Center for Environmental Genetics and Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056
Received May 20, 2004; accepted July 14, 2004
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key Words: Jun N-terminal kinase (JNK); extracellular signal-regulated kinase (ERK); aromatic hydrocarbon receptor (AHR); Ah receptor nuclear translocator (ARNT); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); cytochrome p450 (CYP).
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It is important to note that TCDD exerts diverse species-specific toxic effects in animals and humans, including chloracne, immune, reproductive, and developmental toxicities, carcinogenicity, wasting syndrome, and death. Activation of the Ah receptor by its ligands alone cannot fully explain the diversity of TCDD toxic effects, to which other TCDD-induced molecular pathways also contribute (Enan et al., 1998; Tannheimer et al., 1998
). In addition to its role in AHR binding, TCDD activates various intracellular signal transduction pathways. Recent studies have shown that, independent of the AHR, TCDD activates the ERKs and the JNKs (Tan et al., 2002
), which, along with the p38s, constitute the family of the mitogen-activated protein kinases (MAPK) (Cobb and Goldsmith, 1995
). The MAPKs function as critical intracellular signaling mediators whose activities are controlled by the MAPKKK-MAPKK signaling cascades. The activated MAPKs may in turn phosphorylate transcription factors and modulate the function of these factors, thus participating in the regulation of gene expression responsible for a wide array of biological responses (Hunter and Karin, 1992
). We have shown that TCDD-stimulated MAPKs contribute to Ah receptor activity and receptor-dependent gene expression (Tan et al., 2002
). The MAPKs might be additional cellular targets through which TCDD modulates the function of AHR complexes.
In this work, we have further investigated the effects of MAPK on AHR and ARNT functions. We show that activation of either JNK or ERK is sufficient to potentiate the transcriptional activity of ARNT, leading to the enhancement of AHR/ARNTdependent transcription. Both JNK and ERK activities are essentially required for the optimal induction of AHR-dependent gene expression by TCDD. Furthermore, JNK2 ablation in mice greatly reduces AHR-dependent CYP1A1 induction by TCDD in a tissue-specific manner. These results demonstrate a role for the MAPKs in the control of AHR/ARNT activity, which might contribute to the diverse and tissue-specific toxicity of TCDD.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Mice, cell lines, growth conditions, and transfections. Jnk2-knockout mice (Sabapathy et al., 1999) were backcrossed to C57BL6 mice for five generations. Wild type and Jnk2-knockout mice were injected intraperitoneally with various doses of TCDD dissolved in corn oil or with an equivalent volume of corn oil, and 48 h after injection the mice were sacrificed and thymus, liver, and testis were collected. All experimental procedures using these mice were approved by the Ethics Committee of the University of Cincinnati.
The mouse Hepa-1 hepatoma cell line, its derivative c4, having a mutant inactive ARNT (Reisz-Porszasz et al., 1994), and the African Green Monkey adult kidney CV-1 cells were cultured in D-MEM, supplemented with 10% fetal bovine serum and 1% antibiotics in a humidified 5% CO2 atmosphere. The Jnk1(/)Jnk2(/) (Sabapathy et al., 2001
) and Ahr(/) mouse embryo fibroblasts were prepared as previously described (Tan et al., 2002
). Cells were transfected using Lipofectamine (Introgen, Carlsbad, CA) according to the protocols recommended by the manufacturer. All the cell culture reagents were from Invitrogen. Twenty-four hours after transfection, the cells were starved in serum-free medium for 16 h in the presence of the chemicals to be tested. Cell lysates were prepared in Reporter Lysis Buffer (Promega, Madison, WI) to determine luciferase and ß-galactosidase activities in a Wallac plate reader luminometer. Relative luciferase activities were obtained after normalization to ß-galactosidase activity.
Plasmid constructs. The mammalian expression vectors for AHR, ARNT, and the luciferase reporter pAhRDTKLuc3, which contains the mouse Cyp1a1 AHR-responsive AhRD enhancer fused to the herpes simplex virus type 1 thymidine kinase minimum promoter, have been described elsewhere (Chang and Puga, 1998). To generate the pAd-luc expression vector, a 303 bp Pst I/PvuII fragment containing the adenovirus major late promoter (MLP) with the E-box core sequence CACGTG was isolated from pMLH100 (Hawley and Roeder, 1987
) and cloned into pGL3 by standard molecular cloning procedures. The mammalian expression vectors for kinase-inactive MEKK1 and constitutively active MEKK1, Raf1, MEK1, and MEK6 have been described elsewhere (Baud et al., 1999
). The GAL4 fusion vector for mammalian expression (Sadowski et al., 1992
) was used to construct the expression vectors for fusion proteins containing the DNA-binding domain of the yeast GAL4 protein fused to mouse AHR or ARNT by standard molecular cloning techniques.
In vivo competition assay. Hepa-1 cells at 90% confluence were pre-treated for 0.5 h with TCDD (200 nM), B[a]P (20 µM), and various MAPK inhibitors at 5 µM. 3H-TCDD was added at 2 nM for 0.5 h, and the cells were lysed 90 min thereafter. A total of 800 µm of the lysates were used for immunoprecipitation using anti-AHR antibodies. The amount of 3H-TCDD bound to the AHR in the immunoprecipitates was measured by scintillation counting.
Cell and tissue lysate preparation and Western blot analyses. To measure CYP1A1 induction, Hepa-1 cells were pretreated with 5 µM U0126 (MEK inhibitor) for 30 min. Hepa-1, wild type or Jnk1(/)Jnk2(/) MEFs were incubated in growth medium with 5 nM TCDD for the indicated times. Mouse tissues were homogenized in lysis buffer. Of the total cell and tissue lysates, 100 to 200 µm was resolved in 10% SDS-polyacrylamide gels and transferred to a nitrocellulose membrane, followed by Western blot analyses with antibodies to CYP1A1, AHR, ARNT, and ß-actin, as described elsewhere (Tan et al., 2002).
RNA isolation and real-time RT-PCR. Total RNA was isolated from wild type and Jnk1(/) Jnk2(/) fibroblasts and from thymus, testis, and liver of wild type and Jnk2-knockout mice using Tri-reagent (Molecular Research Center, Cincinnati, OH) and purified by RNeasy Mini Kit (Qiagen, Valencia, CA). Reverse transcription was performed using SuperScript II RNase H reverse transcriptase (Invitrogen). Real-time PCR was carried out with a Cepheid PCR Analyzer using SYBR Green I (Stratagene) as described elsewhere (Zhang et al., 2003), using primers for CYP1A1, CYP1B1, and ß-actin. The cycle threshold (CT) of each sample was automatically determined to be the first cycle at which a significant increase in optical signal above an arbitrary baseline set at 30 fluorescence units was detected. All determinations were done in triplicate and experiments were repeated at least twice. The values shown for fold-induction are calculated by raising 2 to the power of the CT ratios of experimental to control cells normalized to ß-actin mRNA in the same sample.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The only available specific JNK inhibitor is SP600125; hence, a study similar to the one described above could not be done for JNK. To investigate the role of JNK on AHR/ARNTdependent gene expression, we studied CYP1A1 induction in MEFs prepared from Jnk1(/)Jnk2(/) double-knockout fetuses, which lack JNK1 and JNK2 activities. In agreement with our previous observations (Tan et al., 2002), wild type MEFs exhibited very low, if any, basal CYP1A1 expression, and TCDD, by 4 h of treatment, caused an obvious induction of both CYP1A1 mRNA and protein. The induction was markedly reduced to almost basal levels in Jnk1(/)Jnk2(/) MEFs (Fig. 2A and 2B). Because wild type and Jnk1(/)Jnk2(/) fibroblasts have similar levels of AHR and ARNT (Fig. 2C), we conclude that lack of JNK is the major cause of CYP1A1 reduction in these cells. Together, these results indicate that JNK and ERK MAP kinases are essential for maximal induction of an AHR/ARNTdependent gene by TCDD.
|
|
MAPK activation potentiates the activity of AHR/ARNT complexes in gene expression. Next, we asked how the MAPKs affect the activity of AHR/ARNT complexes. As the MAPKs are known for their functions in the nucleus to modulate the activity of transcription factors, we hypothesized that the MAPKs might be involved in the induction of the transcriptional activity of AHR and ARNT in the nucleus. To investigate the possible cross-talk between the MAPKs and AHR complexes, we chose to use the African Green Monkey kidney cell line CV-1, which does not express endogenous AHR, but expresses ARNT. Ectopic expression of exogenous AHR in these cells results in ligand-independent constitutive AHR nuclear localization (Chang and Puga, 1998). This is an important experimental characteristic that makes these cells most suitable for studying the direct effects of MAPKs on nuclear AHR/ARNT complexes, bypassing the requirement for TCDD treatment to induce receptor transformation and translocation.
In agreement with previous reports (Chang and Puga, 1998), ectopic expression of exogenous AHR and ARNT in CV-1 cells in the absence of ligand resulted in high basal levels of luciferase expression from an AHR-dependent luciferase reporter. Previous studies have identified MAPKKKs and MAPKKs that activate specific MAPKs: Raf1 and MEK1(EE) are activators of the ERK pathway (Cobb and Goldsmith, 1995
), MEKK1 preferentially activates the JNK MAPK (Zhang et al., 2003
), and MEK6 (DD) is an upstream activator for p38 (Raingeaud et al., 1996
). We expressed individual MAPK activators, together with AHR and ARNT. The AHR/ARNT-dependent luciferase activities were significantly increased in cells that co-expressed MEK1(EE), a mutant form of MEK1 that constitutively activates the ERK pathway (Fig. 4A). In contrast, the expression of MEK6 (DD), a constitutively active kinase specific for the p38 pathway, did not have an overt effect, confirming our previous observation that p38 did not play a role in TCDD-stimulated Ah receptor activation (Tan et al., 2002
). In the absence of AHR, MEK1(EE) by itself did not activate luciferase expression (data not shown). MEK1(EE)-stimulated AHR activity depended on the activation of ERK, because U0126 prevented nearly 80% of the MEK(EE)-induced and AHR-dependent luciferase activity, whereas SB202190, an inhibitor of the p38 pathways, did not affect it significantly (Fig. 4A).
|
The extracellular factors that activate the MAPKs might activate transcription directed by AHR/ARNT complexes. Indeed, treatment of the AHR/ARNT transfected CV-1 cells with EGF or with serum, both known extracellular stimuli that activate JNK and ERK (Assefa et al., 1997), resulted in a fourfold to fivefold induction of AHR-dependent luciferase activity (Fig. 4C). The enhancement of AHR-dependent luciferase activity by TCDD was further elevated 2.5-fold to threefold after treatment with EGF and serum (Fig. 4C). Not all stimuli that induce MAPK activity, however, lead to the activation of the AHR/ARNT complex. For example, 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of PKC that activates ERK (She et al., 2002
), failed to exert an effect on AHR-dependent luciferase expression (Fig. 4C). Hence, activation of the PKC-ERK pathway is not sufficient, and EGF and serum must activate additional cellular events to potentiate AHR/ARNTdependent transcription.
The MAPKs enhance the transcriptional activity of ARNT, but not AHR. To examine the roles of MAPKs in the transcription activity of AHR and ARNT, we tested fusion proteins containing the GAL4 DNA binding domain fused to AHR or ARNT for their ability to stimulate the expression of a luciferase reporter driven by a GAL4 promoter. We examined the activation of GAL4-AHR in CV-1 cells, which possess normal ARNT levels but are negative for AHR. Expression of GAL4-AHR led to a fivefold induction of luciferase activity over GAL4 alone, suggesting that GAL4-AHR is already transcriptionally active (data not shown). Active MEKK1 and Raf1 increased luciferase activity 2.5-fold and 4.5-fold, respectively, whereas expression of kinase-inactive MEKK1 did not cause any changes in luciferase activity (Fig. 5A). However, when we looked at GAL4-AHR activation in c4 cells, a Hepa-1 derivative lacking functional ARNT, co-expression of active MEKK1 or Raf1 did not further increase luciferase activity over that induced by GAL4-AHR alone. As the active MAPKKKs potentiate AHR transcriptional activity only in ARNT-positive cells, but not in ARNT-negative cells, these results favor the idea that the MAPKs function through the activation of ARNT, the heterodimerization partner of AHR.
|
In addition to being a partner of AHR and HIF-1, ARNT also forms homodimers that bind to the E box core sequence CACGTG within the adenovirus major late promoter (Sogawa et al., 1995b
). This feature allowed us to measure ARNT/ARNT complex activity directly, using the adenovirus promoter-driven luciferase reporter pAd-luc. In AHR-negative CV-1 cells, induction of pAd-luc by ARNT overexpression was further induced eightfold and fourfold, respectively, by
MEKK1-activated JNK and MEK(EE)-activated ERK. Similar induction of luciferase activities was observed on pAhRDTKLuc3, the expression of which was regulated by the AHR/ARNT complexes (Fig. 5C). These data confirm that MAPK-mediated ARNT activation can lead to the transcriptional activation of either ARNT-ARNT homodimers or ARNT-AHR heterodimers.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
How much the ARNT contributes to the transcriptional activity of the AHR/ARNT complex remains a controversial issue (Reisz-Porszasz et al., 1994; Sogawa et al., 1995a
). Important in this context is that ERK inhibition and JNK1 and JNK2 depletion lead to suppression of TCDD-induced CYP1A1 expression. Furthermore, the Jnk2-null mice have reduced CYP1A1 induction in thymus and testis, but not in liver. Although in vitro, JNK2 displays very little, if any, cell-type specificity in activity and function, in vivo, it functions in a tissue-specific and stimulus-dependent manner, required for thymocyte development (Sabapathy et al., 1999
; Conze et al., 2002
). In fact, studies of genetically modified mice have revealed the tissue-specific roles for other MAPKs (Mazzucchelli et al., 2002
; Adams et al., 2000
). Hence, the MAPKs might determine or contribute to ARNT activation in a tissue-specific manner, with JNK2 being critical for some tissues and ERK for others. Our findings might be relevant to unexplained tissue-specific toxicity of TCDD, which, for example, causes hypertrophy of the liver, but atrophy of the thymus and testis (Staples et al., 1998
; Whitlock, 1999
). Atrophy of thymus and testis might be related to JNK2 stimulation by TCDD and a combination of ensuing CYP1A1 induction with other downstream events. Unlike CYP1A1, CYP1B1 is transcriptionally regulated through both AHR-dependent and cAMP-dependent mechanisms (Zheng et al., 2003
). We find that CYP1B1 expression is unaffected by JNK ablation in all tissues examined. Perhaps in tissues where cAMP signals are intense, JNK2-regulated AHR/ARNT activity is less important for CYP1B1 transcription. The contrast between the effects on CYP1A1 and CYP1B1 expression suggests that the role of JNK in AHR activity is not only tissue-specific but also gene-specific. Jnk1(/)Jnk2(/) double knockout mice are not viable, and so it is unfeasible to test whether complete JNK ablation in mice would lead to a more profound effect on the expression of CYP1A1 and CYP1B1.
Growth promoter and MAPK activators, such as EGF and serum, further potentiate TCDD-induced AHR activities, suggesting that maximal AHR activation requires the participation of other environmental and extracellular factors. These observations are particularly intriguing because, in addition to being targets for TCDD, the JNK and ERK are controlled by many other growth and environmental signals. The MAPKs might serve as a centerpiece for signal integration in the regulation of AHR/ARNTmediated gene expression. Activation of MAP kinases might be an alternative combinatorial mechanism by which TCDD and other environmental agents participate in the regulation of AHR functions. The involvement of MAP kinases in TCDD signaling may have a broad impact on the diversity and tissue-specific TCDD toxic, adaptive and biological effects.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
1 To whom correspondences should be addressed at Department of Environmental Health, University of Cincinnati Medical Center, 123 E. Shields Street, Cincinnati, OH 45267-0056. Fax: (513) 558-0974. E-mail: xiay{at}email.uc.edu.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Assefa, Z., Garmyn, M., Bouillon, R., Merlevede, W., Vandenheede, J. R., and Agostinis, P. (1997). Differential stimulation of ERK and JNK activities by ultraviolet B irradiation and epidermal growth factor in human keratinocytes. J. Invest Dermatol. 108, 886891.[Abstract]
Baud, V., Liu, Z. G., Bennett, B., Suzuki, N., Xia, Y., and Karin, M. (1999). Signaling by proinflammatory cytokines: Oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 13, 12971308.
Carlson, D. B., and Perdew, G. H. (2002). A dynamic role for the Ah receptor in cell signaling? Insights from a diverse group of Ah receptor interacting proteins. J. Biochem. Mol. Toxicol. 16, 317325.[CrossRef][ISI][Medline]
Chang, C. Y., and Puga, A. (1998). Constitutive activation of the aromatic hydrocarbon receptor. Mol. Cell Biol. 18, 525535.
Cobb, M. H., and Goldsmith, E. J. (1995). How MAP kinases are regulated. J. Biol. Chem. 270, 1484314846.
Conze, D., Krahl, T., Kennedy, N., Weiss, L., Lumsden, J., Hess, P., Flavell, R. A., Le Gros, G., Davis, R. J., and Rincon, M. (2002). c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J. Exp. Med. 195, 811823.
Delescluse, C., Lemaire, G., de Sousa, G., and Rahmani, R. (2000). Is CYP1A1 induction always related to AHR signaling pathway? Toxicology 153, 7382.[CrossRef][ISI][Medline]
Enan, E., El-Sabeawy, F., Scott, M., Overstreet, J., and Lasley, B. (1998). Alterations in the growth factor signal transduction pathways and modulators of the cell cycle in endocervical cells from macaques exposed to TCDD. Toxicol. Appl. Pharmacol. 151, 283293.[CrossRef][ISI][Medline]
Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., Van Dyk, D. E., Pitts, W. J., Earl, R. A., Hobbs, F. et al. (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 1862318632.
Fernandez-Salguero, P. M., Hilbert, D. M., Rudikoff, S., Ward, J. M., and Gonzalez, F. J. (1996). Aryl-hydrocarbon receptor-deficient mice are resistant to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol. Appl. Pharmacol. 140, 173179.[CrossRef][ISI][Medline]
Gonzalez, F. J. (2001). The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis. Toxicol. Lett. 120, 199208.[CrossRef][ISI][Medline]
Hahn, M. E. (1998). The aryl hydrocarbon receptor: A comparative perspective. Comp. Biochem. Physiol. C, Pharmacol. Toxicol. Endocrinol. 121, 2353.[CrossRef][ISI][Medline]
Han, Z., Boyle, D. L., Chang, L., Bennett, B., Karin, M., Yang, L., Manning, A. M., and Firestein, G. S. (2001). c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest. 108, 7381.
Hawley, D. K., and Roeder, R. G. (1987). Functional steps in transcription initiation and reinitiation from the major late promoter in a HeLa nuclear extract. J. Biol. Chem. 262, 34523461.
Hunter, T., and Karin, M. (1992). The regulation of transcription by phosphorylation. Cell 70, 375387.[ISI][Medline]
Jain, S., Dolwick, K. M., Schmidt, J. V., and Bradfield, C. A. (1994). Potent transactivation domains of the Ah receptor and the Ah receptor nuclear translocator map to their carboxyl termini. J. Biol. Chem. 269, 3151831524.
Joiakim, A., Mathieu, P. A., Palermo, C., Gasiewicz, T. A., and Reiners, J. J., Jr. (2003). The Jun N-terminal kinase inhibitor sp600125 is a ligand and antagonist of the aryl hydrocarbon receptor. Drug. Metab. Dispos. 31, 12791282.
Mandal, P. K., McDaniel, L. R., Prough, R. A., and Clark, B. J. (2001). 7, 12-Dimethylbenz[a]anthracene inhibition of steroid production in MA-10 mouse Leydig tumor cells is not directly linked to induction of CYP1B1. Toxicol. Appl. Pharmacol. 175, 200208.[CrossRef][ISI][Medline]
Manthey, C. L., Wang, S. W., Kinney, S. D., and Yao, Z. (1998). SB202190, a selective inhibitor of p38 mitogen-activated protein kinase, is a powerful regulator of LPS-induced mRNAs in monocytes. J. Leukocyte Biol. 64, 409417.[Abstract]
Mazzucchelli, C., Vantaggiato, C., Ciamei, A., Fasano, S., Pakhotin, P., Krezel, W., Welzl, H., Wolfer, D. P., Pages, G., Valverde, O. et al. (2002). Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. Neuron 34, 807820.[ISI][Medline]
Minsavage, G. D., Vorojeikina, D. P., and Gasiewicz, T. A. (2003). Mutational analysis of the mouse aryl hydrocarbon receptor tyrosine residues necessary for recognition of dioxin response elements. Arch. Biochem. Biophys. 412, 95105.[CrossRef][ISI][Medline]
Nebert, D. W., Roe, A. L., Dieter, M. Z., Solis, W. A., Yang, Y., and Dalton, T. P. (2000). Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem. Pharmacol. 59, 6585.[CrossRef][ISI][Medline]
Raingeaud, J., Whitmarsh, A. J., Barrett, T., Derijard, B., and Davis, R. J. (1996). MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol. Cell. Biol. 16, 124755.[Abstract]
Reiners, J. J., Jr., Lee, J. Y., Clift, R. E., Dudley, D. T., and Myrand, S. P. (1998). PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase. Mol. Pharmacol. 53, 438445.
Reisz-Porszasz, S., Probst, M. R., Fukunaga, B. N., and Hankinson, O. (1994). Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT). Mol. Cell. Biol. 14, 60756086.[Abstract]
Sabapathy, K., Hu, Y., Kallunki, T., Schreiber, M., David, J. P., Jochum, W., Wagner, E. F., and Karin, M. (1999). JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr. Biol. 9, 116125.[CrossRef][ISI][Medline]
Sabapathy, K., Kallunki, T., David, J. P., Graef, I., Karin, M., and Wagner, E. F. (2001). c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J. Exp. Med. 193, 317328.
Sadowski, I., Bell, B., Broad, P., and Hollis, M. (1992). GAL4 fusion vectors for expression in yeast or mammalian cells. Gene 118, 137141.[CrossRef][ISI][Medline]
She, Q. B., Chen, N., Bode, A. M., Flavell, R. A., and Dong, Z. (2002). Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 62, 13431348.
Shimizu, Y., Nakatsuru, Y., Ichinose, M., Takahashi, Y., Kume, H., Mimura, J., Fujii-Kuriyama, Y., and Ishikawa, T. (2000). Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA. 97, 77982.
Sogawa, K., Iwabuchi, K., Abe, H., and Fujii-Kuriyama, Y. (1995a). Transcriptional activation domains of the Ah receptor and Ah receptor nuclear translocator. J. Cancer Res. Clin. Oncol. 121, 612620.[ISI][Medline]
Sogawa, K., Nakano, R., Kobayashi, A., Kikuchi, Y., Ohe, N., Matsushita, N., and Fujii-Kuriyama, Y. (1995b). Possible function of Ah receptor nuclear translocator (Arnt) homodimer in transcriptional regulation. Proc. Natl. Acad. Sci. USA. 92, 19361940.[Abstract]
Staples, J. E., Murante, F. G., Fiore, N. C., Gasiewicz, T. A., and Silverstone, A. E. (1998). Thymic alterations induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin are strictly dependent on aryl hydrocarbon receptor activation in hemopoietic cells. J. Immunol. 160, 38443854.
Swanson, H. I., and Bradfield, C. A. (1993). The AH-receptor: genetics, structure and function. Pharmacogenetics 3, 213230.[ISI][Medline]
Tan, Z., Chang, X., Puga, A., and Xia, Y. (2002). Activation of mitogen-activated protein kinases (MAPKs) by aromatic hydrocarbons: role in the regulation of aryl hydrocarbon receptor (AHR) function. Biochem. Pharmacol. 64, 771780.[CrossRef][ISI][Medline]
Tannheimer, S. L., Ethier, S. P., Caldwell, K. K., and Burchiel, S. W. (1998). Benzo[a]pyrene- and TCDD-induced alterations in tyrosine phosphorylation and insulin-like growth factor signaling pathways in the MCF-10A human mammary epithelial cell line. Carcinogenesis 19, 12911297.[Abstract]
Whitlock, J. P., Jr. (1999). Induction of cytochrome P4501A1. Annu. Rev. Pharmacol. Toxicol. 39, 103125.[CrossRef][ISI][Medline]
Zhang, L., Wang, W., Hayashi, Y., Jester, J. V., Birk, D. E., Gao, M., Liu, C. Y., Kao, W. W., Karin, M., and Xia, Y. (2003). A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure. Embo J. 22, 44434454.
Zheng, W., Brake, P. B., Bhattacharyya, K. K., Zhang, L., Zhao, D., and Jefcoate, C. R. (2003). Cell selective cAMP induction of rat CYP1B1 in adrenal and testis cells. Identification of a novel cAMP-responsive far upstream enhancer and a second Ah receptor-dependent mechanism. Arch. Biochem. Biophys. 416, 5367.[CrossRef][ISI][Medline]