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Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1

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Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1 Research Article Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1 King-Tung Chin,1 Abel C.S. Chun,1 Yick-Pang Ching,1,2 Kuan-Teh Jeang,3 and Dong-Yan Jin1 Departments of 1Biochemistry and 2Pathology, The University of Hong Kong, Pokfulam, Hong Kong and 3Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland Abstract studied. Accordingly, we understand that Tax functions as a Human T-cell leukemia virus type 1 oncoprotein Tax is a homodimer (12, 13), which docks with dimeric CREB in a ternary transcriptional regulator that interacts with a large number of complex onto the HTLV-1 21-bp TRE motifs (14). Optimal activa- host cell factors. Here, we report the novel characterization of tion of the HTLV-1 LTR by Tax requires the core HTLV-1 TATAA promoter, CREB, and the TRE (15). Separately, Tax activation of the interaction of Tax with a human cell protein named Tax1- n binding protein 1 (TAX1BP1). We show that TAX1BP1 is a NF- B is thought to occur through direct interaction with p50/p52, n n g g nuclear receptor coactivator that forms a complex with the I B, and I B kinase (IKK ; ref. 3). Moreover, Tax can also engage glucocorticoid receptor. TAX1BP1 and Tax colocalize into transcriptional coactivators such as CREB-binding protein (CBP), p300, P/CAF, and TORC1/2/3 (16–18). intranuclear speckles that partially overlap with but are not identical to the PML oncogenic domains. Tax binds TAX1BP1 Although we know much about how Tax activates transcription, directly, induces the dissociation of TAX1BP1 from the we know considerably less about how it represses gene expression. glucocorticoid receptor–containing protein complex, and Several ideas have been forwarded as to how Tax may repress the expression of cellular genes. For example, Tax has been reported to represses the coactivator function of TAX1BP1. Genetic b knockout of Tax1bp1 in mice abrogates the influence of Tax suppress the transcription of the DNA polymerase gene via direct on the activation of nuclear receptors. We propose that Tax- inhibition of basic helix-loop-helix factors (19). Tax attenuates cyclin A expression through sequestration of CREB/ATF (8), and TAX1BP1 interaction mechanistically explains the previously h reported repression of nuclear receptor activity by Tax. Tax suppresses transforming growth factor indirectly by activating the NF-nB and c-Jun signaling pathways, respectively [Cancer Res 2007;67(3):1072–81] (9, 11). Finally, Tax physically binds general transcription coactivators such as CBP, p300, and P/CAF (10, 20); its ability to Introduction inactivate the function of the p53 tumor suppressor and other Human T-cell leukemia virus type 1 (HTLV-1) was the first targets is thought to be mediated at least partially through binding retrovirus shown to be associated with a human disease, adult T- to CBP and/or p300 (9, 10, 20). cell leukemia (ATL). ATL is an aggressive neoplasm; however, its Nuclear receptors (NR) are a large family of ligand-activated induction by HTLV-1 is a slow process that takes 20 to 40 years and transcription factors that regulate gene expression in response to apparently requires the consummation of several discrete events in steroids, retinoids, and other signaling molecules (21). These the virus-infected cell (1). transcription factors play an important role in regulating The HTLV-1 Tax oncoprotein can immortalize T cells and development, differentiation, metabolism, and cell proliferation. transforms rat fibroblasts (2). Tax is a transcriptional factor, which Dysregulation of nuclear factor–dependent transcription leads to targets the HTLV-1 long terminal repeats (LTR), heterologous viral various diseases including cancer (22). A few years ago, Doucas and promoters, and a variety of cellular genes (3). Tax acts potently Evans reported that the HTLV-1 Tax protein is a general repressor through Tax-responsive (TRE) DNA elements on the LTR, which are of the transcriptional capacity of several NRs including glucocor- also cyclic AMP (cAMP)–responsive motifs recognized by the cellular ticoid receptor (GR; ref. 7). To date, it has remained unclear how transcription factor cAMP-responsive element binding protein Tax mechanistically suppresses the activity of NRs. Here, we show (CREB). Tax can also activate nuclear factor-nB(NF-nB; that the Tax1-binding protein 1 (TAX1BP1), a human cell encoded ref. 3). In various settings, Tax has been found to repress the Tax-binding protein identified by us (23), is closely related to expression of cellular genes, including DNA polymerase b (4), p53 (5, 6), coiled-coil transcriptional coactivator (CoCoA), a component of the nuclear receptors (7), cyclin A (8), c-Myb (9), MyoD (10), and p160 NR coactivator complex (24, 25). We further show that transforming growth factor b (11). TAX1BP1 is a transcriptional coactivator for NR, and that Tax Transcriptional activation of gene expression exerted by Tax represses NR function through binding to TAX1BP1. through either the CREB or the NF-nB pathway has been well Materials and Methods Plasmids. Human TAX1BP1 cDNA containing a complete coding region Note: D-Y. Jin is a Leukemia and Lymphoma Society Scholar. (Genbank U33821) was derived from an EST clone (ATCC: 104248) obtained Requests for reprints: Dong-Yan Jin, Department of Biochemistry, The University from the American Type Culture Collection (Manassas, VA). Expression of Hong Kong, 3/F Laboratory Block, Faculty of Medicine Building, 21 Sassoon plasmids pSVBP1 and pHABP1 for full-length TAX1BP1 were derived from Road, Pokfulam, Hong Kong. Phone: 852-2819-9491; Fax: 852-2855-1254; E-mail: dyjin@ previously described SV40 promoter-driven expression vectors pSV and hkucc.hku.hk. I2007 American Association for Cancer Research. pHA (26, 27). Plasmid pGSTBP1 contains TAX1BP1 cDNA inserted into doi:10.1158/0008-5472.CAN-06-3053 pGEX4T3 (Amersham, Piscataway, NJ). TAX1BP1, Tax, and the activation Cancer Res 2007; 67: (3). February 1, 2007 1072 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2007 American Association for Cancer Research. HTLV-1 Tax Targets TAX1BP1 to Repress NR Signaling domain (AD) of VP16 fused to Gal4 DNA-binding domain (amino acids 1– reaction. Transfection efficiencies were normalized with a pSV-h-Gal 147) were designated GalBP1, GalTax, and GalVP16, respectively. Mamma- control plasmid (Promega, Madison, WI) expressing h-galactosidase. lian expression plasmid pGALBP1 expressing GalBP1 was derived from pM Luciferase activity was measured as described (33) using the Dual- (Clontech, Mountain View, CA). Truncated versions of TAX1BP1 were Luciferase reagents (Promega). Transfection efficiencies were normalized constructed by PCR, and the sequences of all mutants were determined to with a pRL-TK control plasmid (Promega) expressing Renilla luciferase. À À À confirm that no undesired changes were introduced. Mouse Tax1bp1 cDNA Generation of Tax1bp1+/ and Tax1bp1 / mice. The Tax1bp1 gene is (IMAGE: 1480596) in an SV40 promoter-driven expression vector pME18S- located on chromosome 6. A 12-kb EcoRI-BamHI fragment that contains FL3 was purchased from the American Type Culture Collection. exon 16 and 17 was used for generation of targeting plasmid. The thymidine Expression plasmids for Tax, GalTax, and polyhistidine-tagged Tax (His- kinase (TK) and the neomycin (neo) genes were used as selectable markers. Tax) have been described elsewhere (15, 18). Expression plasmid for In engineering the knockout mice, exon 17 of Tax1bp1 was replaced by neo. GalVP16 was from Clontech. Confirmation of successful knockout was based on PCR and Western À À Chloramphenicol acetyltransferase (CAT) reporter plasmid pG5CAT blotting. Details on knockout and in breeding of Tax1bp1 / animals are containing five copies of Gal4-binding sites was from Clontech. Luciferase presented elsewhere.4 reporter plasmid pLTRLuc under the control of the HTLV-1 LTR has been n described elsewhere (15). Reporter plasmids p BLuc, pSRELuc, and Results pCRELuc were from Stratagene (La Jolla, CA). pGRELuc was from Clontech. Expression plasmid pCDNArGR (28) for rat GR was kindly provided by Interaction of TAX1BP1 and Tax. We screened a human cDNA Dr. Keith Yamamoto (University of California, San Francisco, CA). library for Tax-binding proteins using yeast two-hybrid technology. Expression plasmid pSG5TIF2 (29) for human GR-interacting protein 1 One Tax-binding cDNA was initially designated TXBP151 (Genbank (GRIP1), also known as transcriptional intermediary factor 2 (TIF2), was a U33821) and was subsequently named by the Gene Nomenclature gift from Dr. Hinrich Gronemeyer (Institut de Ge´ne´tiqueet de Biologie Committee of the Human Genome Organization as TAX1BP1. Mole´culaire et Cellulaire, Illkirch Cedex, France). TAX1BP1 has 747-amino-acid residues, and its molecular mass is Antibodies. Polyclonal anti-TAX1BP1 antibody a-151C was raised in predicted to be 86.5 kDa. We previously reported that TAX1BP1 rabbits against a keyhole limpet hemocyanin–conjugated synthetic peptide, interacts with A20, which is an inhibitor of apoptosis and NF-nB which corresponds to the COOH-terminal 21 residues (amino acids 725– 747) of human TAX1BP1. Likewise, a-151A was against a conjugated signaling (23). Moreover, others have identified TAX1BP1 as T6BP, a peptide corresponding to amino acid residues 537 to 556 of human TRAF6-binding protein (34). TAX1BP1. a-151C and a-151A antisera were purified through HiTrap TAX1BP1 contains an NH2-terminal domain (residues 1–150) Sepharose columns (Amersham) activated by N-hydroxysuccinimide and homologous to nuclear dot protein 52 (NDP52), whose function coupled to immunizing peptides. remains elusive and controversial (35). The central region (residues Mouse monoclonal anti-Tax antibody (clone 168A51-42) and rabbit 150–600) of TAX1BP1 is predicted to form a coiled-coil structure polyclonal antiserum against Tax have been described (26, 30). Mouse (36). The COOH-terminal part (residues 668–747) of TAX1BP1 monoclonal anti-a-tubulin (clone B-5-1-2) was from Sigma (St.
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