COMMUNICATION
Role of Adapter Function in Oncoprotein-mediated Activation of NF-kappa B
HUMAN T-CELL LEUKEMIA VIRUS TYPE I Tax INTERACTS DIRECTLY WITH Ikappa B KINASE gamma *

Dong-Yan JinDagger §, Vincenzo GiordanoDagger , Karen V. KiblerDagger , Hiroyasu Nakanoparallel , and Kuan-Teh JeangDagger **

From the Dagger  Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, the  Department of Immunology, Juntendo University School of Medicine, Tokyo 113, Japan, and the parallel  Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo 101-0062, Japan

    ABSTRACT
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES

Mechanisms by which the human T-cell leukemia virus type I Tax oncoprotein activates NF-kappa B remain incompletely understood. Although others have described an interaction between Tax and a holo-Ikappa B kinase (IKK) complex, the exact details of protein-protein contact are not fully defined. Here we show that Tax binds to neither IKK-alpha nor IKK-beta but instead complexes directly with IKK-gamma , a newly characterized component of the IKK complex. This direct interaction with IKK-gamma correlates with Tax-induced Ikappa B-alpha phosphorylation and NF-kappa B activation. Thus, our findings establish IKK-gamma as a key molecule for adapting an oncoprotein-specific signaling to IKK-alpha and IKK-beta .

    INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES

HTLV-I1 Tax is the etiological oncoprotein associated with adult T-cell leukemia (1). Tax is a 40-kDa nuclear phosphoprotein whose expression sufficiently immortalizes T-lymphocytes (2, 3). Although its mechanisms for immortalization are not fully understood, Tax has been shown to dysregulate cell cycle progression (4-6) and to subvert host DNA damage surveillance pathways (7-11). Tax is also a well characterized transcriptional activator of the HTLV-I long terminal repeats as well as many cellular promoters (12, 13) with abilities to activate cAMP-responsive, NF-kappa B-responsive, and serum-responsive promoters (14-16). Despite its pleiotropic effects, specificity of Tax action has been shown to occur through direct contacts with cellular proteins (e.g. Refs. 10 and 17-19).

Through NF-kappa B, Tax modulates the expression of several cytokines and proto-oncogenes. NF-kappa B is a key regulator of inflammatory responses as well as cell death (20, 21). Ambiently, NF-kappa B exists in the cytoplasm tightly associated with inhibitory proteins, Ikappa Bs. Activity of NF-kappa B is stimulated widely by cytokines, oxidative stress, phorbol ester, and virus infection. One mechanism of NF-kappa B activation involves site-specific phosphorylation at serines 32 and 36 of Ikappa B-alpha , followed by its ubiquitination and degradation (20, 21). To date, several Ikappa B kinases, including IKK-alpha and IKK-beta , have been cloned and characterized (22-27). IKK-alpha and IKK-beta have been suggested to be components of a larger multiprotein complex, which includes NF-kappa B/RelA, Ikappa B-alpha , MEKK-1, and NF-kappa B-inducing kinase (NIK) (26, 28-30). Recently, two new proteins, IKK complex-associated protein (IKAP) and IKK-gamma /NEMO, with functions yet to be completely defined, have been identified in this holo complex (31-33).

Because of potential implications for cellular transformation, it is of interest to understand how transforming viruses activate NF-kappa B. HTLV-I represents an attractive model; its oncoprotein, Tax, has been suggested to target both IKK-alpha (34-36) and IKK-beta (34-37), presumably through direct protein-protein contacts. Mechanistically, how IKK-alpha and IKK-beta are impinged upon by Tax has not been defined. Here we show that Tax binds to neither IKK-alpha nor IKK-beta but instead contacts directly IKK-gamma . We propose that IKK-gamma functionally adapts oncoprotein signaling to IKK-alpha /IKK-beta .

    EXPERIMENTAL PROCEDURES
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES

Plasmids-- pHA is a derivative of pM (CLONTECH) in which the Gal4 DNA-binding domain (BD) has been replaced by an HA tag (YPYDVPDYA). pHA-derived plasmids pHAgamma and pHAgamma Delta C contain full-length and C-terminally truncated (amino acids 1-306) human IKK-gamma , respectively. pGST-IKK-gamma contains IKK-gamma cDNA inserted into pGEX 4T-1 (Amersham Pharmacia Biotech). pMBP-Tax, pIE-Tax, pIE-Tax mutants (pIEX, pIEX S258A, and pIEX L320G), and pBD-Tax have been described previously (16, 17, 38). Plasmids expressing IKK-gamma fused to Gal4 activation domain (AD-IKK-gamma ), AD-IKK-alpha , and AD-IKK-beta in yeast are derived from pGAD424 (CLONTECH). Plasmid expressing IKK-gamma in yeast is based on histidine-marked pGHnf (17). Mouse IKK-alpha /beta cDNAs (29), IKK-alpha /beta mutants (29), and NF-kappa B-dependent reporter (pkappa B-CAT) and control plasmids (10, 38, 39) have been described elsewhere.

GST Pull-down Assay-- Expression and purification of GST, GST-IKK-gamma , and MBP-Tax from Escherichia coli were performed using protocols from Amersham Pharmacia Biotech and New England BioLabs. Protein affinity chromatography was performed as described previously (10).

Protein Analysis-- Immunoprecipitations, Western blotting, yeast two-hybrid assay, electrophoretic mobility shift assay (EMSA), and CAT assay were performed as described (10, 17, 38, 39). Luciferase assay was according to Promega.

IKK Assay-- Cells were lysed in buffer (20 mM Hepes, pH 7.3, 2.5 mM MgCl2, 10 mM EGTA, 40 mM beta -glycerophosphate, 1% Nonidet P-40, 1 mM dithiothreitol, 2 mM orthovanadate, and protease inhibitor mixture). Clarified lysates were precipitated with anti-Tax. Precipitates were washed with kinase buffer (20 mM Hepes, pH 7.3, 10 mM MgCl2, 2 mM MnCl2, 0.5 mM EGTA, 0.5 mM NaF, 0.5 mM vanadate, and 12.5 mM beta -glycerophosphate). Kinase assay was performed for 30 min at 30 °C in kinase buffer supplemented with 3.3 µM dithiothreitol, 20 µM ATP, 5 µCi of [gamma -32P]ATP, and 3 µg of GST-Ikappa B-alpha (Santa Cruz).

    RESULTS AND DISCUSSION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES

Tax Interacts Directly with IKK-gamma -- Recently, full-length cDNA clones for both mouse and human IKK-gamma (also termed NEMO) have been isolated (31, 33, 40). Genetically, IKK-gamma is linked to Tax activation of NF-kappa B (31). In assessing this, we considered two other observations. First, IKK-gamma contains a striking coiled-coil domain in its 51-353 residues (33, 40). Second, several other cellular Tax-binding proteins share a characteristically structured coiled-coil domain. Examples include GPS2 (17), ATF4/CREB2 (18, 19), TXBP181/HsMAD1 (10), TXBP151 (19), and TXBP121/KIAA0445 (GenBankTM accession number AB007914). Thus, circumstantially, a particular coiled-coil structure likely represents a recognition motif for Tax. Hence, we wondered whether the coiled-coil IKK-gamma protein could be a direct Tax adapter that would help to explain NF-kappa B activation by this oncoprotein.

To address this issue, we co-expressed Tax (pIEX) and HA-tagged human IKK-gamma (pHAgamma ) in HeLa cells and performed reciprocal co-immunoprecipitations (Fig. 1A). HeLa cells transfected singularly with pHAgamma abundantly expressed HA-IKK-gamma , which was detected easily by direct immunoblotting with a mouse anti-HA antibody (Fig. 1A, lane 1, alpha -HA (m)) and by immunoprecipitation with a rabbit anti-HA antiserum (Fig. 1A, lane 2, alpha -HA (r)) followed by immunoblotting with mouse anti-HA antibody. In HeLa cells co-transfected with pHAgamma and pIEX (Fig. 1A, lanes 5 and 8), HA-IKK-gamma was observed in the mouse anti-Tax precipitate (lane 5), and Tax was found in the rabbit alpha -HA antiserum precipitate (lane 8). These reciprocal findings are consistent with an intracellular Tax-IKK-gamma complex.


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Fig. 1.   Tax binds IKK-gamma directly. A, co-immunoprecipitation of Tax and IKK-gamma from cells. HeLa cells were transfected with pHAgamma alone (lanes 1 and 2) or the indicated plasmids (lanes 3-8). The crude cell extract was analyzed by Western blotting with mouse anti-HA (alpha -HA (m), lane 1). Cell lysates were also immunoprecipitated (i.p.) with either rabbit alpha -HA (alpha -HA (r); lanes 2 and 6-8) or rabbit anti-Tax (alpha -Tax (r), lanes 3-5). The precipitates were analyzed by Western blotting with mouse alpha -HA (alpha -HA (m), lanes 3-5) or mouse anti-Tax (alpha -Tax (m), lanes 6-8). Relative migrations of molecular mass markers are as shown. B, in vitro GST pull-down assay. GST (lanes 1 and 2) and GST-IKK-gamma (lanes 3 and 4) proteins were bound to Sepharose beads. Beads were incubated with MBP-Tax, and bound proteins were then eluted. Flow-through (FT, lanes 1 and 3) and eluates (lanes 2 and 4) were analyzed by Western blotting with rabbit anti-Tax. Anti-Tax-reactive proteins are marked by an arrow and an asterisk. The band marked by an asterisk likely represents a degradation product. C, yeast two-hybrid assay. Yeast SFY526 was transformed with plasmids expressing the indicated proteins. Stable transformants were selected and assayed for relative beta -galactosidase activity in chlorophenol red-beta -D-galactopyranoside (CPRG) units (38). Results are representative of three independent experiments.

IKK-gamma is one component of a larger holo-IKK complex (31, 33). In view of this, the observed co-immunoprecipitation of IKK-gamma and Tax does not exclude the possibility that IKK-gamma is simply a passenger protein recovered as a consequence of Tax interaction with another member of the IKK complex. To challenge this possibility, we performed in vitro pull-down assays with GST-IKK-gamma and MBP-Tax purified from E. coli. In agreement with a direct contact between Tax and IKK-gamma , Fig. 1B verified that MBP-Tax bound to GST-IKK-gamma (lane 4) but not to GST alone (lane 2).

To confirm the association between Tax and IKK-gamma within a eukaryotic cell, we checked for interactions in yeast (Fig. 1C). When BD-Tax was co-expressed in yeast with AD-IKK-gamma , we observed that this pair (Fig. 1C, column 4) conferred >20-fold stimulation over the background beta -galactosidase activity induced by each plasmid singularly (Fig. 1C, columns 1 and 2). The interaction measured for Tax and IKK-gamma (Fig. 1C, column 4) is comparable with the previously characterized binding between Tax and HsMAD1 (Fig. 1C, column 6, and Ref. 10). Because no IKK homologs have been identified in the complete sequence of the yeast genome, we are reassured that the observed results are unlikely to be consequences of bridging fortuitously supplied by yeast IKKs. Hence, the GST pull-down assays and the yeast two-hybrid results collectively support a direct interaction between Tax and IKK-gamma .

Tax and IKK-gamma Interaction Correlates with Ikappa B-alpha Phosphorylation and NF-kappa B Activation-- Tax activates NF-kappa B (14, 34-36). Although the involvement of MEKK-1, IKK-alpha , IKK-beta , and NIK have been suggested (34-37), the exact mechanisms for this activation are not fully understood. Based on the above observation, we next asked whether binding of IKK-gamma to Tax correlates functionally with Tax activation of NF-kappa B.

Previously, we have constructed and characterized 47 Tax point mutants (16). The phenotypes of two mutants, Tax S258A and Tax L320G, distinguish clearly between activity through the cellular CREB/ATF versus the NF-kappa B pathways. Thus, Tax S258A activates CREB/ATF but not NF-kappa B; whereas Tax L320G activates NF-kappa B but not CREB/ATF (3, 16). We used these two mutants to clarify the significance of Tax-IKK-gamma interaction for NF-kappa B activation.

HeLa cells were separately co-transfected with pHAgamma and pIE vector (Fig. 2, lane 1), pHAgamma and pIEX (Tax wild type; lane 2), pHAgamma and pIEX S258A (lane 3), or pHAgamma and pIEX L320G (lane 4). The equivalent expression of Tax and Tax mutants was verified by Western blotting (Fig. 2A). In parallel, nuclear NF-kappa B DNA binding activity and cytoplasmic IKK activity associated with Tax were assessed by EMSA (Fig. 2B) and in vitro kinase assay (IKK act.; Fig. 2C), respectively. Consistent with previous findings (16), Tax L320G activated NF-kappa B and IKK in a manner similar to wild type Tax (Fig. 2, B and C, compare lanes 4 with lanes 2). By contrast, Tax S258A was defective for this activation (Fig. 2, B and C, compare lanes 3 to lanes 1 and 2). Concordantly, anti-Tax serum (alpha -Tax; Fig. 2D) co-immunoprecipitated IKK-beta (as detected by immunoblotting with alpha -IKK-beta serum) from cells that expressed Tax or Tax L320G (Fig. 2D, lanes 2 and 4), but not from cells that expressed Tax S258A (Fig. 2D, lane 3). In the same immunoprecipitations, we also found that Tax or Tax L320G but not Tax S258A associated with HA-IKK-gamma (Fig. 2E). Considered together, these findings correlated Tax/Tax mutant binding to IKK-gamma (Fig. 2E) with nuclear NF-kappa B activity (Fig. 2B), Ikappa B-alpha phosphorylation (Fig. 2C), and co-immunoprecipitation with IKK-beta (Fig. 2D).


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Fig. 2.   Tax interaction with IKK-gamma correlates with NF-kappa B activation. HeLa cells were transfected with pHAgamma and pIE (lanes 1), pHAgamma and pIEX (lanes 2), pHAgamma and pIEX S258A (lanes 3), or pHAgamma and pIEX L320G (lanes 4). A, expression of wild type and mutant Tax. HeLa extracts with 12 µg of protein were analyzed by Western blotting with mouse anti-Tax antibody. B, NF-kappa B DNA binding activity by EMSA. HeLa nuclear extracts (1.5 µg of protein) were used for each lane. Positions of the NF-kappa B shifted band and the free probe (FP) are indicated. C, in vitro IKK assay. Extracts from 5 × 106 HeLa cells were incubated with 3 µg of mouse anti-Tax antibody. Immunoprecipitates were assayed for IKK activity using GST-Ikappa B-alpha as substrate. Phosphorylated Ikappa B-alpha was separated by 10% SDS-polyacrylamide gel electrophoresis, and the autoradiograph was visualized with a Fuji FLA-2000 phosphorimager. D, Tax association with IKK-beta . Monoclonal anti-Tax (alpha -Tax) immunoprecipitates (i.p.) were probed with rabbit anti-IKK-beta in Western blotting. E, Tax association with IKK-gamma . Anti-Tax immunoprecipitates were probed with rabbit anti-HA in Western blotting.

Evidence Supports Direct Contact of Tax with IKK-gamma but Not with IKK-alpha nor IKK-beta -- Data presented here and elsewhere are compatible with the following: (a) direct binding of Tax to IKK-gamma (Fig. 1); (b) direct/indirect association of Tax with IKK-alpha and/or IKK-beta (Fig. 2D and Ref. 34); and (c) a Tax-induced increase in IKK activity (Fig. 2C and Refs. 34-36). Others have shown that IKK-gamma can bind IKK-beta directly (31) and associates with IKK-alpha in vivo (33). Based on these observations, one cannot formally distinguish between a model in which Tax contacts all three IKK-proteins (IKK-alpha , IKK-beta , and IKK-gamma ; Fig. 3A) equally versus another model in which Tax contacts only IKK-gamma , which then intermediates a signal to IKK-alpha and IKK-beta (Fig. 3B).


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Fig. 3.   Tax association with IKK-alpha /beta is mediated by IKK-gamma . A, schematic representation of direct contacts between Tax and IKK-alpha /beta and IKK-gamma . Binding of IKK-gamma to IKK-beta is also depicted. B, alternative representation of direct interaction of Tax with only IKK-gamma . C, IKK-gamma bridges Tax to IKK-alpha /beta as revealed by modified yeast protein hybrid assay. Yeast SFY526 was transformed with plasmids carrying different markers and expressing the indicated proteins. D, IKK-gamma activates NF-kappa B through IKK-alpha /beta . HeLa cells were transfected with pkappa BCAT (column 1), pkappa BCAT plus pHAgamma (column 2), or pkappa BCAT plus pHAgamma plus increasing amounts of plasmids expressing the indicated DN mutants (columns 3-6). These mutants have little effect on the basal CAT activity (data not shown). Results are representative of three independent experiments. CPRG, chlorophenol red beta -D-galactopyranoside.

To define better the details of protein-protein contact, we performed modified protein hybrid assays in yeast (Fig. 3C). First we sought to determine whether there was a direct contact of Tax with either IKK-alpha or IKK-beta . We co-expressed either BD-Tax and AD-IKK-alpha (Fig. 3C, column 2) or BD-Tax and AD-IKK-beta (Fig. 3C, column 3) in yeast. Neither pair showed any increased reporter activity over the background level observed with BD-Tax alone (Fig. 3C, column 1). By contrast, yeast transformants that co-expressed BD-Tax and AD-IKK-gamma showed an activity >10-fold over background (Fig. 3C, compare column 4 with column 1). These results are most simply interpreted by a direct Tax interaction with IKK-gamma but not with IKK-alpha nor IKK-beta (Fig. 3B).

That IKK-gamma adapts Tax to either IKK-alpha or IKK-beta is supported by further functional evidence. Thus, if one co-expresses three proteins simultaneously in yeast, either a nonfused IKK-gamma with BD-Tax and AD-IKK-alpha (Fig. 3C, column 5) or a nonfused IKK-gamma with BD-Tax and AD-IKK-beta (Fig. 3C, column 6), then >5-fold IKK-gamma -dependent increases in reporter activity are measured (Fig. 3C, compare columns 5 and 6 with columns 1-3). This role for unfused IKK-gamma in reconstructing BD-Tax and AD-IKK-alpha /AD-IKK-beta activity is fully consistent with a model in which IKK-gamma contacts IKK-alpha , IKK-beta , and Tax independently while bridging a functional interaction between Tax and either IKK-alpha or IKK-beta (Fig. 3B). Thus, for Tax oncoprotein signaling, IKK-gamma is positioned upstream of IKK-alpha /IKK-beta activation and Ikappa B-alpha phosphorylation.

The model deduced from results in yeast can be further tested in mammalian cells. Indeed, if IKK-gamma represents an upstream adapter whereas IKK-alpha /IKK-beta represent downstream effectors, then one prediction is that a dominant negative (DN) form of the latter would repress activity from the former. When overexpressed in HeLa cells, IKK-gamma conferred a 4-fold activation of an NF-kappa B-dependent reporter (Fig. 3D, compare column 2 with column 1). Notably, this activation was abrogated by co-expression of DN mutants of either IKK-alpha or IKK-beta (Fig. 3D, columns 3-6). We observed that compared with DN IKK-beta (Fig. 3C, columns 5 and 6), a higher dosage of DN IKK-alpha is required for the inhibition of IKK-gamma -mediated activation (columns 3 and 4). This might be explained by the intrinsic differences in specific kinase-activity for IKK-alpha and IKK-beta (27).

IKK-gamma Is a Mediator for Tax Activation of NF-kappa B-- Previously, a C-terminal truncated form of IKK-gamma (IKK-gamma Delta C) has been described as a DN inhibitor of IKK-gamma function (33). We used a similarly constructed IKK-gamma Delta C mutant to explore the role of IKK-gamma in Tax activation of NF-kappa B. In HeLa and Jurkat cells, expression of wild type IKK-gamma enhanced Tax activation of an NF-kappa B-dependent reporter (Fig. 4, compare group 3 with group 2). In contrast, activation by Tax was progressively diminished with increased expression of IKK-gamma Delta C (Fig. 4, groups 4-6, compared with group 2), consistent with a DN inhibition of function. This finding agrees with the demonstration that a genetic defect in IKK-gamma led to loss of responsiveness to several NF-kappa B-activating stimuli including Tax (31).


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Fig. 4.   A dominant negative IKK-gamma protein abrogates Tax activation of NF-kappa B. Left y axis and open bars, CAT assay in HeLa cells. The reporter plasmid is pkappa BCAT. Right y axis and filled bars: luciferase (luc.) assay in Jurkat cells. The reporter plasmid is pNFkB-Luc (Stratagene). Results are representative of three independent repetitions. The IKK-gamma Delta C mutant has minimal effect on the basal CAT and luciferase activity (data not shown).

Two salient points emerge from the current work. The first is the unexpected finding of IKK-gamma as a direct Tax-binding factor. Previously, several studies have shown an association of Tax with IKK complex (34-37). Although contact with IKK-alpha and IKK-beta was suggested (34), the exact details were not defined. We now show that the functional ability of Tax to activate IKK-alpha /IKK-beta is unlikely to stem from immediate contact but occurs indirectly through binding between Tax and IKK-gamma .

The second instructive point from this work is that IKK-gamma , previously shown to be essential for IKK-alpha /IKK-beta activation of NF-kappa B (31, 33), is located functionally and physically upstream of its kinase counterparts. Although our work does not directly address how Tax activates IKK-alpha /IKK-beta , the finding that Tax binds IKK-gamma but not IKK-alpha /IKK-beta ascribes physical recruitment of Tax into the holo-IKK complex to the functional adapter function suggested for IKK-gamma . IKK-gamma -tethered Tax protein is further expected to bring Tax-associated kinase(s) (e.g. MEKK-1 and/or NIK (35-37)) to the local proximity of IKK-alpha /IKK-beta for phosphorylation-mediated activation.

An obvious question raised by our results is why should oncoproteins interact via an adapter rather than directly with the IKK-alpha /IKK-beta kinases? Although this is not completely understood, one suggestive explanation is provoked by our recent finding that the human gene for IKK-gamma localizes on the X chromosome (40). If IKK-gamma is indeed essential (as has been shown in Refs. 31 and 33) for a multitude of signals that activate NF-kappa B, then some hints of gender-linked NF-kappa B-based diseases might have been expected. In the absence of evidence for such, a reasonable deduction is that many yet to be described IKK-associated proteins (another example is IKAP; Ref. 32) might also provide adapter function. The predicted existence of many adapters could explain specificity and redundancy of signaling that cannot otherwise be easily reconciled if each of the numerously different NF-kappa B-activating signals all contacted directly IKK-alpha /IKK-beta . Future studies are needed to clarify the identities of other adapters and how they function in dictating specificity of IKK activation.

    ACKNOWLEDGEMENT

We thank Ko Okumura.

    FOOTNOTES

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Inst. of Molecular Biology, The University of Hong Kong, Pokfulam, Hong Kong.

** To whom correspondence should be addressed: LMM/NIAID/NIH, Bldg. 4, Rm. 306, 9000 Rockville Pike, Bethesda, MD 20892-0460. Tel.: 301-496-6680; Fax: 301-480-3686; E-mail: kjeang{at}niaid.nih.gov.

    ABBREVIATIONS

The abbreviations used are: HTLV-I, human T-cell leukemia virus type I; IKK, Ikappa B kinase; MEKK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase; NIK, NF-kappa B-inducing kinase; IKAP, IKK complex-associated protein; NEMO, NF-kappa B essential modulator; HA, hemagglutinin; BD, Gal4 DNA-binding domain; AD, Gal4 activation domain; GST, glutathione S-transferase; MBP, maltose-binding protein; EMSA, electrophoretic mobility shift assay; CAT, chloramphenicol acetyltransferase; CREB, cAMP-responsive element-binding protein; ATF, activating transcription factor; DN, dominant negative.

    REFERENCES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
  1. Uchiyama, T. (1997) Annu. Rev. Immunol. 15, 15-37[CrossRef][Medline] [Order article via Infotrieve]
  2. Grassmann, R., Dengler, C., Muller-Fleckenstein, I., Fleckenstein, B., McGuire, K., Dokhelar, M. C., Sodroski, J. G., and Haseltine, W. A. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 3351-3355[Abstract]
  3. Rosin, O., Koch, C., Schmitt, I., Semmes, O. J., Jeang, K.-T., and Grassmann, R. (1998) J. Biol. Chem. 273, 6698-6703[Abstract/Free Full Text]
  4. Suzuki, T., Kitao, S., Matsushime, H., and Yoshida, M. (1996) EMBO J. 15, 1607-1614[Abstract]
  5. Low, K. G., Dorner, L. F., Fernando, D. B., Grossman, J., Jeang, K.-T., and Comb, M. J. (1997) J. Virol. 71, 1956-1962[Abstract]
  6. Neuveut, C., Low, K. G., Maldarelli, F., Schmitt, I., Majone, F., Grassmann, R., and Jeang, K.-T. (1998) Mol. Cell. Biol. 18, 3620-3632[Abstract/Free Full Text]
  7. Jeang, K.-T., Widen, S. G., Semmes, O. J., and Wilson, S. H. (1990) Science 247, 1082-1084[Medline] [Order article via Infotrieve]
  8. Majone, F., Semmes, O. J., and Jeang, K.-T. (1993) Virology 193, 456-459[CrossRef][Medline] [Order article via Infotrieve]
  9. Reid, R. L., Lindholm, P. F., Mireskandari, A., Dittmer, J., and Brady, J. N. (1993) Oncogene 8, 3029-3036[Medline] [Order article via Infotrieve]
  10. Jin, D.-Y., Spencer, F., and Jeang, K.-T. (1998) Cell 93, 81-91[Medline] [Order article via Infotrieve]
  11. Jin, D.-Y., Kozak, C. A., Pangilinan, F., Spencer, F., Green, E. D., and Jeang, K.-T. (1999) Genomics 55, 363-364[CrossRef][Medline] [Order article via Infotrieve]
  12. Franklin, A. A., and Nyborg, J. K. (1995) J. Biomed. Sci. 2, 17-29[Medline] [Order article via Infotrieve]
  13. Flint, J., and Shenk, T. (1997) Annu. Rev. Genet. 31, 177-212[CrossRef][Medline] [Order article via Infotrieve]
  14. Ballard, D. W., Bohnlein, E., Lowenthal, J. W., Wano, Y., Franza, B. R., and Greene, W. C. (1988) Science 241, 1652-1655[Medline] [Order article via Infotrieve]
  15. Fujii, M., Sassone-Corsi, P., and Verma, I. M. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 8526-8530[Abstract]
  16. Semmes, O. J., and Jeang, K.-T. (1992) J. Virol. 66, 7183-7192[Abstract]
  17. Jin, D.-Y., Teramoto, H., Giam, C.-Z., Chun, R. F., Gutkind, J. S., and Jeang, K.-T. (1997) J. Biol. Chem. 272, 25816-25823[Abstract/Free Full Text]
  18. Reddy, T. R., Tang, H., Li, X., and Wong-Staal, F. (1997) Oncogene 14, 2785-2792[CrossRef][Medline] [Order article via Infotrieve]
  19. Gachon, F., Peleraux, A., Thebault, S., Dick, J., Lemasson, I., Devaux, C., and Mesnard, J. M. (1998) J. Virol. 72, 8332-8337[Abstract/Free Full Text]
  20. Verma, I. M., Stevenson, J. K., Schwarz, E. M., Van Antwerp, D., and Miyamoto, S. (1995) Genes Dev. 9, 2723-2735[CrossRef][Medline] [Order article via Infotrieve]
  21. Ghosh, S., May, M. J., and Kopp, E. B. (1998) Annu. Rev. Immunol. 16, 225-260[CrossRef][Medline] [Order article via Infotrieve]
  22. DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., and Karin, M. (1997) Nature 388, 548-554[CrossRef][Medline] [Order article via Infotrieve]
  23. Mercurio, F., Zhu, H., Murray, B. W., Shevchenko, A., Bennett, B. L., Li, J. W., Young, D. B., Barbosa, M., Mann, M., Manning, A., and Rao, A. (1997) Science 278, 860-866[Abstract/Free Full Text]
  24. Regnier, C. H., Song, H. Y., Gao, X., Goeddel, D. V., Cao, Z., and Rothe, M. (1997) Cell 90, 373-383[Medline] [Order article via Infotrieve]
  25. Zandi, E., Chen, Y., and Karin, M. (1998) Science 281, 1360-1363[Abstract/Free Full Text]
  26. Lee, F. S., Peters, R. T., Dang, L. C., and Maniatis, T. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 9319-9324[Abstract/Free Full Text]
  27. Li, J., Peet, G. W., Pullen, S. S., Schembri-King, J., Warren, T. C., Marcu, K. B., Kehry, M. R., Barton, R., and Jakes, S. (1998) J. Biol. Chem. 273, 30736-30741[Abstract/Free Full Text]
  28. Lin, X., Mu, Y., Cunningham, E. T., Jr., Marcu, K. B., Geleziunas, R., and Greene, W. C. (1998) Mol. Cell. Biol. 18, 5899-5907[Abstract/Free Full Text]
  29. Nakano, H., Shindo, M., Sakon, S., Nishinaka, S., Mihara, M., Yagita, H., and Okumura, K. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 3537-3542[Abstract/Free Full Text]
  30. Nemoto, S., DiDonato, J. A., and Lin, A. (1998) Mol. Cell. Biol. 18, 7336-7343[Abstract/Free Full Text]
  31. Yamaoka, S., Courtois, G., Bessia, C., Whiteside, S. T., Weil, R., Agou, F., Kirk, H. E., Kay, R. J., and Israel, A. (1998) Cell 93, 1231-1240[Medline] [Order article via Infotrieve]
  32. Cohen, L., Henzel, W. J., and Baeuerle, P. A. (1998) Nature 395, 292-296[CrossRef][Medline] [Order article via Infotrieve]
  33. Rothwarf, D. M., Zandi, E., Natoli, G., and Karin, M. (1998) Nature 395, 297-300[CrossRef][Medline] [Order article via Infotrieve]
  34. Chu, Z.-L., DiDonato, J. A., Hawiger, J., and Ballard, D. W. (1998) J. Biol. Chem. 273, 15891-15894[Abstract/Free Full Text]
  35. Geleziunas, R., Ferrell, S., Lin, X., Mu, Y., Cunningham, E. T., Jr., Grant, M., Connelly, M. A., Hambor, J. E., Marcu, K. B., and Greene, W. C. (1998) Mol. Cell. Biol. 18, 5157-5165[Abstract/Free Full Text]
  36. Uhlik, M., Good, L., Xiao, G., Harhaj, E. W., Zandi, E., Karin, M., and Sun, S.-C. (1998) J. Biol. Chem. 273, 21132-21136[Abstract/Free Full Text]
  37. Yin, M.-J., Christerson, L. B., Yamamoto, Y., Kwak, Y.-T., Xu, S., Mercurio, F., Barbosa, M., Cobb, M. H., and Gaynor, R. B. (1998) Cell 93, 875-884[Medline] [Order article via Infotrieve]
  38. Jin, D.-Y., and Jeang, K.-T. (1997) Nucleic Acids Res. 25, 379-387[Abstract/Free Full Text]
  39. Jin, D.-Y., Chae, H. Z., Rhee, S. G., and Jeang, K.-T. (1997) J. Biol. Chem. 272, 30952-30961[Abstract/Free Full Text]
  40. Jin, D.-Y., and Jeang, K.-T. (1999) J. Biomed. Sci. 6, 91-96


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