1887

Abstract

Human T-cell leukaemia virus type 1 (HTLV-I), the aetiological agent of adult T-cell leukaemia (ATL) and tropical spastic paraparesis (TSP/HAM), transforms human T-cells and . The Tax protein of HTLV-I is essential for cellular transformation as well as viral and cellular gene transactivation. The interaction of Tax with cellular proteins is critical for these functions. We previously isolated and characterized a novel Tax-binding protein, TRX (TAX1BP2), by screening a Jurkat T-cell cDNA library. In the present study, we present evidence that the tumour suppressor p53 targets the TRX protein for proteasome degradation. Pulse–chase experiments revealed that p53 enhanced the degradation of TRX protein and reduced the half-life from 2·0 to 0·25 h. p53 mutants R248W and R273H enhance TRX degradation suggesting a transcriptionally independent mechanism. Both HTLV-I Tax and the proteasome-specific inhibitor MG132 inhibited p53-mediated TRX protein degradation. These results suggest that TRX degradation is mediated through activation of the proteasome protein degradation pathway independent of transcriptional function of p53. Our results provide the first experimental evidence that Tax inhibits transciption-dependent and independent functions of p53.

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2003-04-01
2019-12-13
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References

  1. Adya, N., Zhao, L. J., Huang, W., Boros, I. & Giam, C. Z. ( 1994; ). Expansion of CREB's DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282–284 near the conserved DNA-binding domain of CREB. Proc Natl Acad Sci U S A 91, 5642–5646.[CrossRef]
    [Google Scholar]
  2. Amundson, S. A., Myers, T. G. & Fornace, A. J., Jr ( 1998; ). Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene 17, 3287–3299.
    [Google Scholar]
  3. Ariumi, Y., Kaida, A., Lin, J. Y., Hirota, M., Masui, O., Yamaoka, S., Taya, Y. & Shimotohno, K. ( 2000; ). HTLV-I Tax oncoprotein represses the p53-mediated trans-activation function through coactivator CBP sequestration. Oncogene 19, 1491–1499.[CrossRef]
    [Google Scholar]
  4. Ausubel, F. M., Brent, R., Kingston, R. E., Moore, D. D., Seidman, J. G., Smith, J. A. & Struhl, K. (editors) ( 1989; ). Current Protocols in Molecular Biology. New York: John Wiley & Sons.
  5. Azimi, N., Brown, K., Bamford, R. N., Tagaya, Y., Siebenlist, U. & Waldmann, T. A. ( 1998; ). Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-κB site. Proc Natl Acad Sci U S A 95, 2452–2457.[CrossRef]
    [Google Scholar]
  6. Bates, S. & Vousden, K. H. ( 1999; ). Mechanisms of p53-mediated apoptosis. Cell Mol Life Sci 55, 28–37.[CrossRef]
    [Google Scholar]
  7. Bex, F., Yin, M. J., Burny, A. & Gaynor, R. B. ( 1998; ). Differential transcriptional activation by human T-cell leukemia virus type 1 Tax mutants is mediated by distinct interactions with CREB binding protein and p300. Mol Cell Biol 18, 2392–2405.
    [Google Scholar]
  8. Brady, J. N. ( 1996; ). Biology of HTLV-I: host cell interactions. In Human T-cell Lymphotropic Virus Type 1, pp. 79–112. Edited by P. Höllsberg & D. A. Hafler. New York: John Wiley & Sons.
  9. Buckbinder, L., Talbott, R., Velasco-Miguel, S., Takenaka, I., Faha, B., Seizinger, B. R. & Kley, N. ( 1995; ). Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377, 646–649.[CrossRef]
    [Google Scholar]
  10. Castillo, J. P., Yurochko, A. D. & Kowalik, T. F. ( 2000; ). Role of human cytomegalovirus immediate-early proteins in cell growth control. J Virol 74, 8028–8037.[CrossRef]
    [Google Scholar]
  11. Cereseto, A., Diella, F., Mulloy, J. C., Cara, A., Michieli, P., Grassmann, R., Franchini, G. & Klotman, M. E. ( 1996; ). p53 functional impairment and high p21waf1/cip1 expression in human T-cell lymphotropic/leukemia virus type I-transformed T cells. Blood 88, 1551–1560.
    [Google Scholar]
  12. Chin, K. V., Ueda, K., Pastan, I. & Gottesman, M. M. ( 1992; ). Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 255, 459–462.[CrossRef]
    [Google Scholar]
  13. Choi, Y. H. ( 2001; ). Proteasome-mediated degradation of BRCA1 protein in MCF-7 human breast cancer cells. Int J Oncol 19, 687–693.
    [Google Scholar]
  14. el-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. ( 1992; ). Definition of a consensus binding site for p53. Nat Genet 1, 45–49.[CrossRef]
    [Google Scholar]
  15. el-Deiry, W. S., Tokino, T., Velculescu, V. E. & 7 other authors ( 1993; ). WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825.[CrossRef]
    [Google Scholar]
  16. Fields, S. & Jang, S. K. ( 1990; ). Presence of a potent transcription activating sequence in the p53 protein. Science 249, 1046–1049.[CrossRef]
    [Google Scholar]
  17. Flatt, P. M., Polyak, K., Tang, L. J. & 8 other authors ( 2000; ). p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest. Cancer Lett 156, 63–72.[CrossRef]
    [Google Scholar]
  18. Fujii, M., Niki, T., Mori, T., Matsuda, T., Matsui, M., Nomura, N. & Seiki, M. ( 1991; ). HTLV-I Tax induces expression of various immediate early serum responsive genes. Oncogene 6, 1023–1029.
    [Google Scholar]
  19. Fukazawa, T., Fujiwara, T., Uno, F. & 8 other authors ( 2001; ). Accelerated degradation of cellular FLIP protein through the ubiquitin-proteasome pathway in p53-mediated apoptosis of human cancer cells. Oncogene 20, 5225–5231.[CrossRef]
    [Google Scholar]
  20. Gessain, A., Barin, F., Vernant, J. C., Gout, O., Maurs, L., Calender, A. & de The, G. ( 1985; ). Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet ii, 407–410.
    [Google Scholar]
  21. Ginsberg, D., Mechta, F., Yaniv, M. & Oren, M. ( 1991; ). Wild-type p53 can down-modulate the activity of various promoters. Proc Natl Acad Sci U S A 88, 9979–9983.[CrossRef]
    [Google Scholar]
  22. Gottlieb, E. & Oren, M. ( 1998a; ). p53 facilitates pRb cleavage in IL-3-deprived cells: novel pro-apoptotic activity of p53. EMBO J 17, 3587–3596.[CrossRef]
    [Google Scholar]
  23. Gottlieb, T. M. & Oren, M. ( 1998b; ). p53 and apoptosis. Semin Cancer Biol 8, 359–368.[CrossRef]
    [Google Scholar]
  24. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. J. ( 1993; ). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816.[CrossRef]
    [Google Scholar]
  25. Harris, C. C. ( 1993; ). p53: at the crossroads of molecular carcinogenesis and risk assessment. Science 262, 1980–1981.[CrossRef]
    [Google Scholar]
  26. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. ( 1991; ). p53 mutations in human cancers. Science 253, 49–53.[CrossRef]
    [Google Scholar]
  27. Irminger-Finger, I., Siegel, B. D. & Leung, W. C. ( 1999; ). The functions of breast cancer susceptibility gene 1 (BRCA1) product and its associated proteins. Biol Chem 380, 117–128.
    [Google Scholar]
  28. Jeang, K. T., Widen, S. G., Semmes, O. J., IV & Wilson, S. H. ( 1990; ). HTLV-I trans-activator protein, Tax, is a trans-repressor of the human beta-polymerase gene. Science 247, 1082–1084.[CrossRef]
    [Google Scholar]
  29. Kanno, T., Brown, K., Franzoso, G. & Siebenlist, U. ( 1994; ). Kinetic analysis of human T-cell leukemia virus type I Tax-mediated activation of NF-κB. Mol Cell Biol 14, 6443–6451.
    [Google Scholar]
  30. Kashanchi, F., Duvall, J. F., Kwok, R. P., Lundblad, J. R., Goodman, R. H. & Brady, J. N. ( 1998; ). The coactivator CBP stimulates human T-cell lymphotrophic virus type I Tax transactivation in vitro. J Biol Chem 273, 34646–34652.[CrossRef]
    [Google Scholar]
  31. Kastan, M. B., Canman, C. E. & Leonard, C. J. ( 1995; ). p53, cell cycle control and apoptosis: implications for cancer. Cancer Metastasis Rev 14, 3–15.[CrossRef]
    [Google Scholar]
  32. Ko, L. J. & Prives, C. ( 1996; ). p53: puzzle and paradigm. Genes Dev 10, 1054–1072.[CrossRef]
    [Google Scholar]
  33. Kwok, R. P., Laurance, M. E., Lundblad, J. R., Goldman, P. S., Shih, H., Connor, L. M., Marriott, S. J. & Goodman, R. H. ( 1996; ). Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature 380, 642–646.[CrossRef]
    [Google Scholar]
  34. Lechner, M. S., Mack, D. H., Finicle, A. B., Crook, T., Vousden, K. H. & Laimins, L. A. ( 1992; ). Human papillomavirus E6 proteins bind p53 in vivo and abrogate p53-mediated repression of transcription. EMBO J 11, 3045–3052; erratum 11, 4248.
    [Google Scholar]
  35. Lemasson, I. & Nyborg, J. K. ( 2001; ). Human T-cell leukemia virus type I Tax repression of p73β is mediated through competition for the C/H1 domain of CBP. J Biol Chem 276, 15720–15727.[CrossRef]
    [Google Scholar]
  36. Levine, A. J. ( 1997; ). p53, the cellular gatekeeper for growth and division. Cell 88, 323–331.[CrossRef]
    [Google Scholar]
  37. Liu, Y. & Kulesz-Martin, M. ( 2001; ). p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding. Carcinogenesis 22, 851–860.[CrossRef]
    [Google Scholar]
  38. Magae, J., Illenye, S., Tejima, T., Chang, Y. C., Mitsui, Y., Tanaka, K., Omura, S. & Heintz, N. H. ( 1997; ). Transcriptional squelching by ectopic expression of E2F-1 and p53 is alleviated by proteasome inhibitors MG-132 and lactacystin. Oncogene 15, 759–769.[CrossRef]
    [Google Scholar]
  39. Meriin, A. B., Gabai, V. L., Yaglom, J., Shifrin, V. I. & Sherman, M. Y. ( 1998; ). Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis. J Biol Chem 273, 6373–6379.[CrossRef]
    [Google Scholar]
  40. Mireskandari, A., Reid, R. L., Kashanchi, F., Dittmer, J., Li, W. B. & Brady, J. N. ( 1996; ). Isolation of a cDNA clone, TRX encoding a human T-cell lymphotrophic virus type-I Tax1 binding protein. Biochim Biophys Acta 1306, 9–13.[CrossRef]
    [Google Scholar]
  41. Miyashita, T. & Reed, J. C. ( 1995; ). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299.[CrossRef]
    [Google Scholar]
  42. Mori, N. & Prager, D. ( 1998; ). Interleukin-10 gene expression and adult T-cell leukemia. Leuk Lymphoma 29, 239–248.[CrossRef]
    [Google Scholar]
  43. Mori, N., Mukaida, N., Ballard, D. W., Matsushima, K. & Yamamoto, N. ( 1998; ). Human T-cell leukemia virus type I Tax transactivates human interleukin 8 gene through acting concurrently on AP-1 and nuclear factor-κB-like sites. Cancer Res 58, 3993–4000.
    [Google Scholar]
  44. Mulloy, J. C., Kislyakova, T., Cereseto, A. & 8 other authors ( 1998; ). Human T-cell lymphotropic/leukemia virus type 1 Tax abrogates p53-induced cell cycle arrest and apoptosis through its CREB/ATF functional domain. J Virol 72, 8852–8860.
    [Google Scholar]
  45. Neuveut, C., Low, K. G., Maldarelli, F., Schmitt, I., Majone, F., Grassmann, R. & Jeang, K. T. ( 1998; ). Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of cyclin D-cdk and p110Rb. Mol Cell Biol 18, 3620–3632.
    [Google Scholar]
  46. Nicot, C., Mahieux, R., Opavsky, R., Cereseto, A., Wolff, L., Brady, J. N. & Franchini, G. ( 2000; ). HTLV-I Tax transrepresses the human c-Myb promoter independently of its interaction with CBP or p300. Oncogene 19, 2155–2164.[CrossRef]
    [Google Scholar]
  47. Nigro, J. M., Baker, S. J., Preisinger, A. C. & others ( 1989; ). Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705–708.[CrossRef]
    [Google Scholar]
  48. Nimer, S. ( 1991; ). Tax responsiveness of the GM-CSF promoter is mediated by mitogen-inducible sequences other than kappa B. New Biol 3, 997–1004.
    [Google Scholar]
  49. Osame, M., Usuku, K., Izumo, S., Ijichi, N., Amitani, H., Igata, A., Matsumoto, M. & Tara, M. ( 1986; ). HTLV-I associated myelopathy, a new clinical entity. Lancet i, 1031–1032.
    [Google Scholar]
  50. Pise-Masison, C. A., Choi, K. S., Radonovich, M., Dittmer, J., Kim, S. J. & Brady, J. N. ( 1998; ). Inhibition of p53 transactivation function by the human T-cell lymphotropic virus type 1 Tax protein. J Virol 72, 1165–1170.
    [Google Scholar]
  51. Pise-Masison, C. A., Mahieux, R., Jiang, H., Ashcroft, M., Radonovich, M., Duvall, J., Guillerm, C. & Brady, J. N. ( 2000; ). Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-κB pathway and is dependent on p53 phosphorylation. Mol Cell Biol 20, 3377–3386.[CrossRef]
    [Google Scholar]
  52. Pise-Masison, C. A., Mahieux, R., Radonovich, M., Jiang, H. & Brady, J. N. ( 2001; ). Human T-lymphotropic virus type I Tax protein utilizes distinct pathways for p53 inhibition that are cell type-dependent. J Biol Chem 276, 200–205.[CrossRef]
    [Google Scholar]
  53. Poiesz, B. J., Ruscetti, F. W., Mier, J. W., Woods, A. M. & Gallo, R. C. ( 1980; ). T-cell lines established from human T-lymphocytic neoplasias by direct response to T-cell growth factor. Proc Natl Acad Sci U S A 77, 6815–6819.[CrossRef]
    [Google Scholar]
  54. Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W. & Vogelstein, B. ( 1997; ). A model for p53-induced apoptosis. Nature 389, 300–305.[CrossRef]
    [Google Scholar]
  55. Prives, C. & Manley, J. L. ( 2001; ). Why is p53 acetylated? Cell 107, 815–818.[CrossRef]
    [Google Scholar]
  56. Ragimov, N., Krauskopf, A., Navot, N., Rotter, V., Oren, M. & Aloni, Y. ( 1993; ). Wild-type but not mutant p53 can repress transcription initiation in vitro by interfering with the binding of basal transcription factors to the TATA motif. Oncogene 8, 1183–1193.
    [Google Scholar]
  57. Ratovitski, E. A., Patturajan, M., Hibi, K., Trink, B., Yamaguchi, K. & Sidransky, D. ( 2001; ). p53 associates with and targets Delta Np63 into a protein degradation pathway. Proc Natl Acad Sci U S A 98, 1817–1822.[CrossRef]
    [Google Scholar]
  58. Ravi, R., Mookerjee, B., Bhujwalla, Z. M. & 7 other authors ( 2000; ). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev 14, 34–44.
    [Google Scholar]
  59. Raycroft, L., Wu, H. Y. & Lozano, G. ( 1990; ). Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 249, 1049–1051.[CrossRef]
    [Google Scholar]
  60. Ryan, K. M., Phillips, A. C. & Vousden, K. H. ( 2001; ). Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol 13, 332–337.[CrossRef]
    [Google Scholar]
  61. Sadot, E., Geiger, B., Oren, M. & Ben-Ze'ev, A. ( 2001; ). Down-regulation of beta-catenin by activated p53. Mol Cell Biol 21, 6768–6781.[CrossRef]
    [Google Scholar]
  62. Salvant, B. S., Fortunato, E. A. & Spector, D. H. ( 1998; ). Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription. J Virol 72, 3729–3741.
    [Google Scholar]
  63. Santhanam, U., Ray, A. & Sehgal, P. B. ( 1991; ). Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A 88, 7605–7609.[CrossRef]
    [Google Scholar]
  64. Sawada, M., Suzumura, A., Kondo, N. & Marunouchi, T. ( 1992; ). Induction of cytokines in glial cells by trans-activator of human T-cell lymphotropic virus type I. FEBS Lett 313, 47–50.[CrossRef]
    [Google Scholar]
  65. Selivanova, G. & Wiman, K. G. ( 1995; ). p53: a cell cycle regulator activated by DNA damage. Adv Cancer Res 66, 143–180.
    [Google Scholar]
  66. Shen, Y. & White, E. ( 2001; ). p53-dependent apoptosis pathways. Adv Cancer Res 82, 55–84.
    [Google Scholar]
  67. Shiio, Y., Yamamoto, T. & Yamaguchi, N. ( 1992; ). Negative regulation of Rb expression by the p53 gene product. Proc Natl Acad Sci U S A 89, 5206–5210.[CrossRef]
    [Google Scholar]
  68. Siekevitz, M., Josephs, S. F., Dukovich, M., Peffer, N., Wong-Staal, F. & Greene, W. C. ( 1987; ). Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-I. Science 238, 1575–1578.[CrossRef]
    [Google Scholar]
  69. Smith, M. R. & Greene, W. C. ( 1990; ). Identification of HTLV-I Tax trans-activator mutants exhibiting novel transcriptional phenotypes. Genes Dev 4, 1875–1885.[CrossRef]
    [Google Scholar]
  70. Subler, M. A., Martin, D. W. & Deb, S. ( 1992; ). Inhibition of viral and cellular promoters by human wild-type p53. J Virol 66, 4757–4762.
    [Google Scholar]
  71. Suzuki, T., Kitao, S., Matsushime, H. & Yoshida, M. ( 1996; ). HTLV-I Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4. EMBO J 15, 1607–1614.
    [Google Scholar]
  72. Suzuki, T., Uchida-Toita, M. & Yoshida, M. ( 1999; ). Tax protein of HTLV-I inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site. Oncogene 18, 4137–4143.[CrossRef]
    [Google Scholar]
  73. Van Orden, K., Giebler, H. A., Lemasson, I., Gonzales, M. & Nyborg, J. K. ( 1999; ). Binding of p53 to the KIX domain of CREB binding protein. A potential link to human T-cell leukemia virus, type I-associated leukemogenesis. J Biol Chem 274, 26321–26328.[CrossRef]
    [Google Scholar]
  74. Wiebusch, L. & Hagemeier, C. ( 1999; ). Human cytomegalovirus 86-kilodalton IE2 protein blocks cell cycle progression in G1. J Virol 73, 9274–9283.
    [Google Scholar]
  75. Wu, G. S., Burns, T. F., McDonald, E. R., III, Meng, R. D., Kao, G., Muschel, R., Yen, T. & el-Deiry, W. S. ( 1999; ). Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 18, 6411–6418.[CrossRef]
    [Google Scholar]
  76. Yamaguchi, M., Hayashi, Y., Matsuoka, S., Takahashi, T. & Matsukage, A. ( 1994; ). Differential effect of p53 on the promoters of mouse DNA polymerase beta gene and proliferating-cell-nuclear-antigen gene. Eur J Biochem 221, 227–237.[CrossRef]
    [Google Scholar]
  77. Yamashita, I., Katamine, S., Moriuchi, R., Nakamura, Y., Miyamoto, T., Eguchi, K. & Nagataki, S. ( 1994; ). Transactivation of the human interleukin-6 gene by human T-lymphotropic virus type 1 Tax protein. Blood 84, 1573–1578.
    [Google Scholar]
  78. Yoshida, M., Seiki, M., Yamaguchi, K. & Takatsuki, K. ( 1984; ). Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci U S A 81, 2534–2537.[CrossRef]
    [Google Scholar]
  79. Yu, J., Zhang, L., Hwang, P. M., Rago, C., Kinzler, K. W. & Vogelstein, B. ( 1999; ). Identification and classification of p53-regulated genes. Proc Natl Acad Sci U S A 96, 14517–14522.[CrossRef]
    [Google Scholar]
  80. Zhu, H., Shen, Y. & Shenk, T. ( 1995; ). Human cytomegalovirus IE1 and IE2 proteins block apoptosis. J Virol 69, 7960–7970.
    [Google Scholar]
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