgenic mice. Moreover, we find that the human homolog of sky is expressed at elevated levels when normal human mammary epithelial cells are rendered tumorigenic by the introduction of two viral oncogenes. Transient transfection of the human SKY cDNA into the quail fibrosarcoma cell line QT6 reveals that SKY is an active tyrosine kinase that augments the level of cellular phosphotyrosine. Introduction of murine Sky into RatB1a fibroblasts by retrovirus-mediated gene transfer results in morphological transformation, growth in soft agar, and the formation of tumors in nude mice. These data raise the possibility that the Sky tyrosine kinase is involved in the development and/or progression of mammary tumors. AD - Department of Microbiology and Immunology, University of California, San Francisco 94143. FAU - Taylor, I C AU - Taylor IC FAU - Roy, S AU - Roy S FAU - Yaswen, P AU - Yaswen P FAU - Stampfer, M R AU - Stampfer MR FAU - Varmus, H E AU - Varmus HE LA - eng GR - CA-24844/CA/NCI GR - CA-39832/CA/NCI GR - CA-54247/CA/NCI PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (DNA, Complementary) RN - 0 (RNA, Messenger) RN - EC 2.7.1.- (TYRO3 protein, human) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - Breast Neoplasms/metabolism MH - Cell Transformation, Neoplastic MH - DNA, Complementary/isolation & purification MH - *Gene Expression Regulation, Neoplastic MH - Glycosylation MH - Humans MH - Mammary Glands, Animal/metabolism MH - Mammary Neoplasms, Experimental/*metabolism MH - Mice MH - Molecular Sequence Data MH - RNA, Messenger/*analysis MH - Receptor Protein-Tyrosine Kinases/analysis/*genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, Non-P.H.S. MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 1995/03/24 MHDA- 1995/03/24 00:01 PST - ppublish SO - J Biol Chem 1995 Mar 24;270(12):6872-80. -------------------------------------------------------------------------------- 283: Ogawa W et al. Activation of protein kinase ...[PMID: 7835279] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7835279 OWN - NLM STAT- MEDLINE DA - 19950302 DCOM- 19950302 LR - 20041117 PUBM- Print IS - 0013-7227 VI - 136 IP - 2 DP - 1995 Feb TI - Activation of protein kinase C stimulates the tyrosine phosphorylation and guanosine triphosphatase-activating protein association of p60 in rat hepatoma cells. PG - 476-81 AB - In the present studies, insulin was found to stimulate in a rat hepatoma cell line (called FAO cells) the tyrosine phosphorylation of the 60-kilodalton p21ras GTPase-activating protein (GAP)-associated protein called p60. Surprisingly, the tyrosine phosphorylation of this protein was also almost equally stimulated by an activator of protein kinase C (PKC), the phorbol ester phorbol 12-myristate 13-acetate (PMA). The tyrosine phosphorylation of p60 induced by either agent correlated with the formation of the GAP-p60 complex in situ and an increase in the ability of p60 to directly bind to the SH2 domain of GAP in vitro. Several lines of evidence indicated that the PMA-induced tyrosine phosphorylation of p60 occurred through a different mechanism than that induced by insulin. First, the stimulation of tyrosine phosphorylation of p60 by maximal concentrations of the two agents was almost additive. Second, down-regulation of PKC or pretreatment with a specific inhibitor of PKC abolished the ability of PMA to stimulate tyrosine phosphorylation of p60 but had no effect on the insulin stimulation. And third, long-term pretreatment with insulin abolished the insulin response but did not affect the response to PMA. The PMA effect did seem to be mediated via a tyrosine kinase, since it was blocked by quercetin, an inhibitor of tyrosine kinases. These results indicate that both PMA and insulin can equally stimulate in FAO cells the tyrosine phosphorylation of p60 and its association with GAP, although these two agents seem to act via different signaling systems. AD - Department of Molecular Pharmacology, Stanford University School of Medicine, California 94305. FAU - Ogawa, W AU - Ogawa W FAU - Hosomi, Y AU - Hosomi Y FAU - Roth, R A AU - Roth RA LA - eng GR - DK-41765/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Endocrinology JID - 0375040 RN - 0 (GTPase-Activating Proteins) RN - 0 (Proteins) RN - 11061-68-0 (Insulin) RN - 16561-29-8 (Tetradecanoylphorbol Acetate) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Protein Kinase C) SB - AIM SB - IM MH - Animals MH - Down-Regulation MH - GTPase-Activating Proteins MH - Insulin/pharmacology MH - Liver Neoplasms, Experimental/*metabolism MH - Phosphorylation/drug effects MH - Protein Kinase C/*metabolism MH - Proteins/*metabolism MH - Rats MH - Receptor, Insulin/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Second Messenger Systems MH - Signal Transduction MH - Tetradecanoylphorbol Acetate/*pharmacology MH - Tumor Cells, Cultured MH - Tyrosine/*metabolism EDAT- 1995/02/01 MHDA- 1995/02/01 00:01 PST - ppublish SO - Endocrinology 1995 Feb;136(2):476-81. -------------------------------------------------------------------------------- 284: Calalb MB et al. Tyrosine phosphorylation of f...[PMID: 7529876] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, OMIM, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 7529876 OWN - NLM STAT- MEDLINE DA - 19950216 DCOM- 19950216 LR - 20050209 PUBM- Print IS - 0270-7306 VI - 15 IP - 2 DP - 1995 Feb TI - Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. PG - 954-63 AB - Focal adhesion kinase (FAK) is a widely expressed nonreceptor protein-tyrosine kinase implicated in integrin-mediated signal transduction pathways and in the process of oncogenic transformation by v-Src. Elevation of FAK's phosphotyrosine content, following both cell adhesion to extracellular matrix substrata and cell transformation by Rous sarcoma virus, correlates directly with an increased kinase activity. To help elucidate the role of FAK phosphorylation in signal transduction events, we used a tryptic phosphopeptide mapping approach to identify tyrosine sites of phosphorylation responsive to both cell adhesion and Src transformation. We have identified four tyrosines, 397, 407, 576, and 577, which are phosphorylated in mouse BALB/3T3 fibroblasts in an adhesion-dependent manner. Tyrosine 397 has been previously recognized as the major site of FAK autophosphorylation. Phosphorylation of tyrosines 407, 576, and 577, which are previously unrecognized sites, is significantly elevated in the presence of c-Src in vitro and v-Src in vivo. Tyrosines 576 and 577 lie within catalytic subdomain VIII--a region recognized as a target for phosphorylation-mediated regulation of protein kinase activity. We found that maximal kinase activity of FAK immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of FAK by Src (or other Src family kinases) is an important step in the formation of an active signaling complex. AD - Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. FAU - Calalb, M B AU - Calalb MB FAU - Polte, T R AU - Polte TR FAU - Hanks, S K AU - Hanks SK LA - eng PT - Journal Article PL - UNITED STATES TA - Mol Cell Biol JID - 8109087 RN - 0 (Cell Adhesion Molecules) RN - 0 (Oligodeoxyribonucleotides) RN - 0 (Phosphopeptides) RN - 0 (Recombinant Proteins) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 56-65-5 (Adenosine Triphosphate) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Proto-Oncogene Protein pp60(c-src)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (focal adhesion kinase) SB - IM MH - 3T3 Cells MH - Adenosine Triphosphate/metabolism MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - Binding Sites MH - Cell Adhesion MH - Cell Adhesion Molecules/*metabolism MH - Cell Transformation, Neoplastic MH - Cercopithecus aethiops MH - Comparative Study MH - Electrophoresis, Gel, Two-Dimensional MH - Mice MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - Oligodeoxyribonucleotides MH - Peptide Mapping MH - Phosphopeptides/chemistry/isolation & purification MH - Phosphorylation MH - Phosphotyrosine MH - Protein-Tyrosine Kinase/*metabolism MH - Proto-Oncogene Protein pp60(c-src)/*metabolism MH - Receptor, Insulin/metabolism MH - Recombinant Proteins MH - Sarcoma Viruses, Avian MH - Transfection MH - Tyrosine/*analogs & derivatives/analysis/metabolism EDAT- 1995/02/01 MHDA- 1995/02/01 00:01 PST - ppublish SO - Mol Cell Biol 1995 Feb;15(2):954-63. -------------------------------------------------------------------------------- 285: Xu YY et al. Insulin-induced differentiati...[PMID: 8746448] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8746448 OWN - NLM STAT- MEDLINE DA - 19961011 DCOM- 19961011 LR - 20050316 PUBM- Print IS - 0895-8696 VI - 6 IP - 2 DP - 1995 TI - Insulin-induced differentiation and modulation of neuronal thread protein expression in primitive neuroectodermal tumor cells is linked to phosphorylation of insulin receptor substrate-1. PG - 91-108 AB - Neuronal thread proteins (NTPs) are a family of developmentally regulated molecules expressed in central nervous system (CNS) neurons and primitive neuroectodermal tumor (PNET) cell lines. NTP gene expression is modulated with DNA synthesis, neuritic sprouting, and neuronal differentiation. The present study explores the mechanism of insulin modulation of NTP gene expression during neuronal differentiation using PNET cell lines of CNS origin. PNET2 cells underwent neuronal differentiation with neurite outgrowth coupled with transient up-regulation of several species of NTP. In contrast, PNET1 cells failed to differentiate in response to insulin stimulation, although insulin receptors were more abundant than in PNET2 cells. Analysis of the insulin-mediated signal transduction pathway demonstrated that the lack of insulin responsiveness in PNET1 cells was primarily caused by impaired insulin-mediated tyrosyl phosphorylation of the insulin receptor substrate-1 (IRS-1). Correspondingly, the association between phosphatidyl-inositol 3 (PI3) kinase and phosphorylated IRS-1 was reduced in PNET1 compared with PNET2 cells. In contrast, the levels of IRS-1 protein were similar in PNET1 and PNET2 cells, and expression of the insulin receptor beta subunit (Ir beta) and insulin-mediated tyrosyl phosphorylation of the Ir beta were greater in PNET1 than PNET2 cells. The findings suggest that insulin effected neuronal differentiation and modulation of NTP gene expression in PNET cells utilizes a signal transduction cascade that requires tyrosyl phosphorylation of IRS-1. AD - Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. FAU - Xu, Y Y AU - Xu YY FAU - Bhavani, K AU - Bhavani K FAU - Wands, J R AU - Wands JR FAU - de la Monte, S M AU - de la Monte SM LA - eng GR - AA-02666/AA/NIAAA GR - CA-35711/CA/NCI GR - NS-29793/NS/NINDS GR - etc. PT - Journal Article PL - UNITED STATES TA - J Mol Neurosci JID - 9002991 RN - 0 (Calcium-Binding Proteins) RN - 0 (DNA, Neoplasm) RN - 0 (Nerve Tissue Proteins) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 0 (lithostathine) RN - 11061-68-0 (Insulin) SB - IM MH - Blotting, Western MH - Calcium-Binding Proteins/analysis/*biosynthesis/isolation & purification MH - Cell Differentiation/drug effects/*physiology MH - Cell Line MH - DNA, Neoplasm/biosynthesis/drug effects MH - Gene Expression/*drug effects MH - Humans MH - Immunohistochemistry MH - Insulin/*pharmacology MH - Kinetics MH - Nerve Tissue Proteins/biosynthesis MH - Neuroectodermal Tumors, Primitive, Peripheral MH - Phosphoproteins/biosynthesis/*metabolism MH - Phosphorylation MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction MH - Tumor Cells, Cultured EDAT- 1995/01/01 MHDA- 1995/01/01 00:01 PST - ppublish SO - J Mol Neurosci 1995;6(2):91-108. -------------------------------------------------------------------------------- 286: Zong CS et al. Modulatory effect of the tran...[PMID: 7526386] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Cited in Books, Books, LinkOut PMID- 7526386 OWN - NLM STAT- MEDLINE DA - 19941212 DCOM- 19941212 LR - 20041118 PUBM- Print IS - 0027-8424 VI - 91 IP - 23 DP - 1994 Nov 8 TI - Modulatory effect of the transmembrane domain of the protein-tyrosine kinase encoded by oncogene ros: biological function and substrate interaction. PG - 10982-6 AB - There is a 3-aa insertion in the transmembrane (TM) domain of the p68gag-ros protein-tyrosine kinase encoded by avian sarcoma virus UR2 v-ros as compared with that of the protooncogene c-ros. The effect of this insertion on biological function and biochemical properties of v-Ros protein was investigated by deleting these 3 aa to generate the mutant TM1. This mutant has greatly reduced transforming, mitogenic, and tumorigenic activities despite the fact that the protein-tyrosine kinase activity and cell-surface localization of TM1 protein are unaffected. However, unlike UR2 protein, mutant TM1 protein becomes glycosylated, is differentially phosphorylated, and fails to induce tyrosine phosphorylation of a 88-kDa protein and a major substrate of insulin receptor, insulin receptor substrate 1. The TM1 protein is unable to associate with phosphatidylinositol 3-kinase and fails to promote association of insulin receptor substrate 1 with phosphatidylinositol 3-kinase. By contrast, tyrosine phosphorylation of Shc protein and phospholipase C gamma as well as interaction of Grb2 protein with Shc and SOS protein signaling components are unaltered in the TM1 infected cells. Our results show that the TM-domain sequence of p68gag-ros profoundly affects its function and substrate interaction. The mutant defines a signaling pathway including phosphatidylinositol 3-kinase, insulin receptor substrate 1, and possibly an 88-kDa protein that does not overlap the Ras pathway and is important for full transforming and mitogenic potency of v-ros protein-tyrosine kinase. AD - Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029. FAU - Zong, C S AU - Zong CS FAU - Wang, L H AU - Wang LH LA - eng GR - CA29339/CA/NCI PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Membrane Glycoproteins) RN - 0 (Mitogens) RN - 0 (Oncogene Proteins, Viral) RN - 0 (Proto-Oncogene Proteins) RN - 0 (v-ros protein, Avian sarcoma virus UR2) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Animals MH - Cell Transformation, Neoplastic MH - Cells, Cultured MH - Chick Embryo MH - In Vitro MH - Membrane Glycoproteins/chemistry MH - Mitogens MH - Mutagenesis, Site-Directed MH - Oncogene Proteins, Viral/*chemistry MH - Peptide Mapping MH - Phosphotyrosine MH - Protein-Tyrosine Kinase/*chemistry MH - Proto-Oncogene Proteins/*chemistry MH - Receptor Protein-Tyrosine Kinases/*chemistry MH - Research Support, U.S. Gov't, P.H.S. MH - Structure-Activity Relationship MH - Tyrosine/analogs & derivatives/metabolism EDAT- 1994/11/08 MHDA- 1994/11/08 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1994 Nov 8;91(23):10982-6. -------------------------------------------------------------------------------- 287: Resnicoff M et al. Ethanol inhibits insulin-like...[PMID: 7526037] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7526037 OWN - NLM STAT- MEDLINE DA - 19941227 DCOM- 19941227 LR - 20041117 PUBM- Print IS - 0023-6837 VI - 71 IP - 5 DP - 1994 Nov TI - Ethanol inhibits insulin-like growth factor-1-mediated signalling and proliferation of C6 rat glioblastoma cells. PG - 657-62 AB - BACKGROUND: Alcohol consumption during pregnancy often results in disorders of fetal development (Fetal Alcohol Syndrome). The brain appears to be particularly vulnerable, and alcohol abuse during pregnancy is probably the most common cause of acquired mental retardation. We therefore studied the in vitro effects of ethanol on insulin-like growth factor-1 (IGF-1)-mediated proliferation of rat C6 glioblastoma cells. EXPERIMENTAL DESIGN: The proliferation of C6 rat glioblastoma cells was measured in serum-free medium supplemented with specific growth factors in the presence or absence of ethanol. The effect of ethanol on IGF-1 receptor and insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation was determined by immunoprecipitation and Western blotting, as was the phosphatidylinositol 3-kinase content within IRS-1 immunoprecipitates. RESULTS: C6 cells grew slowly in serum-free medium and proliferated in response to IGF-1. Ethanol, at physiologically tolerated concentrations, markedly inhibited the growth of C6 cells in response to IGF-1, but had no effect on the proliferative rate in the presence of platelet-derived growth factor or 1% fetal bovine serum. Inhibition of cell proliferation was evident when ethanol was only present during a 1-hour pulse of IGF-1. Cell growth in the presence of IGF-2 was also prevented by ethanol. The inhibition of IGF-1-mediated cell proliferation was accompanied by abrogation of IGF-1 receptor tyrosine autophosphorylation. Ethanol also interfered with the IGF-1-induced tyrosine phosphorylation of IRS-1, and the association of phosphatidylinositol-3 kinase with IRS-1. CONCLUSIONS: The data indicate that physiologically relevant concentrations of ethanol inhibit the responses of glial cells to IGF-1, including IGF-1 receptor autophosphorylation, IRS-1 and phosphatidylinositol-3 kinase activation, and cell growth. AD - Department of Pathology and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania. FAU - Resnicoff, M AU - Resnicoff M FAU - Rubini, M AU - Rubini M FAU - Baserga, R AU - Baserga R FAU - Rubin, R AU - Rubin R LA - eng GR - AA-0123/AA/NIAAA GR - AA-07186/AA/NIAAA GR - AA-07309/AA/NIAAA PT - Journal Article PL - UNITED STATES TA - Lab Invest JID - 0376617 RN - 0 (DNA Primers) RN - 0 (Peptides) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - 64-17-5 (Ethanol) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.1.112 (Receptor, IGF Type 1) SB - IM MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - Cell Division/drug effects MH - DNA Primers/chemistry MH - Ethanol/*pharmacology MH - Glioblastoma/pathology MH - In Vitro MH - Insulin-Like Growth Factor I/*antagonists & inhibitors MH - Molecular Sequence Data MH - Neuroglia/*cytology MH - Peptides/chemistry/immunology MH - Phosphoproteins/metabolism MH - Phosphotyrosine MH - Rats MH - Receptor Protein-Tyrosine Kinases/metabolism MH - Receptor, IGF Type 1/drug effects MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects MH - Tumor Cells, Cultured MH - Tyrosine/analogs & derivatives/metabolism EDAT- 1994/11/01 MHDA- 1994/11/01 00:01 PST - ppublish SO - Lab Invest 1994 Nov;71(5):657-62. -------------------------------------------------------------------------------- 288: Lazar DF et al. Stimulation of glycogen synth...[PMID: 7524086] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 7524086 OWN - NLM STAT- MEDLINE DA - 19941110 DCOM- 19941110 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 91 IP - 21 DP - 1994 Oct 11 TI - Stimulation of glycogen synthesis by insulin in human erythroleukemia cells requires the synthesis of glycosyl-phosphatidylinositol. PG - 9665-9 AB - Although the insulin-dependent hydrolysis of glycosyl-phosphatidylinositol (GPI) may play an important role in insulin action, an absolute requirement for this glycolipid has not been demonstrated. Human K562 cells were mutated to produce a cell line (IA) incapable of the earliest step in PI glycosylation, the formation of PI-GlcNAc. Another cell line (IVD) was deficient in the deacetylation of PI-GlcNAc to form PI-GlcN and subsequent mannosylated species. Each line was transfected with wild-type human insulin receptors. Similar insulin-stimulated receptor autophosphorylation was observed in all three lines, along with a nearly identical increase in the association of phosphorylated insulin receptor substrate 1 with endogenous PI 3-kinase. Both normal and GPI-defective lines also displayed a similar 2- to 3-fold increase in phosphorylation of the Shc protein and its association with growth factor receptor-bound protein 2 in response to insulin. In contrast to these results, striking differences were noted in insulin-stimulated glycogen synthesis. In normal cells, glycogen synthesis was significantly increased by insulin, whereas no insulin stimulation was observed in GPI-deficient IA cells, and only a trace of stimulation was detected in IVD cells. These results indicate that tyrosine phosphorylation produced by insulin is not dependent on GPI synthesis, and this effect is not sufficient to elicit at least some of the metabolic effects of the hormone. In contrast, GPI synthesis is required for the stimulation of glycogen synthesis by insulin in these cells. These findings support the existence of divergent pathways in the action of insulin. AD - Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division, Ann Arbor, MI 48105. FAU - Lazar, D F AU - Lazar DF FAU - Knez, J J AU - Knez JJ FAU - Medof, M E AU - Medof ME FAU - Cuatrecasas, P AU - Cuatrecasas P FAU - Saltiel, A R AU - Saltiel AR LA - eng PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Glycosylphosphatidylinositols) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Recombinant Proteins) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 50-99-7 (Glucose) RN - 55520-40-6 (Tyrosine) RN - 9005-79-2 (Glycogen) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Cell Line MH - Flow Cytometry MH - Glucose/metabolism MH - Glycogen/*biosynthesis MH - Glycosylphosphatidylinositols/*biosynthesis MH - Humans MH - Insulin/*pharmacology MH - Kinetics MH - Leukemia, Erythroblastic, Acute/*metabolism MH - Mutagenesis MH - Phosphorylation MH - Phosphotyrosine MH - Receptor, Insulin/biosynthesis/isolation & purification/*physiology MH - Recombinant Fusion Proteins/biosynthesis MH - Recombinant Proteins/biosynthesis/isolation & purification/metabolism MH - Transfection MH - Tumor Cells, Cultured MH - Tyrosine/analogs & derivatives/analysis EDAT- 1994/10/11 MHDA- 1994/10/11 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1994 Oct 11;91(21):9665-9. -------------------------------------------------------------------------------- 289: Kim HH et al. Epidermal growth factor-depen...[PMID: 7929151] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7929151 OWN - NLM STAT- MEDLINE DA - 19941104 DCOM- 19941104 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 269 IP - 40 DP - 1994 Oct 7 TI - Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. PG - 24747-55 AB - The ErbB3 protein is a member of the ErbB subfamily of receptor protein tyrosine kinases. In the present study, the mechanism by which the ErbB3 protein is phosphorylated and the signal-transducing functions of this phosphorylated protein were investigated. When phosphorylated by the epidermal growth factor receptor in vitro, the ErbB3 protein strongly associated with the regulatory p85 subunit and the catalytic activity of phosphatidylinositol (PI) 3-kinase. The association of PI 3-kinase with ErbB3 in human breast cancer cells was found to be correlated with the constitutive phosphorylation of ErbB3 on tyrosine residues. In MDA-MB-468 breast cancer cells in which the ErbB3 protein is not constitutively phosphorylated, stimulation with epidermal growth factor led to the phosphorylation of ErbB3 on tyrosine residues and the formation of a functional signal transduction complex involving the ErbB3 protein and PI 3-kinase. These results suggest that the ErbB3 protein can be phosphorylated on tyrosine residues by a cross-phosphorylation mechanism and that the phosphorylated ErbB3 protein can couple other growth factor receptor protein tyrosine kinases to the PI 3-kinase pathway in a manner similar to the insulin receptor substrate 1 protein. AD - Department of Pharmacology, University of Iowa, College of Medicine, Iowa City 52242-1109. FAU - Kim, H H AU - Kim HH FAU - Sierke, S L AU - Sierke SL FAU - Koland, J G AU - Koland JG LA - eng GR - DK-25295/DK/NIDDK GR - DK-44684/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Proto-Oncogene Proteins) RN - 62229-50-9 (Epidermal Growth Factor) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.112 (Receptor, Epidermal Growth Factor) RN - EC 2.7.1.112 (Receptor, erbB-3) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - 3T3 Cells MH - Animals MH - Breast Neoplasms/metabolism MH - Epidermal Growth Factor/*pharmacology MH - Humans MH - Mice MH - Phosphorylation MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - Proto-Oncogene Proteins/*metabolism MH - Rabbits MH - Receptor, Epidermal Growth Factor/*metabolism/physiology MH - Receptor, erbB-3 MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 1994/10/07 MHDA- 1994/10/07 00:01 PST - ppublish SO - J Biol Chem 1994 Oct 7;269(40):24747-55. -------------------------------------------------------------------------------- 290: Sepp-Lorenzino L et al. Insulin and insulin-like grow...[PMID: 7848909] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7848909 OWN - NLM STAT- MEDLINE DA - 19950314 DCOM- 19950314 LR - 20041117 PUBM- Print IS - 1044-9523 VI - 5 IP - 10 DP - 1994 Oct TI - Insulin and insulin-like growth factor signaling are defective in the MDA MB-468 human breast cancer cell line. PG - 1077-83 AB - Polypeptide growth factors including the insulin-like growth factors (IGFs), insulin, and transforming growth factor-alpha are mitogens for many breast cancer cell lines and may act as regulators of cancer cell growth. In a human breast cancer cell line MCF-7, which expresses IGF-I receptor (IGF-IR), stimulation with insulin or IGFs resulted in autophosphorylation of the IGF-IR in an increased proportion of ras bound to GTP and in the association of phosphatidylinositol 3'-kinase (PI3K) activity and of p85-PI3K with M(r) 185,000 phosphotyrosinylated proteins corresponding in size to insulin/IGF-IR substrates. These events were associated with enhanced proliferation. MDA MB-468 is a human breast cancer cell line which expresses insulin receptor and high levels of epidermal growth factor/transforming growth factor alpha receptor but low levels of IGF-IR. In this cell line, insulin stimulated autophosphorylation of IR at physiological concentrations and promoted the association of PI3K activity and of p85 with phosphotyrosine-containing proteins. Insulin did not, however, induce increased ras.GTP, and the cells exhibited minimal proliferation in response to insulin. Unlike insulin treatment, epidermal growth factor stimulation of MDA MB-468 cells is mitogenic and resulted in increased ras.GTP content, suggesting that the failure of insulin to induce these changes is not due to alterations in these signaling molecules. We conclude that there is a postreceptor defect in insulin signaling in MDA MB-468 which prevents the activation of ras and the induction of mitogenesis. Activation of PI3K by insulin is not sufficient to mediate mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) AD - Breast and Gynecologic Service, Memorial Sloan Kettering Cancer Center,New York, New York 10021. FAU - Sepp-Lorenzino, L AU - Sepp-Lorenzino L FAU - Rosen, N AU - Rosen N FAU - Lebwohl, D E AU - Lebwohl DE LA - eng GR - P20 CA-91-33/CA/NCI GR - RO1 CA 58706-01/CA/NCI PT - Journal Article PL - UNITED STATES TA - Cell Growth Differ JID - 9100024 RN - 0 (Somatomedins) RN - 11061-68-0 (Insulin) SB - IM MH - Base Sequence MH - Breast Neoplasms/*physiopathology MH - Cell Division/drug effects MH - Humans MH - Insulin/*pharmacology MH - Molecular Sequence Data MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*drug effects MH - Somatomedins/*pharmacology MH - Tumor Cells, Cultured EDAT- 1994/10/01 MHDA- 1994/10/01 00:01 PST - ppublish SO - Cell Growth Differ 1994 Oct;5(10):1077-83. -------------------------------------------------------------------------------- 291: Baron-Delage S et al. [Oncogenic activation of p21(...[PMID: 7734771] Related Articles, Substance via MeSH, Books, LinkOut PMID- 7734771 OWN - NLM STAT- MEDLINE DA - 19950606 DCOM- 19950606 LR - 20041117 PUBM- Print IS - 0007-4551 VI - 81 IP - 10 DP - 1994 Oct TI - [Oncogenic activation of p21(ras) and pp60(c-src) in human colonic Caco-2 cells decreases insulin receptor function and expression through protein kinase C-dependent and independent pathways] PG - 882-5 AB - In view of the potent mitogenic effect exerted by insulin in human colonic cells, we used Caco-2 cells transfected with an activated (Val12) human Ha-ras gene or the polyoma middle T (PyMT) oncogene, a constitutive activator of pp60c-src tyrosine kinase activity, to investigate the effect of oncogenic p21ras and PyMT/pp60c-src on insulin mitogenic signaling. As compared to vector control Caco-2 cells, both oncogene-transfected cells exhibited: 1) a lost of response to insulin's stimulatory effect on mitogen-activated protein (MAP) kinase activity and cell proliferation, both of which were constitutively increased; 2) a decrease in insulin receptor (IR) affinity and insulin-stimulated exogenous tyrosine kinase activity, which resulted, at least in part, from increased protein kinase C (PKC) activity (4), since both IR alterations were partially corrected by PKC down-regulation; and 3) a decrease in both insulin receptor mRNA level and insulin receptor number, which was independent of PKC since it persisted after PKC down-regulation. In conclusion, oncogenic p21ras and PyMT/pp60c-src abolished insulin mitogenic signaling in Caco-2 cells through mechanisms involving (i) constitutive activation of MAP kinase, and (ii) marked decreases in both insulin receptor function and expression which were mediated by PKC-dependent and PKC-independent pathways respectively. This is the first evidence that, when oncogenically activated, p21ras and pp60c-src not only exert a negative control on insulin receptor function but also repress insulin receptor gene expression in human colonic cells. AD - Laboratoire de biologie cellulaire, Inserm U402, faculte de medecine Saint-Antoine, Paris, France. FAU - Baron-Delage, S AU - Baron-Delage S FAU - Barbu, V AU - Barbu V FAU - Bertrand, F AU - Bertrand F FAU - Chastre, E AU - Chastre E FAU - Levy, P AU - Levy P FAU - Gespach, C AU - Gespach C FAU - Capeau, J AU - Capeau J FAU - Cherqui, G AU - Cherqui G LA - fre PT - Journal Article TT - L'activation oncogenique de p21(ras) et pp60(c-src) dans les cellules coliques humaines Caco-2 diminue la fonction et l'expression du recepteur de l'insuline par des voies dependante et independante de la proteine kinase C. PL - FRANCE TA - Bull Cancer JID - 0072416 RN - EC 2.7.1.112 (Oncogene Protein pp60(v-src)) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.37 (Protein Kinase C) RN - EC 3.6.1.- (Oncogene Protein p21(ras)) SB - IM MH - Carcinoma/*genetics/metabolism MH - Colonic Neoplasms/*genetics/metabolism MH - English Abstract MH - Gene Expression Regulation, Neoplastic/*physiology MH - Humans MH - Mitosis/physiology MH - Oncogene Protein p21(ras)/*genetics/metabolism MH - Oncogene Protein pp60(v-src)/*genetics/metabolism MH - Protein Kinase C/*metabolism MH - Receptor, Insulin/*metabolism MH - Tumor Cells, Cultured/metabolism EDAT- 1994/10/01 MHDA- 1994/10/01 00:01 PST - ppublish SO - Bull Cancer 1994 Oct;81(10):882-5. -------------------------------------------------------------------------------- 292: Hotamisligil GS et al. Reduced tyrosine kinase activ...[PMID: 7523453] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 7523453 OWN - NLM STAT- MEDLINE DA - 19941110 DCOM- 19941110 LR - 20041118 PUBM- Print IS - 0021-9738 VI - 94 IP - 4 DP - 1994 Oct TI - Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. PG - 1543-9 AB - Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat. AD - Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115. FAU - Hotamisligil, G S AU - Hotamisligil GS FAU - Budavari, A AU - Budavari A FAU - Murray, D AU - Murray D FAU - Spiegelman, B M AU - Spiegelman BM LA - eng GR - DK-42539/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - J Clin Invest JID - 7802877 RN - 0 (Immunoglobulin G) RN - 0 (Phosphoproteins) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (insulin receptor substrate-1 protein) RN - 11061-68-0 (Insulin) RN - 21820-51-9 (Phosphotyrosine) RN - 55520-40-6 (Tyrosine) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) SB - AIM SB - IM MH - Adipose Tissue/metabolism MH - Animals MH - Diabetes Mellitus/enzymology/*metabolism MH - Diabetes Mellitus, Type 2/chemically induced/enzymology/*metabolism MH - Disease Models, Animal MH - Immunoglobulin G/genetics MH - Insulin/blood/pharmacology MH - Insulin Resistance MH - Liver/metabolism MH - Male MH - Muscles/metabolism MH - Neutralization Tests MH - *Obesity MH - Phosphoproteins/metabolism MH - Phosphorylation MH - Phosphotyrosine MH - Protein-Tyrosine Kinase/*metabolism MH - Rats MH - Rats, Zucker MH - Receptor, Insulin/*metabolism MH - Receptors, Tumor Necrosis Factor/genetics MH - Recombinant Fusion Proteins/pharmacology MH - Research Support, U.S. Gov't, P.H.S. MH - Specific Pathogen-Free Organisms MH - Tumor Necrosis Factor-alpha/*physiology MH - Tyrosine/analogs & derivatives/analysis EDAT- 1994/10/01 MHDA- 1994/10/01 00:01 PST - ppublish SO - J Clin Invest 1994 Oct;94(4):1543-9. -------------------------------------------------------------------------------- 293: Furusaka A et al. Expression of insulin recepto...[PMID: 8076365] Related Articles, Books, LinkOut PMID- 8076365 OWN - NLM STAT- MEDLINE DA - 19941003 DCOM- 19941003 LR - 20041117 PUBM- Print IS - 0304-3835 VI - 84 IP - 1 DP - 1994 Aug 29 TI - Expression of insulin receptor substrate-1 in hepatocytes: an investigation using monoclonal antibodies. PG - 85-92 AB - To investigate the expression and subcellular distribution of insulin receptor substrate-1 in hepatocytes, which are major targets of insulin along with muscle and adipose tissue, we obtained monoclonal antibodies by immunizing mice with a fusion protein consisting of the C-terminal portion of the human insulin receptor substrate-1 and glutathione-S-transferase. Two of the monoclonal antibodies (designated as 7B3 and 6G5) were found to be useful for immunohistochemical studies. Using 6G5 we demonstrate a high level of expression of insulin receptor substrate-1 in liver cirrhosis hepatocytes and variable expression in hepatocellular carcinoma cells. These results suggest that insulin receptor substrate-1 may play a role in liver regeneration during cirrhosis and that an insulin signaling cascade may be involved in hepatocarcinogenesis. AD - Department of Internal Medicine (Daisan Hospital), Tokyo, Japan. FAU - Furusaka, A AU - Furusaka A FAU - Nishiyama, M AU - Nishiyama M FAU - Ohkawa, K AU - Ohkawa K FAU - Yamori, T AU - Yamori T FAU - Tsuruo, T AU - Tsuruo T FAU - Yonezawa, K AU - Yonezawa K FAU - Kasuga, M AU - Kasuga M FAU - Hayashi, S AU - Hayashi S FAU - Tanaka, T AU - Tanaka T LA - eng PT - Journal Article PL - IRELAND TA - Cancer Lett JID - 7600053 RN - 0 (Antibodies, Monoclonal) RN - 0 (Phosphoproteins) RN - 0 (insulin receptor substrate-1 protein) SB - IM MH - Animals MH - *Antibodies, Monoclonal/biosynthesis MH - CHO Cells MH - Carcinoma, Hepatocellular/etiology MH - Hamsters MH - Humans MH - Immunohistochemistry MH - Liver/*chemistry/cytology MH - Liver Cirrhosis, Experimental/metabolism MH - Liver Neoplasms, Experimental/etiology MH - Mice MH - Mice, Inbred BALB C MH - Phosphoproteins/*analysis MH - Sensitivity and Specificity MH - Subcellular Fractions/chemistry EDAT- 1994/08/29 MHDA- 1994/08/29 00:01 PST - ppublish SO - Cancer Lett 1994 Aug 29;84(1):85-92. -------------------------------------------------------------------------------- 294: Dikic I et al. PC12 cells overexpressing the...[PMID: 7953556] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7953556 OWN - NLM STAT- MEDLINE DA - 19941212 DCOM- 19941212 LR - 20041117 PUBM- Print IS - 0960-9822 VI - 4 IP - 8 DP - 1994 Aug 1 TI - PC12 cells overexpressing the insulin receptor undergo insulin-dependent neuronal differentiation. PG - 702-8 AB - BACKGROUND: Stimulation of phaeochromocytoma PC12 cells by nerve growth factor leads to growth arrest and neuronal differentiation, whereas insulin induces various metabolic responses such as metabolism of glucose and lipids. Moreover, both insulin and epidermal growth factor stimulate the proliferation of PC12 cells. In spite of their different biological effects, nerve growth factor, insulin and epidermal growth factor induce very similar early responses in PC12 cells. Stimulation with nerve growth factor leads to the sustained activation and nuclear translocation of mitogen-activated protein (MAP) kinase. By contrast, both insulin and epidermal growth factor induce the transient activation of MAP kinase, without pronounced nuclear translocation of the enzyme. We have investigated whether the differential activation of signaling pathway components can account for the distinct cellular responses to these different growth factors. RESULTS: By overexpressing insulin receptors in PC12 cells, we observed insulin-dependent neurite outgrowth, similar to that induced by nerve growth factor in both non-transfected and overexpressing cells. Overexpression of insulin receptors in PC12 cells leads to a more pronounced, but similar pattern of insulin-induced tyrosine-phosphorylated proteins in PC12 cells, including enhanced recruitment of Grb2/Sos into a complex with either Shc or IRS1. MAP kinase activation in response to insulin stimulation of cells overexpressing the insulin receptor is similar to MAP kinase activation in response to NGF stimulation of parental or overexpressing PC12 cells: the activation is prolonged and nuclear translocation of the enzyme occurs. CONCLUSION: The differential subcellular localization and duration of MAP kinase activation induced by insulin and NGF may explain the difference in the biological actions of these two factors on PC12 cells. Our results show that the strength of the signal generated by a receptor with tyrosine kinase activity can influence the downstream signaling pathway, leading to cell differentiation instead of cell proliferation. AD - Department of Pharmacology, New York University Medical Center, New York 10016. FAU - Dikic, I AU - Dikic I FAU - Schlessinger, J AU - Schlessinger J FAU - Lax, I AU - Lax I LA - eng PT - Journal Article PL - ENGLAND TA - Curr Biol JID - 9107782 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Membrane Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Nerve Growth Factors) RN - 0 (Proteins) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Son of Sevenless Proteins) RN - 0 (growth factor receptor-bound protein-2) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Animals MH - Biological Transport MH - Ca(2+)-Calmodulin Dependent Protein Kinase/physiology MH - Cell Differentiation MH - Cell Nucleus/enzymology MH - Gene Expression MH - Humans MH - Insulin/pharmacology MH - Membrane Proteins/physiology MH - Neoplasm Proteins/biosynthesis/genetics/physiology MH - Nerve Growth Factors/pharmacology MH - PC12 Cells/drug effects/*physiology MH - Phosphorylation MH - Protein Processing, Post-Translational MH - Protein Structure, Tertiary MH - Proteins/chemistry/physiology MH - Rats MH - Receptor, Insulin/biosynthesis/genetics/*physiology MH - Recombinant Fusion Proteins/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - Son of Sevenless Proteins MH - Transfection EDAT- 1994/08/01 MHDA- 1994/08/01 00:01 PST - ppublish SO - Curr Biol 1994 Aug 1;4(8):702-8. -------------------------------------------------------------------------------- 295: Baron-Delage S et al. Reduced insulin receptor expr...[PMID: 8034618] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8034618 OWN - NLM STAT- MEDLINE DA - 19940817 DCOM- 19940817 LR - 20041117 PUBM- Print IS - 0021-9258 VI - 269 IP - 28 DP - 1994 Jul 15 TI - Reduced insulin receptor expression and function in human colonic Caco-2 cells by ras and polyoma middle T oncogenes. PG - 18686-93 AB - Taking advantage of the potent mitogenic effect exerted by insulin in human colonic cells, we used Caco-2 cells transfected with an activated (Val-12) human Haras gene or the polyoma middle T (PyMT) oncogene, a constitutive activator of pp60c-src tyrosine kinase activity, to investigate the effect of oncogenic p21ras and PyMT/pp60c-src on insulin mitogenic signaling. As compared to vector control Caco-2 cells, both oncogene-transfected cells exhibited: 1) a loss of response to insulin's stimulatory effect on mitogen-activated protein (MAP) kinase activity and cell proliferation, both of which were constitutively increased; 2) a decrease in insulin receptor (IR) affinity and insulin-stimulated exogenous tyrosine kinase activity, which resulted from increased protein kinase C (PKC) activity (Delage, S., Chastre, E., Empereur, S., Wicek, D., Veissiere, D., Capeau, J., Gespach, C., and Cherqui, G. (1993) Cancer Res. 53, 2762-2770), since IR alterations were corrected by PKC down-regulation; and 3) a decrease in both IR mRNA level and IR number, which was independent of PKC since it persisted after PKC down-regulation. In conclusion, this is the first evidence that oncogenic p21ras and PyMT/pp60c-src abolish insulin mitogenic signaling in human colonic cells through mechanisms involving (i) constitutive activation of MAP kinase and (ii) marked decreases in both IR function and expression which are mediated by PKC-dependent and PKC-independent pathways, respectively. AD - Laboratoire de Biologie Cellulaire, INSERM U.402, Faculte de Medecine Saint-Antoine, Paris, France. FAU - Baron-Delage, S AU - Baron-Delage S FAU - Capeau, J AU - Capeau J FAU - Barbu, V AU - Barbu V FAU - Chastre, E AU - Chastre E FAU - Levy, P AU - Levy P FAU - Gespach, C AU - Gespach C FAU - Cherqui, G AU - Cherqui G LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Antigens, Polyomavirus Transforming) RN - 0 (RNA, Messenger) RN - 11061-68-0 (Insulin) RN - 50-89-5 (Thymidine) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.123 (Ca(2+)-Calmodulin Dependent Protein Kinase) RN - EC 2.7.1.37 (Protein Kinase C) SB - IM GS - Ha-ras GS - ras MH - Antigens, Polyomavirus Transforming/*genetics MH - Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism MH - Cell Division/drug effects MH - Cell Line MH - Colonic Neoplasms MH - DNA Replication/drug effects MH - Dose-Response Relationship, Drug MH - *Genes, ras MH - Humans MH - Insulin/metabolism/*pharmacology MH - Insulin-Like Growth Factor I/metabolism/pharmacology MH - Kinetics MH - *Oncogenes MH - Protein Kinase C/metabolism MH - RNA, Messenger/metabolism MH - Receptor, Insulin/biosynthesis/*metabolism MH - Research Support, Non-U.S. Gov't MH - Thymidine/metabolism MH - *Transfection MH - Tumor Cells, Cultured EDAT- 1994/07/15 MHDA- 1994/07/15 00:01 PST - ppublish SO - J Biol Chem 1994 Jul 15;269(28):18686-93. -------------------------------------------------------------------------------- 296: Chen H et al. Proximal enhancer of the huma...[PMID: 8013752] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8013752 OWN - NLM STAT- MEDLINE DA - 19940725 DCOM- 19940725 LR - 20041117 PUBM- Print IS - 0012-1797 VI - 43 IP - 7 DP - 1994 Jul TI - Proximal enhancer of the human insulin receptor gene binds the transcription factor Sp1. PG - 884-9 AB - The insulin receptor is a growth regulator present on the surface of most cells that transmits a mitogenic signal in response to insulin. Thus, the gene for the insulin receptor is constitutively expressed at low levels in all cells. We characterize a constitutive enhancer element that is present in the proximal promoter of the human insulin receptor gene. We have localized the enhancer to a 26-base-pair (26-bp) sequence from -528 to -503. When this sequence is inserted into the proximal promoter, a three- to fourfold increase in promoter activity is observed, and when two copies are inserted, a five- to sixfold increase is seen. Electrophoretic mobility shift analysis demonstrates that nuclear factors binding to this sequence are found in many different cell types. At least two proteins with different specificities bind within this 26-bp sequence. The identity of the predominant binding protein is Sp1, because an oligonucleotide composed of an Sp1 consensus binding sequence can compete for several of the DNA-protein complexes. In addition, we demonstrate that purified Sp1 can bind to the 26-bp oligonucleotide and that this complex comigrates with a DNA-protein complex formed with a HeLa nuclear extract. Finally, an antibody to human Sp1 protein is able to bind to the enhancer DNA/HeLa protein complex and supershift this complex. These findings suggest that this sequence corresponds to a general element that may contribute to the ubiquitous expression of the human insulin receptor gene. AD - National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892. FAU - Chen, H AU - Chen H FAU - Walker, G E AU - Walker GE FAU - Taylor, S I AU - Taylor SI FAU - McKeon, C AU - McKeon C LA - eng PT - Journal Article PL - UNITED STATES TA - Diabetes JID - 0372763 RN - 0 (Oligodeoxyribonucleotides) RN - 0 (Transcription Factor, Sp1) RN - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.2.1.23 (beta-Galactosidase) SB - AIM SB - IM MH - 3T3 Cells MH - Animals MH - Base Sequence MH - Binding Sites MH - Carcinoma, Hepatocellular MH - Cell Line MH - Chloramphenicol O-Acetyltransferase/biosynthesis MH - Comparative Study MH - Consensus Sequence MH - *Enhancer Elements (Genetics) MH - Humans MH - Liver Neoplasms MH - Mice MH - Molecular Sequence Data MH - Oligodeoxyribonucleotides MH - *Promoter Regions (Genetics) MH - Receptor, Insulin/biosynthesis/*genetics MH - Research Support, Non-U.S. Gov't MH - Sequence Homology, Nucleic Acid MH - Transcription Factor, Sp1/isolation & purification/*metabolism MH - Transfection MH - Tumor Cells, Cultured MH - beta-Galactosidase/biosynthesis EDAT- 1994/07/01 MHDA- 1994/07/01 00:01 PST - ppublish SO - Diabetes 1994 Jul;43(7):884-9. -------------------------------------------------------------------------------- 297: Freund GG et al. Functional insulin and insuli...[PMID: 8205537] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8205537 OWN - NLM STAT- MEDLINE DA - 19940713 DCOM- 19940713 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 54 IP - 12 DP - 1994 Jun 15 TI - Functional insulin and insulin-like growth factor-1 receptors are preferentially expressed in multiple myeloma cell lines as compared to B-lymphoblastoid cell lines. PG - 3179-85 AB - While IGF-1 plays a role in early B-cell development, little is known of insulin and insulin-like growth factor-1 (IGF-1) action in post-marrow B-cells. Recently, our laboratory demonstrated that mouse and human multiple myeloma (MM) cell lines possess functional insulin receptors (IRs) and IGF-1 receptors (IGF-1Rs). In this study, we show that responsiveness to insulin and IGF-1 is more developed in human MM cell lines than in human B-lymphoblastoid cell lines. Two human MM cell lines (U266 and RPMI 8226) were compared to three B-lymphoblastoid cell lines [Epstein-Barr virus immortalized B-cells (EBV), a Burkitt lymphoma cell line (Ramos), and a non-EBV lymphoblastoid cell line (HS Sultan)]. Surface IR and IGF-1R expression, measured by flow cytometry, demonstrated that the MM cell lines expressed more IRs and IGF-1Rs than did the EBV, Ramos, or HS Sultan cell lines. In vitro receptor kinase activity of affinity-purified receptors showed that the MM cells had more phosphorylated receptors than did the EBV, Ramos, or HS Sultan cells. Intracellular receptor signaling was also markedly different between the two cell groups. Whole cell phosphorylation studies showed that MM cells possessed not only hormone-dependent receptor autophosphorylation (M(r) 97,000) but also substrate phosphorylation (M(r) 185,000; 60,000). The lymphoblastoid cells, while demonstrating receptor autophosphorylation (IR autophosphorylation in the EBV cell line at 200 nM hormone was similar to MM receptor phosphorylation at 2 nM), lacked hormone-responsive substrates. The MM cell lines contained significantly more hormone-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity than the B-lymphoblastoid cell lines. In the MM cells, PI 3-kinase was activated by at least 10-fold, but, in the B-lymphoblastoid cell lines, it was activated by no more than 2-fold. Hormone-responsive glucose metabolism was also greater in the MM cell lines. In the U266 cells, insulin increased lactate production 62 +/- 9 and 101 +/- 12% (mean +/- SE) at concentrations of 2 nM and 200 nM, respectively. IGF-1 produced 72 +/- 9 and 99 +/- 13% increases at similar concentrations. In the 8226 cells, insulin increased lactate production 4 +/- 4 and 36 +/- 15% at 2 and 200 nM, respectively. IGF-1 produced a 13 +/- 6 and 70 +/- 18% increase. In the EBV and Ramos cells, neither hormone increased lactate production by more than 10 +/- 3%.(ABSTRACT TRUNCATED AT 400 WORDS) AD - Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, New York 14642. FAU - Freund, G G AU - Freund GG FAU - Kulas, D T AU - Kulas DT FAU - Way, B A AU - Way BA FAU - Mooney, R A AU - Mooney RA LA - eng GR - DK 07092/DK/NIDDK GR - DK-38138/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Cancer Res JID - 2984705R RN - 11061-68-0 (Insulin) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - B-Lymphocytes/microbiology/physiology/*ultrastructure MH - Burkitt Lymphoma/metabolism/physiopathology/ultrastructure MH - Cell Line MH - Comparative Study MH - Herpesvirus 4, Human MH - Humans MH - Insulin/metabolism/pharmacology/physiology MH - Insulin-Like Growth Factor I/metabolism/pharmacology/physiology MH - Mice MH - Multiple Myeloma/metabolism/*pathology/physiopathology MH - Phenotype MH - Phosphorylation MH - Receptor, IGF Type 1/*physiology MH - Receptor, Insulin/*physiology MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/drug effects/physiology MH - Tumor Cells, Cultured/drug effects EDAT- 1994/06/15 MHDA- 1994/06/15 00:01 PST - ppublish SO - Cancer Res 1994 Jun 15;54(12):3179-85. -------------------------------------------------------------------------------- 298: Livingstone C et al. Analysis of the adenylate cyc...[PMID: 8010967] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8010967 OWN - NLM STAT- MEDLINE DA - 19940721 DCOM- 19940721 LR - 20041117 PUBM- Print IS - 0264-6021 VI - 300 ( Pt 3) DP - 1994 Jun 15 TI - Analysis of the adenylate cyclase signalling system, and alterations induced by culture with insulin, in a novel SV40-DNA-immortalized hepatocyte cell line (P9 cells). PG - 835-42 AB - An immortalized cell line, called P9, was derived from hepatocytes by transfection with SV40 DNA. These cells expressed enzyme activities characteristic of hepatocytes, namely glucose-6-phosphatase, glycogen phosphorylase, bilirubin glucuronyltransferase and both glucagon- and prostaglandin E1 (PGE1)-stimulated adenylate cyclase activities, albeit at decreased levels compared with native hepatocytes. Levels of the G-protein subunits alpha-Gi-2, alpha-Gi-3, G beta and the 'long' form of alpha-G2 (45 kDa) were approximately 4-fold higher relative to native hepatocytes, whereas those of the 'short' form of alpha-G2 (42 kDa) were lower by approximately 40%. Associated with this were marked alterations in the guanine nucleotide regulation of adenylate cyclase. Receptor-mediated stimulation, achieved by either PGE1 or glucagon, was apparent in P9 cells, although the latter was only evident upon amplification with forskolin. Glucagon-stimulated cyclic AMP accumulation in P9 cells did not exhibit desensitization, as in hepatocytes, nor was the phosphorylation of alpha-Gi-2 evident. Culture of P9 cells with insulin led to a dose-dependent decrease (EC50 0.2 +/- 0.1 nM) in the ability of PGE1 to stimulate adenylate cyclase activity, with the maximum effect attained after approximately 6 h. A comparable attenuation of stimulation was seen for glucagon- and guanine-nucleotide-stimulated adenylate cyclase activities. In cells cultured with insulin, lower levels of GTP were required to stimulate adenylate cyclase, ADP-ribosylation of the 45 kDa form of alpha-Gs with cholera toxin was attenuated, and the expression of both alpha Gi-2 and alpha-Gi-3 was increased. It is suggested that the expression of alpha-Gi-2 and alpha-Gi-3 may be directly regulated by the action of insulin in hepatocytes and P9 cells. AD - Department of Biochemistry, University of Glasgow, Scotland, U.K. FAU - Livingstone, C AU - Livingstone C FAU - MacDonald, C AU - MacDonald C FAU - Willett, B AU - Willett B FAU - Houslay, M D AU - Houslay MD LA - eng PT - Journal Article PL - ENGLAND TA - Biochem J JID - 2984726R RN - 11061-68-0 (Insulin) RN - 20762-30-5 (Adenosine Diphosphate Ribose) RN - 66428-89-5 (Forskolin) RN - 745-65-3 (Alprostadil) RN - 86-01-1 (Guanosine Triphosphate) RN - 9007-92-5 (Glucagon) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 3.6.1.- (GTP-Binding Proteins) RN - EC 4.6.1.1 (Adenylate Cyclase) SB - IM MH - Adenosine Diphosphate Ribose/metabolism MH - Adenylate Cyclase/*metabolism MH - Alprostadil/pharmacology MH - Animals MH - Cell Line MH - Cell Transformation, Viral MH - Forskolin/pharmacology MH - GTP-Binding Proteins/physiology MH - Glucagon/pharmacology MH - Guanosine Triphosphate/metabolism MH - Insulin/*pharmacology MH - Liver/cytology/*metabolism MH - Male MH - Rats MH - Rats, Sprague-Dawley MH - Receptor, Insulin/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction EDAT- 1994/06/15 MHDA- 1994/06/15 00:01 PST - ppublish SO - Biochem J 1994 Jun 15;300 ( Pt 3):835-42. -------------------------------------------------------------------------------- 299: Peterson EP et al. NIH 3T3 cells transfected wit...[PMID: 8188769] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8188769 OWN - NLM STAT- MEDLINE DA - 19940621 DCOM- 19940621 LR - 20041117 PUBM- Print IS - 0021-9541 VI - 159 IP - 3 DP - 1994 Jun TI - NIH 3T3 cells transfected with a yeast H(+)-ATPase have altered sensitivity to insulin, insulin growth factor-I, and platelet-derived growth factor-AA. PG - 551-60 AB - The role of intracellular pH (pHin) in the regulation of cell growth in both normal and transformed cells is a topic of considerable controversy. In an effort to study this relationship NIH 3T3 cells were stably transfected with the gene for the yeast H(+)-ATPase, constitutively elevating their pHin. The resulting cell line, RN1a, has a transformed phenotype: The cells are serum independent for growth, clone in soft agar, and form tumors in nude mice. In the present study, we further characterize this system in order to understand how transfection with this proton pump leads to serum-independent growth, using defined media to investigate the effects of specific growth factors on the transfected and parental NIH 3T3 cells. While both cell lines show similar growth increases in response to platelet-derived growth factor (PDGF)-BB and epidermal growth factor (EGF), they respond differently to insulin, insulin-like growth factor-I (IGF-I) and PDGF-AA. RN1a cells exhibit increased growth at nanomolar concentrations of insulin but the parental cells had only a relatively minor response to insulin at 10 microM. Both cell lines showed some response to IGF-I in the nanomolar range but the response of RN1a cells was much larger. Differences in insulin and IGF-I receptor number alone could not explain these results. The two cell lines also respond differently to PDGF-AA. RN1a cells are relatively insensitive to stimulation by PDGF-AA and express fewer PDGF alpha receptors as shown by Northern blots and receptor-binding studies. We propose a unifying hypothesis in which the H(+)-ATPase activates a downstream element in the PDGF-AA signal transduction pathway that complements insulin and IGF-I signals, while leading to downregulation of the PDGF alpha receptor. AD - Departments of Biochemistry, University of Arizona, College of Medicine, Tucson 85724. FAU - Peterson, E P AU - Peterson EP FAU - Martinez, G M AU - Martinez GM FAU - Martinez-Zaguilan, R AU - Martinez-Zaguilan R FAU - Perona, R AU - Perona R FAU - Gillies, R J AU - Gillies RJ LA - eng PT - Journal Article PL - UNITED STATES TA - J Cell Physiol JID - 0050222 RN - 0 (Culture Media, Serum-Free) RN - 0 (Platelet-Derived Growth Factor) RN - 0 (Recombinant Proteins) RN - 0 (platelet-derived growth factor A) RN - 0 (platelet-derived growth factor BB) RN - 11061-68-0 (Insulin) RN - 62229-50-9 (Epidermal Growth Factor) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.112 (Receptor, IGF Type 1) RN - EC 2.7.1.112 (Receptor, Insulin) RN - EC 2.7.1.112 (Receptors, Platelet-Derived Growth Factor) RN - EC 3.6.3.14 (Proton-Translocating ATPases) SB - IM MH - 3T3 Cells MH - Animals MH - Cell Division/*drug effects MH - Cell Line MH - Cell Line, Transformed MH - *Cell Transformation, Neoplastic MH - Comparative Study MH - Culture Media, Serum-Free MH - Epidermal Growth Factor/pharmacology MH - Hydrogen-Ion Concentration MH - Insulin/*pharmacology MH - Insulin-Like Growth Factor I/*pharmacology MH - Kidney MH - Kinetics MH - Mice MH - Mice, Nude MH - Platelet-Derived Growth Factor/*pharmacology MH - Point Mutation MH - Proton-Translocating ATPases/biosynthesis/*metabolism MH - Rats MH - Receptor, IGF Type 1/biosynthesis MH - Receptor, Insulin/biosynthesis MH - Receptors, Platelet-Derived Growth Factor/biosynthesis MH - Recombinant Proteins/pharmacology MH - Research Support, Non-U.S. Gov't MH - Saccharomyces cerevisiae/*enzymology/genetics MH - Transfection EDAT- 1994/06/01 MHDA- 1994/06/01 00:01 PST - ppublish SO - J Cell Physiol 1994 Jun;159(3):551-60. -------------------------------------------------------------------------------- 300: Hotamisligil GS et al. Tumor necrosis factor alpha i...[PMID: 8197147] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 8197147 OWN - NLM STAT- MEDLINE DA - 19940627 DCOM- 19940627 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 91 IP - 11 DP - 1994 May 24 TI - Tumor necrosis factor alpha inhibits signaling from the insulin receptor. PG - 4854-8 AB - Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin. AD - Dana-Farber Cancer Institute, Boston, MA 02115. FAU - Hotamisligil, G S AU - Hotamisligil GS FAU - Murray, D L AU - Murray DL FAU - Choy, L N AU - Choy LN FAU - Spiegelman, B M AU - Spiegelman BM LA - eng GR - DK 42539/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Tumor Necrosis Factor-alpha) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - 3T3 Cells MH - Adipocytes/cytology/drug effects MH - Animals MH - Cell Line MH - Insulin/metabolism MH - Mice MH - Receptor, Insulin/*antagonists & inhibitors/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Signal Transduction/*drug effects MH - Tumor Necrosis Factor-alpha/*pharmacology EDAT- 1994/05/24 MHDA- 1994/05/24 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1994 May 24;91(11):4854-8. -------------------------------------------------------------------------------- 301: Prasad KV et al. T-cell antigen CD28 interacts...[PMID: 8146197] Related Articles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 8146197 OWN - NLM STAT- MEDLINE DA - 19940505 DCOM- 19940505 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 91 IP - 7 DP - 1994 Mar 29 TI - T-cell antigen CD28 interacts with the lipid kinase phosphatidylinositol 3-kinase by a cytoplasmic Tyr(P)-Met-Xaa-Met motif. PG - 2834-8 AB - The T-cell antigen CD28 provides a costimulatory signal that is required for T-cell proliferation. T-cell receptor zeta/CD3 engagement without CD28 ligation leads to a state of nonresponsiveness/anergy, thereby implicating CD28 in the control of peripheral tolerance to foreign antigens or tumors. A key unresolved question has concerned the mechanism by which CD28 generates intracellular signals. Phosphatidylinositol 3-kinase (PI 3-kinase) is a lipid kinase with Src-homology 2 (SH2) domain(s) that binds to the platelet-derived growth factor receptor (PDGF-R), an interaction that is essential for signaling by growth factor. In this study, we demonstrate that CD28 binds to PI 3-kinase by means of a Y(P)MXM motif within its cytoplasmic tail. CD28-associated PI 3-kinase was detected by lipid kinase and HPLC analysis as well as by reconstitution experiments with baculoviral-expressed p85 subunit of PI 3-kinase. CD28 bound directly to the p85 subunit without the need for the associated p110 subunit. Site-directed mutagenesis and peptide competition analysis using Y(P)-MXM-containing peptides showed that PI 3-kinase bound to a Y(P)MXM motif within the CD28 cytoplasmic tail (residues 191-194). Mutation of the Y191 within the motif resulted in a complete loss of binding, while mutation of M194 caused partial loss of binding. Binding analysis showed that the CD28 Y(P)-MXM motif bound to the p85 C- and N-terminal SH2 domains with an affinity comparable to that observed for PDGF-R and insulin receptor substrate 1. In terms of signaling, CD28 ligation induced a dramatic increase in the recruitment and association of PI 3-kinase with the receptor. CD28 is likely to use PI 3-kinase as the second signal leading to T-cell proliferation, an event with implications for anergy and peripheral T-cell tolerance. AD - Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA 02115. FAU - Prasad, K V AU - Prasad KV FAU - Cai, Y C AU - Cai YC FAU - Raab, M AU - Raab M FAU - Duckworth, B AU - Duckworth B FAU - Cantley, L AU - Cantley L FAU - Shoelson, S E AU - Shoelson SE FAU - Rudd, C E AU - Rudd CE LA - eng PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Antigens, CD28) RN - 0 (Peptide Fragments) RN - 0 (Recombinant Proteins) RN - EC 2.7.1 (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 2.7.1.137 (1-Phosphatidylinositol 3-Kinase) SB - IM MH - 1-Phosphatidylinositol 3-Kinase MH - Amino Acid Sequence MH - Animals MH - Antigens, CD28/genetics/*metabolism MH - Baculoviridae/genetics MH - Binding, Competitive MH - Cells, Cultured MH - DNA Mutational Analysis MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - Peptide Fragments/metabolism MH - Phosphotransferases (Alcohol Group Acceptor)/*metabolism MH - Recombinant Proteins/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction MH - T-Lymphocytes/*immunology EDAT- 1994/03/29 MHDA- 1994/03/29 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1994 Mar 29;91(7):2834-8. -------------------------------------------------------------------------------- 302: Morris SW et al. Fusion of a kinase gene, ALK,...[PMID: 8122112] Related Articles, Gene, UniGene, Nucleotide, Protein, OMIM, GEO Profiles, Cited in PMC, Cited in Books, Books, LinkOut PMID- 8122112 OWN - NLM STAT- MEDLINE DA - 19940404 DCOM- 19940404 LR - 20041117 PUBM- Print IS - 0036-8075 VI - 263 IP - 5151 DP - 1994 Mar 4 TI - Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. PG - 1281-4 AB - The 2;5 chromosomal translocation occurs in most anaplastic large-cell non-Hodgkin's lymphomas arising from activated T lymphocytes. This rearrangement was shown to fuse the NPM nucleolar phosphoprotein gene on chromosome 5q35 to a previously unidentified protein tyrosine kinase gene, ALK, on chromosome 2p23. In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK). Expressed in the small intestine, testis, and brain but not in normal lymphoid cells, ALK shows greatest sequence similarity to the insulin receptor subfamily of kinases. Unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas. AD - Department of Experimental Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105. FAU - Morris, S W AU - Morris SW FAU - Kirstein, M N AU - Kirstein MN FAU - Valentine, M B AU - Valentine MB FAU - Dittmer, K G AU - Dittmer KG FAU - Shapiro, D N AU - Shapiro DN FAU - Saltman, D L AU - Saltman DL FAU - Look, A T AU - Look AT LA - eng SI - GENBANK/U04946 GR - CA 21765/CA/NCI GR - KO8 CA 01702/CA/NCI GR - PO1 CA 20180/CA/NCI PT - Journal Article PL - UNITED STATES TA - Science JID - 0404511 RN - 0 (Nuclear Proteins) RN - 0 (Phosphoproteins) RN - 0 (RNA, Messenger) RN - 117896-08-9 (nucleophosmin) RN - EC 2.7.1.- (anaplastic lymphoma kinase) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) SB - IM EIN - Science. 1995 Jan 20;267(5196):316-7. PMID: 7824924 GS - ALK GS - NPM MH - Amino Acid Sequence MH - Base Sequence MH - Brain/enzymology MH - Cell Transformation, Neoplastic MH - Chromosome Walking MH - Chromosomes, Human, Pair 2 MH - Chromosomes, Human, Pair 5 MH - Cloning, Molecular MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Intestine, Small/enzymology MH - Lymphoma, Large-Cell, Ki-1/chemistry/enzymology/*genetics MH - Male MH - Molecular Sequence Data MH - Nuclear Proteins/chemistry/*genetics MH - Phosphoproteins/chemistry/*genetics MH - Promoter Regions (Genetics) MH - Protein-Tyrosine Kinase/chemistry/*genetics MH - RNA, Messenger/genetics/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Alignment MH - Signal Transduction MH - Testis/enzymology MH - *Translocation, Genetic MH - Tumor Cells, Cultured EDAT- 1994/03/04 MHDA- 1994/03/04 00:01 PST - ppublish SO - Science 1994 Mar 4;263(5151):1281-4. -------------------------------------------------------------------------------- 303: Nielsen SU et al. Differentiational regulation ...[PMID: 8117746] Related Articles, Substance via MeSH, Protein, Books, LinkOut PMID- 8117746 OWN - NLM STAT- MEDLINE DA - 19940407 DCOM- 19940407 LR - 20041203 PUBM- Print IS - 0006-3002 VI - 1211 IP - 2 DP - 1994 Mar 3 TI - Differentiational regulation and phosphorylation of the fatty acid-binding protein from rat mammary epithelial cells. PG - 189-97 AB - From the soluble protein fraction of lactating rat mammary epithelial cells, fatty acid-binding protein (FABP) was isolated by immunoaffinity chromatography. After digestion with trypsin, peptides were characterized with time-of-flight mass spectrometry and revealed identity with corresponding peptides derived from the heart-type FABP isolated from rat heart. In addition, by electrospray mass spectrometry the molecular mass has been determined to 14683.9 +/- 3 Da, further corroborating the identity. The content of FABP in mammary glands from virgin, pregnant and lactating rats was evaluated using two-dimensional gel electrophoresis and a FABP-specific immunosorbent assay. In the two-dimensional gels FABP was the apparently most abundant cytosolic protein in mammary epithelial cells from rats in late pregnancy as well as from lactating rats. The content of FABP was 59 +/- 19 microgram/mg (n = 11) of soluble proteins from the fully differentiated lactating mammary gland as determined by ELISA. This value represented an 80-fold increase compared with the FABP content of mammary gland from virgin rats, and is comparable with the level found in rat heart. Upon stimulation with insulin a small fraction of FABP was phosphorylated in lactating mammary epithelial cells. In conclusion, these findings indicate that the FABPs from rat mammary gland and heart are identical and further suggest that in mammary gland this FABP may play a role in signal transduction downstream from the insulin receptor. AD - Department of Biochemistry, University of Munster, Germany. FAU - Nielsen, S U AU - Nielsen SU FAU - Rump, R AU - Rump R FAU - Hojrup, P AU - Hojrup P FAU - Roepstorff, P AU - Roepstorff P FAU - Spener, F AU - Spener F LA - eng PT - Journal Article PL - NETHERLANDS TA - Biochim Biophys Acta JID - 0217513 RN - 0 (Carrier Proteins) RN - 0 (Fabp5 protein, mouse) RN - 0 (Fabp7 protein, rat) RN - 0 (Neoplasm Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (fatty acid-binding proteins) RN - 11061-68-0 (Insulin) RN - EC 3.4.21.4 (Trypsin) SB - IM MH - Amino Acid Sequence MH - Animals MH - Carrier Proteins/chemistry/isolation & purification/*metabolism MH - Cell Differentiation MH - Chromatography, Affinity MH - Electrophoresis, Gel, Two-Dimensional MH - Epithelium/chemistry MH - Female MH - Homeostasis MH - Insulin/pharmacology MH - Lactation MH - Mammary Glands, Animal/*chemistry MH - Molecular Sequence Data MH - Molecular Weight MH - *Neoplasm Proteins MH - *Nerve Tissue Proteins MH - Phosphorylation MH - Pregnancy MH - Rats MH - Rats, Wistar MH - Research Support, Non-U.S. Gov't MH - Spectrum Analysis, Mass MH - Trypsin/metabolism EDAT- 1994/03/03 MHDA- 1994/03/03 00:01 PST - ppublish SO - Biochim Biophys Acta 1994 Mar 3;1211(2):189-97. -------------------------------------------------------------------------------- 304: Sung CK et al. Deletion of residues 485-599 ...[PMID: 8015549] Related Articles, Substance via MeSH, Books, LinkOut PMID- 8015549 OWN - NLM STAT- MEDLINE DA - 19940728 DCOM- 19940728 LR - 20041117 PUBM- Print IS - 0888-8809 VI - 8 IP - 3 DP - 1994 Mar TI - Deletion of residues 485-599 from the human insulin receptor abolishes antireceptor antibody binding and influences tyrosine kinase activation. PG - 315-24 AB - We have studied insulin and antireceptor antibody binding to mutated human insulin receptors deleted of residues 485-599 in the alpha-subunit by site-directed mutagenesis. Both normal and mutated receptors were expressed in rat HTC hepatoma cells. Cells expressing either the normal receptor or the mutated receptor retained the ability to bind insulin. In contrast to the normal receptor, however, the mutated receptor failed to interact with antireceptor alpha-subunit antibodies. The inability of the mutated receptor to interact with various antireceptor antibodies was further documented by photoaffinity labeling studies. In intact HTC cells expressing mutated receptors, basal insulin receptor tyrosine autophosphorylation was 2-fold elevated when compared to cells expressing normal receptors. In these cells, however, the response of this function to insulin was blunted. When receptors were isolated from these cells and assayed for both autophosphorylation and phosphotransferase activities toward the synthetic substrate poly(Glu, Tyr), the response to insulin was also blunted. To study the ability of the mutated receptor to transmembrane signal, insulin stimulation of S6 kinase activity was measured. In cells with mutated receptors, in concert with the insulin receptor kinase data, basal S6 kinase activity was elevated, and the response to insulin was blunted. The data suggest, therefore, that residues 485-599 in the alpha-subunit of the insulin receptor are critical for antireceptor antibody binding, but not for insulin binding. Moreover, these data suggest that residues 485-599 contain a regulatory domain for insulin regulation of receptor beta-subunit functions. AD - Department of Medicine, Mount Zion Medical Center, University of California, San Francisco 94115. FAU - Sung, C K AU - Sung CK FAU - Wong, K Y AU - Wong KY FAU - Yip, C C AU - Yip CC FAU - Hawley, D M AU - Hawley DM FAU - Goldfine, I D AU - Goldfine ID LA - eng GR - DK-44834/DK/NIDDK PT - Journal Article PL - UNITED STATES TA - Mol Endocrinol JID - 8801431 RN - 0 (Antibodies, Monoclonal) RN - 0 (DNA, Neoplasm) RN - 0 (Iodine Radioisotopes) RN - 11061-68-0 (Insulin) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.112 (Receptor, Insulin) SB - IM MH - Animals MH - Antibodies, Monoclonal/*immunology/*metabolism MH - Base Sequence MH - Blotting, Western MH - DNA, Neoplasm/analysis/genetics MH - Enzyme Activation/genetics MH - *Gene Deletion MH - Humans MH - Insulin/metabolism/physiology MH - Iodine Radioisotopes MH - Liver Neoplasms, Experimental/chemistry/pathology/ultrastructure MH - Molecular Sequence Data MH - Mutation MH - Phosphorylation MH - Precipitin Tests MH - Protein-Tyrosine Kinase/*metabolism MH - Rats MH - *Receptor, Insulin/*genetics/immunology/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 1994/03/01 MHDA- 1994/03/01 00:01 PST - ppublish SO - Mol Endocrinol 1994 Mar;8(3):315-24.