1887

Abstract

The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein transforms human lymphocytes and is critical for the pathogenesis of HTLV-1-induced adult T-cell leukaemia. In HTLV-transformed cells, Tax upregulates interleukin (IL)-13, a cytokine with proliferative and anti-apoptotic functions that is linked to leukaemogenesis. Tax-stimulated IL-13 is thought to result in autocrine stimulation of HTLV-infected cells and thus may be relevant to their growth. The causal transactivation of the promoter by Tax is predominantly dependent on a nuclear factor of activated T cells (NFAT)-binding P element. Here, it was shown that the isolated IL-13 Tax-responsive element (IL13TaxRE) was sufficient to mediate IL-13 transactivation by Tax and NFAT1. However, cyclosporin A, a specific NFAT inhibitor, revealed that Tax transactivation of IL13TaxRE or wild-type promoter was independent of NFAT and that NFAT did not contribute to upregulation in HTLV-transformed cells. By contrast, Tax stimulation was repressible by an efficient nuclear factor (NF)-B inhibitor (IkBaDN), indicating the requirement for NF-B. The capacity of NF-B to stimulate IL13TaxRE was demonstrated by a strong response to NF-B in reporter assays and by direct binding of NF-B to IL13TaxRE. Thus, IL13TaxRE in the promoter represents a dually active promoter element responsive to NF-B and NFAT. Together, these results indicate that Tax causes IL-13 upregulation in HTLV-1-infected cells via NF-B.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.2008/003699-0
2008-11-01
2024-12-06
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/11/2788.html?itemId=/content/journal/jgv/10.1099/vir.0.2008/003699-0&mimeType=html&fmt=ahah

References

  1. Ahlers J. D., Belyakov I. M., Terabe M., Koka R., Donaldson D. D., Thomas E. K., Berzofsky J. A. 2002; A push–pull approach to maximize vaccine efficacy: abrogating suppression with an IL-13 inhibitor while augmenting help with granulocyte/macrophage colony-stimulating factor and CD40L. Proc Natl Acad Sci U S A 99:13020–13025 [CrossRef]
    [Google Scholar]
  2. Akagi T., Ono H., Nyunoya H., Shimotohno K. 1997; Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans -activating phenotypes. Oncogene 14:2071–2078 [CrossRef]
    [Google Scholar]
  3. Bargou R. C., Leng C., Krappmann D., Emmerich F., Mapara M. Y., Bommert K., Royer H. D., Scheidereit C., Dorken B. 1996; High-level nuclear NF- κ B and Oct-2 is a common feature of cultured Hodgkin/Reed–Sternberg cells. Blood 87:4340–4347
    [Google Scholar]
  4. Bargou R. C., Emmerich F., Krappmann D., Bommert K., Mapara M. Y., Arnold W., Royer H. D., Grinstein E., Greiner A. other authors 1997; Constitutive nuclear factor- κ B-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest 100:2961–2969 [CrossRef]
    [Google Scholar]
  5. Birnie G. D. 1978; Isolation of nuclei from animal cells in culture. Methods Cell Biol 17:13–26
    [Google Scholar]
  6. Chung H. K., Young H. A., Goon P. K., Heidecker G., Princler G. L., Shimozato O., Taylor G. P., Bangham C. R., Derse D. 2003; Activation of interleukin-13 expression in T cells from HTLV-1-infected individuals and in chronically infected cell lines. Blood 102:4130–4136 [CrossRef]
    [Google Scholar]
  7. Crabtree G. R., Olson E. N. 2002; NFAT signaling: choreographing the social lives of cells. Cell 109:Suppl.S67–S79 [CrossRef]
    [Google Scholar]
  8. Deepak P., Sanjay K., Acharya A. 2007; IL-13 R α 2-mediated interleukin-13 neutralization represses in vivo progressive growth of a T-cell lymphoma. J Exp Clin Cancer Res 26:347–352
    [Google Scholar]
  9. Dolganov G., Bort S., Lovett M., Burr J., Schubert L., Short D., McGurn M., Gibson C., Lewis D. B. 1996; Coexpression of the interleukin-13 and interleukin-4 genes correlates with their physical linkage in the cytokine gene cluster on human chromosome 5q23-31. Blood 87:3316–3326
    [Google Scholar]
  10. Farmer P. K., He X., Schmitz M. L., Rubin J., Nanes M. S. 2000; Inhibitory effect of NF- κ B on 1,25-dihydroxyvitamin D3 and retinoid X receptor function. Am J Physiol Endocrinol Metab 279:E213–E220
    [Google Scholar]
  11. Fraedrich K., Muller B., Grassmann R. 2005; The HTLV-1 Tax protein binding domain of cyclin-dependent kinase 4 (CDK4) includes the regulatory PSTAIRE helix. Retrovirology 2:54 [CrossRef]
    [Google Scholar]
  12. Fujii M., Chuhjo T., Minamino T., Masaaki N., Miyamoto K., Seiki M. 1995; Identification of the Tax interaction region of serum response factor that mediates the aberrant induction of immediate early genes through CArG boxes by HTLV-I Tax. Oncogene 11:7–14
    [Google Scholar]
  13. Gauchat J. F., Schlagenhauf E., Feng N. P., Moser R., Yamage M., Jeannin P., Alouani S., Elson G., Notarangelo L. D. other authors 1997; A novel 4-kb interleukin-13 receptor alpha mRNA expressed in human B, T, and endothelial cells encoding an alternate type-II interleukin-4/interleukin-13 receptor. Eur J Immunol 27:971–978 [CrossRef]
    [Google Scholar]
  14. 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 2:407–410
    [Google Scholar]
  15. Good L., Maggirwar S. B., Sun S. C. 1996; Activation of the IL-2 gene promoter by HTLV-I tax involves induction of NF-AT complexes bound to the CD28-responsive element. EMBO J 15:3744–3750
    [Google Scholar]
  16. Good L., Maggirwar S. B., Harhaj E. W., Sun S. C. 1997; Constitutive dephosphorylation and activation of a member of the nuclear factor of activated T cells, NF-AT1, in Tax-expressing and type I human T-cell leukemia virus-infected human T cells. J Biol Chem 272:1425–1428 [CrossRef]
    [Google Scholar]
  17. Grassmann R., Aboud M., Jeang K. T. 2005; Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene 24:5976–5985 [CrossRef]
    [Google Scholar]
  18. Grossman W. J., Kimata J. T., Wong F. H., Zutter M., Ley T. J., Ratner L. 1995; Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A 92:1057–1061 [CrossRef]
    [Google Scholar]
  19. Hall W. W., Fujii M. 2005; Deregulation of cell-signaling pathways in HTLV-1 infection. Oncogene 24:5965–5975 [CrossRef]
    [Google Scholar]
  20. Haller K., Wu Y., Derow E., Schmitt I., Jeang K. T., Grassmann R. 2002; Physical interaction of human T-cell leukemia virus type 1 Tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Mol Cell Biol 22:3327–3338 [CrossRef]
    [Google Scholar]
  21. Hasegawa H., Sawa H., Lewis M. J., Orba Y., Sheehy N., Yamamoto Y., Ichinohe T., Tsunetsugu-Yokota Y., Katano H. other authors 2006; Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med 12:466–472 [CrossRef]
    [Google Scholar]
  22. Heinemann S., Biesinger B., Fleckenstein B., Albrecht J. C. 2006; NF κ B signaling is induced by the oncoprotein Tio through direct interaction with TRAF6. J Biol Chem 281:8565–8572 [CrossRef]
    [Google Scholar]
  23. Hinz M., Lemke P., Anagnostopoulos I., Hacker C., Krappmann D., Mathas S., Dorken B., Zenke M., Stein H., Scheidereit C. 2002; Nuclear factor κ B-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 196:605–617 [CrossRef]
    [Google Scholar]
  24. Jeang K. T. 2001; Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF- κ B. Cytokine Growth Factor Rev 12:207–217 [CrossRef]
    [Google Scholar]
  25. Jinquan T., Frydenberg J., Mukaida N., Bonde J., Larsen C. G., Matsushima K., Thestrup-Pedersen K. 1995; Recombinant human growth-regulated oncogene-alpha induces T lymphocyte chemotaxis. A process regulated via IL-8 receptors by IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-13. J Immunol 155:5359–5368
    [Google Scholar]
  26. Jost P. J., Ruland J. 2007; Aberrant NF- κ B signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 109:2700–2707
    [Google Scholar]
  27. Kapp U., Yeh W. C., Patterson B., Elia A. J., Kagi D., Ho A., Hessel A., Tipsword M., Williams A. other authors 1999; Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed–Sternberg cells. J Exp Med 189:1939–1946 [CrossRef]
    [Google Scholar]
  28. Krueger A., Fas S. C., Giaisi M., Bleumink M., Merling A., Stumpf C., Baumann S., Holtkotte D., Bosch V. other authors 2006; HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP. Blood 107:3933–3939 [CrossRef]
    [Google Scholar]
  29. Li-Weber M., Giaisi M., Baumann S., Palfi K., Krammer P. H. 2004; NF- κ B synergizes with NF-AT and NF-IL6 in activation of the IL-4 gene in T cells. Eur J Immunol 34:1111–1118 [CrossRef]
    [Google Scholar]
  30. Lomo J., Blomhoff H. K., Jacobsen S. E., Krajewski S., Reed J. C., Smeland E. B. 1997; Interleukin-13 in combination with CD40 ligand potently inhibits apoptosis in human B lymphocytes: upregulation of Bcl-xL and Mcl-1. Blood 89:4415–4424
    [Google Scholar]
  31. Macián F., García-Cózar F., Im S. H., Horton H. F., Byrne M. C., Rao A. 2002; Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109:719–731 [CrossRef]
    [Google Scholar]
  32. Manna S. K., Aggarwal B. B. 1998; IL-13 suppresses TNF-induced activation of nuclear factor- κ B, activation protein-1, and apoptosis. J Immunol 161:2863–2872
    [Google Scholar]
  33. Mathas S., Lietz A., Janz M., Hinz M., Jundt F., Scheidereit C., Bommert K., Dorken B. 2003; Inhibition of NF- κ B essentially contributes to arsenic-induced apoptosis. Blood 102:1028–1034 [CrossRef]
    [Google Scholar]
  34. Monticelli S., Solymar D. C., Rao A. 2004; Role of NFAT proteins in IL13 gene transcription in mast cells. J Biol Chem 279:36210–36218 [CrossRef]
    [Google Scholar]
  35. 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]
  36. Nicot C., Mahieux R., Takemoto S., Franchini G. 2000; Bcl-XL is up-regulated by HTLV-I and HTLV-II in vitro and in ex vivo ATLL samples. Blood 96:275–281
    [Google Scholar]
  37. Niinuma A., Higuchi M., Takahashi M., Oie M., Tanaka Y., Gejyo F., Tanaka N., Sugamura K., Xie L. other authors 2005; Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus. J Virol 79:11925–11934 [CrossRef]
    [Google Scholar]
  38. Northrop J. P., Ho S. N., Chen L., Thomas D. J., Timmerman L. A., Nolan G. P., Admon A., Crabtree G. R. 1994; NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369:497–502 [CrossRef]
    [Google Scholar]
  39. Okamoto K., Fujisawa J., Reth M., Yonehara S. 2006; Human T-cell leukemia virus type-I oncoprotein Tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of NF- κ B. Genes Cells 11:177–191 [CrossRef]
    [Google Scholar]
  40. Okamura H., Aramburu J., García-Rodríguez C., Viola J. P., Raghavan A., Tahiliani M., Zhang X., Qin J., Hogan P. G., Rao A. 2000; Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol Cell 6:539–550 [CrossRef]
    [Google Scholar]
  41. Peloponese J. M., Yeung M. L., Jeang K. T. 2006; Modulation of nuclear factor- κ B by human T cell leukemia virus type 1 Tax protein: implications for oncogenesis and inflammation. Immunol Res 34:1–12 [CrossRef]
    [Google Scholar]
  42. Pichler K., Kattan T., Gentzsch J., Kress A. K., Taylor G. P., Bangham C. R., Grassmann R. 2008; Strong induction of 4-1BB, a growth and survival promoting costimulatory receptor, in HTLV-1-infected cultured and patients' T-cells by the viral Tax oncoprotein. Blood 111:4741–4751 [CrossRef]
    [Google Scholar]
  43. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. 1980; Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 77:7415–7419 [CrossRef]
    [Google Scholar]
  44. Princler G. L., Julias J. G., Hughes S. H., Derse D. 2003; Roles of viral and cellular proteins in the expression of alternatively spliced HTLV-1 pX mRNAs. Virology 317:136–145 [CrossRef]
    [Google Scholar]
  45. Radonic A., Thulke S., Mackay I. M., Landt O., Siegert W., Nitsche A. 2004; Guideline to reference gene selection for quantitative real-time PCR. Biochem Biophys Res Commun 313:856–862 [CrossRef]
    [Google Scholar]
  46. Relic B., Guicheux J., Mezin F., Lubberts E., Togninalli D., Garcia I., van den Berg W. B., Guerne P. A. 2001; IL-4 and IL-13, but not IL-10, protect human synoviocytes from apoptosis. J Immunol 166:2775–2782 [CrossRef]
    [Google Scholar]
  47. Rivera I., Harhaj E. W., Sun S. C. 1998; Involvement of NF-AT in type I human T-cell leukemia virus Tax-mediated Fas ligand promoter transactivation. J Biol Chem 273:22382–22388 [CrossRef]
    [Google Scholar]
  48. Romanchikova N., Ivanova V., Scheller C., Jankevics E., Jassoy C., Serfling E. 2003; NFAT transcription factors control HIV-1 expression through a binding site downstream of TAR region. Immunobiology 208:361–365 [CrossRef]
    [Google Scholar]
  49. Ruben S. M., Dillon P. J., Schreck R., Henkel T., Chen C. H., Maher M., Baeuerle P. A., Rosen C. A. 1991; Isolation of a rel -related human cDNA that potentially encodes the 65-kD subunit of NF- κ B. Science 251:1490–1493 [CrossRef]
    [Google Scholar]
  50. Schmitt I., Rosin O., Rohwer P., Gossen M., Grassmann R. 1998; Stimulation of cyclin-dependent kinase activity and G1- to S-phase transition in human lymphocytes by the human T-cell leukemia/lymphotropic virus type 1 Tax protein. J Virol 72:633–640
    [Google Scholar]
  51. Serfling E., Berberich-Siebelt F., Chuvpilo S., Jankevics E., Klein-Hessling S., Twardzik T., Avots A. 2000; The role of NF-AT transcription factors in T cell activation and differentiation. Biochim Biophys Acta 14981–18 [CrossRef]
    [Google Scholar]
  52. Sharma S., Mamane Y., Grandvaux N., Bartlett J., Petropoulos L., Lin R., Hiscott J. 2000; Activation and regulation of interferon regulatory factor 4 in HTLV type 1-infected T lymphocytes. AIDS Res Hum Retroviruses 16:1613–1622 [CrossRef]
    [Google Scholar]
  53. Sharma S., Grandvaux N., Mamane Y., Genin P., Azimi N., Waldmann T., Hiscott J. 2002; Regulation of IFN regulatory factor 4 expression in human T cell leukemia virus-I-transformed T cells. J Immunol 169:3120–3130 [CrossRef]
    [Google Scholar]
  54. Silbermann K., Grassmann R. 2007; Human T cell leukemia type 1 Tax-induced signals in cell survival, proliferation, and transformation. Signal Transduct 7:34–52 [CrossRef]
    [Google Scholar]
  55. Skinnider B. F., Elia A. J., Gascoyne R. D., Trumper L. H., von Bonin F., Kapp U., Patterson B., Snow B. E., Mak T. W. 2001; Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma. Blood 97:250–255 [CrossRef]
    [Google Scholar]
  56. Skinnider B. F., Kapp U., Mak T. W. 2002; The role of interleukin 13 in classical Hodgkin lymphoma. Leuk Lymphoma 43:1203–1210 [CrossRef]
    [Google Scholar]
  57. 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]
  58. Stuver S. O., Tachibana N., Okayama A., Mueller N. E. 1996; Evaluation of morbidity among human T lymphotropic virus type 1 carriers in Miyazaki. Jpn J Infect Dis 173:584–591 [CrossRef]
    [Google Scholar]
  59. Sun S. C., Yamaoka S. 2005; Activation of NF- κ B by HTLV-I and implications for cell transformation. Oncogene 24:5952–5964 [CrossRef]
    [Google Scholar]
  60. Taguchi H. 1989; Immunologic deficiency in HTLV-I infection. Rinsho Ketsueki 30:1751–1754 (in Japanese
    [Google Scholar]
  61. Taylor G. 2007; Molecular aspects of HTLV-I infection and adult T-cell leukaemia/lymphoma. J Clin Pathol 60:1392–1396
    [Google Scholar]
  62. Terabe M., Matsui S., Noben-Trauth N., Chen H., Watson C., Donaldson D. D., Carbone D. P., Paul W. E., Berzofsky J. A. 2000; NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515–520 [CrossRef]
    [Google Scholar]
  63. Wäldele K., Schneider G., Ruckes T., Grassmann R. 2004; Interleukin-13 overexpression by Tax transactivation: a potential autocrine stimulus in human T-cell leukemia virus-infected lymphocytes. J Virol 78:6081–6090 [CrossRef]
    [Google Scholar]
  64. Wäldele K., Silbermann K., Schneider G., Ruckes T., Cullen B. R., Grassmann R. 2006; Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood 107:4491–4499 [CrossRef]
    [Google Scholar]
  65. Wright K., Kolios G., Westwick J., Ward S. G. 1999; Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric oxide formation. Evidence for an interleukin-13-driven phosphatidylinositol 3-kinase-dependent survival mechanism. J Biol Chem 274:17193–17201 [CrossRef]
    [Google Scholar]
  66. Yasunaga J., Matsuoka M. 2007; Leukaemogenic mechanism of human T-cell leukaemia virus type I. Rev Med Virol 17:301–311 [CrossRef]
    [Google Scholar]
  67. 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]
  68. Yu C. R., Kirken R. A., Malabarba M. G., Young H. A., Ortaldo J. R. 1998; Differential regulation of the Janus kinase–STAT pathway and biologic function of IL-13 in primary human NK and T cells: a comparative study with IL-4. J Immunol 161:218–227
    [Google Scholar]
/content/journal/jgv/10.1099/vir.0.2008/003699-0
Loading
/content/journal/jgv/10.1099/vir.0.2008/003699-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error