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. 1996 May;70(5):2730–2735. doi: 10.1128/jvi.70.5.2730-2735.1996

Persistent activation of NF-kappa B/Rel by human T-cell leukemia virus type 1 tax involves degradation of I kappa B beta.

L Good 1, S C Sun 1
PMCID: PMC190129  PMID: 8627746

Abstract

Activation of the eukaryotic NF-kappaB/Rel transcription factors by various cytokines and mitogens is a transient event, reflecting the fact that these inducers trigger the degradation and resynthesis of the dynamic NF-kappaB/Rel inhibitor IkappaBalpha. However, the tax gene product of the human T-cell leukemia virus type 1 (HTLV-1) is known to induce the persistent nuclear expression of various NF-kappaB/Rel factors, especially the c-Rel proto-oncoprotein, although the underlying mechanism remains unclear. In the present study, we demonstrate that Tax induces the degradation Of IkappaBbeta, another NF-kappaB/Rel cytoplasmic inhibitor that differs from IkappaBalpha in signal responses. Unlike that observed with IkappaBalpha, the degradation Of IkappaBbeta is not associated with its rapid resynthesis, apparently because of the failure of Tax to stimulate IkappaBbeta gene transcription. Thus, expression of Tax in Jurkat T cells leads to the gradual depletion of IkappaBbeta, which is correlated with the induction of c-Rel-containing kappaB binding complexes. Remarkably, in the three HTLV-1-infected T-cell lines investigated, little or no detectable amount of IkappaBbeta was found. We further demonstrate that Tax is able to override the cytoplasmic retention of c-Rel by 1kappaBbeta in transiently transfected cells. Together, these studies suggest that Tax-mediated inactivation Of IkappaBbeta may play a role in the persistent nuclear expression of c-Rel induced by HTLV-I infection.

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Selected References

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  1. Andersson S., Davis D. L., Dahlbäck H., Jörnvall H., Russell D. W. Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem. 1989 May 15;264(14):8222–8229. [PubMed] [Google Scholar]
  2. Baeuerle P. A., Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. doi: 10.1126/science.3140380. [DOI] [PubMed] [Google Scholar]
  3. Ballard D. W., Böhnlein E., Hoffman J. A., Bogerd H. P., Dixon E. P., Franza B. R., Greene W. C. Activation of the interleukin-2 receptor alpha gene: regulatory role for DNA-protein interactions flanking the kappa B enhancer. New Biol. 1989 Oct;1(1):83–92. [PubMed] [Google Scholar]
  4. Ballard D. W., Böhnlein E., Lowenthal J. W., Wano Y., Franza B. R., Greene W. C. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science. 1988 Sep 23;241(4873):1652–1655. doi: 10.1126/science.241.4873.1652. [DOI] [PubMed] [Google Scholar]
  5. Beg A. A., Baldwin A. S., Jr The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. Genes Dev. 1993 Nov;7(11):2064–2070. doi: 10.1101/gad.7.11.2064. [DOI] [PubMed] [Google Scholar]
  6. Beg A. A., Finco T. S., Nantermet P. V., Baldwin A. S., Jr Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol. 1993 Jun;13(6):3301–3310. doi: 10.1128/mcb.13.6.3301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brockman J. A., Scherer D. C., McKinsey T. A., Hall S. M., Qi X., Lee W. Y., Ballard D. W. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol. 1995 May;15(5):2809–2818. doi: 10.1128/mcb.15.5.2809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brown K., Park S., Kanno T., Franzoso G., Siebenlist U. Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2532–2536. doi: 10.1073/pnas.90.6.2532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Béraud C., Sun S. C., Ganchi P., Ballard D. W., Greene W. C. Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency. Mol Cell Biol. 1994 Feb;14(2):1374–1382. doi: 10.1128/mcb.14.2.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cordle S. R., Donald R., Read M. A., Hawiger J. Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells. J Biol Chem. 1993 Jun 5;268(16):11803–11810. [PubMed] [Google Scholar]
  11. Crenon I., Béraud C., Simard P., Montagne J., Veschambre P., Jalinot P. The transcriptionally active factors mediating the effect of the HTLV-I Tax transactivator on the IL-2R alpha kappa B enhancer include the product of the c-rel proto-oncogene. Oncogene. 1993 Apr;8(4):867–875. [PubMed] [Google Scholar]
  12. Cross S. L., Feinberg M. B., Wolf J. B., Holbrook N. J., Wong-Staal F., Leonard W. J. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. doi: 10.1016/0092-8674(87)90754-9. [DOI] [PubMed] [Google Scholar]
  13. Doerre S., Sista P., Sun S. C., Ballard D. W., Greene W. C. The c-rel protooncogene product represses NF-kappa B p65-mediated transcriptional activation of the long terminal repeat of type 1 human immunodeficiency virus. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1023–1027. doi: 10.1073/pnas.90.3.1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ganchi P. A., Sun S. C., Greene W. C., Ballard D. W. I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B p65 and requires the transactivation domain to inhibit NF-kappa B p65 DNA binding. Mol Biol Cell. 1992 Dec;3(12):1339–1352. doi: 10.1091/mbc.3.12.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gilmore T. D. NF-kappa B, KBF1, dorsal, and related matters. Cell. 1990 Sep 7;62(5):841–843. doi: 10.1016/0092-8674(90)90257-f. [DOI] [PubMed] [Google Scholar]
  16. Grassmann R., Berchtold S., Radant I., Alt M., Fleckenstein B., Sodroski J. G., Haseltine W. A., Ramstedt U. Role of human T-cell leukemia virus type 1 X region proteins in immortalization of primary human lymphocytes in culture. J Virol. 1992 Jul;66(7):4570–4575. doi: 10.1128/jvi.66.7.4570-4575.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Greene W. C., Böhnlein E., Ballard D. W. HIV-1, HTLV-1 and normal T-cell growth: transcriptional strategies and surprises. Immunol Today. 1989 Aug;10(8):272–278. doi: 10.1016/0167-5699(89)90141-2. [DOI] [PubMed] [Google Scholar]
  18. Haskill S., Beg A. A., Tompkins S. M., Morris J. S., Yurochko A. D., Sampson-Johannes A., Mondal K., Ralph P., Baldwin A. S., Jr Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell. 1991 Jun 28;65(7):1281–1289. doi: 10.1016/0092-8674(91)90022-q. [DOI] [PubMed] [Google Scholar]
  19. Henkel T., Machleidt T., Alkalay I., Krönke M., Ben-Neriah Y., Baeuerle P. A. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature. 1993 Sep 9;365(6442):182–185. doi: 10.1038/365182a0. [DOI] [PubMed] [Google Scholar]
  20. Hinrichs S. H., Nerenberg M., Reynolds R. K., Khoury G., Jay G. A transgenic mouse model for human neurofibromatosis. Science. 1987 Sep 11;237(4820):1340–1343. doi: 10.1126/science.2888191. [DOI] [PubMed] [Google Scholar]
  21. Hirai H., Fujisawa J., Suzuki T., Ueda K., Muramatsu M., Tsuboi A., Arai N., Yoshida M. Transcriptional activator Tax of HTLV-1 binds to the NF-kappa B precursor p105. Oncogene. 1992 Sep;7(9):1737–1742. [PubMed] [Google Scholar]
  22. Hirai H., Suzuki T., Fujisawa J., Inoue J., Yoshida M. Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor kappa B and induces nuclear translocation of transcription factor NF-kappa B proteins for transcriptional activation. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3584–3588. doi: 10.1073/pnas.91.9.3584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Holbrook N. J., Gulino A., Ruscetti F. Cis-acting transcriptional regulatory sequences in the gibbon ape leukemia virus (GALV) long terminal repeat. Virology. 1987 Mar;157(1):211–219. doi: 10.1016/0042-6822(87)90330-8. [DOI] [PubMed] [Google Scholar]
  24. Inoue J., Seiki M., Taniguchi T., Tsuru S., Yoshida M. Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 1986 Nov;5(11):2883–2888. doi: 10.1002/j.1460-2075.1986.tb04583.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kanno T., Brown K., Franzoso G., Siebenlist U. Kinetic analysis of human T-cell leukemia virus type I Tax-mediated activation of NF-kappa B. Mol Cell Biol. 1994 Oct;14(10):6443–6451. doi: 10.1128/mcb.14.10.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kanno T., Brown K., Siebenlist U. Evidence in support of a role for human T-cell leukemia virus type I Tax in activating NF-kappa B via stimulation of signaling pathways. J Biol Chem. 1995 May 19;270(20):11745–11748. doi: 10.1074/jbc.270.20.11745. [DOI] [PubMed] [Google Scholar]
  27. Kanno T., Franzoso G., Siebenlist U. Human T-cell leukemia virus type I Tax-protein-mediated activation of NF-kappa B from p100 (NF-kappa B2)-inhibited cytoplasmic reservoirs. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12634–12638. doi: 10.1073/pnas.91.26.12634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lacoste J., Petropoulos L., Pépin N., Hiscott J. Constitutive phosphorylation and turnover of I kappa B alpha in human T-cell leukemia virus type I-infected and Tax-expressing T cells. J Virol. 1995 Jan;69(1):564–569. doi: 10.1128/jvi.69.1.564-569.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lanoix J., Lacoste J., Pepin N., Rice N., Hiscott J. Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway. Oncogene. 1994 Mar;9(3):841–852. [PubMed] [Google Scholar]
  30. Lenardo M. J., Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. doi: 10.1016/0092-8674(89)90833-7. [DOI] [PubMed] [Google Scholar]
  31. Li C. C., Ruscetti F. W., Rice N. R., Chen E., Yang N. S., Mikovits J., Longo D. L. Differential expression of Rel family members in human T-cell leukemia virus type I-infected cells: transcriptional activation of c-rel by Tax protein. J Virol. 1993 Jul;67(7):4205–4213. doi: 10.1128/jvi.67.7.4205-4213.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Maggirwar S. B., Harhaj E., Sun S. C. Activation of NF-kappa B/Rel by Tax involves degradation of I kappa B alpha and is blocked by a proteasome inhibitor. Oncogene. 1995 Sep 7;11(5):993–998. [PubMed] [Google Scholar]
  33. Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
  34. Mercurio F., DiDonato J. A., Rosette C., Karin M. p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes Dev. 1993 Apr;7(4):705–718. doi: 10.1101/gad.7.4.705. [DOI] [PubMed] [Google Scholar]
  35. Muñoz E., Courtois G., Veschambre P., Jalinot P., Israël A. Tax induces nuclear translocation of NF-kappa B through dissociation of cytoplasmic complexes containing p105 or p100 but does not induce degradation of I kappa B alpha/MAD3. J Virol. 1994 Dec;68(12):8035–8044. doi: 10.1128/jvi.68.12.8035-8044.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nagata K., Ohtani K., Nakamura M., Sugamura K. Activation of endogenous c-fos proto-oncogene expression by human T-cell leukemia virus type I-encoded p40tax protein in the human T-cell line, Jurkat. J Virol. 1989 Aug;63(8):3220–3226. doi: 10.1128/jvi.63.8.3220-3226.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Naumann M., Nieters A., Hatada E. N., Scheidereit C. NF-kappa B precursor p100 inhibits nuclear translocation and DNA binding of NF-kappa B/rel-factors. Oncogene. 1993 Aug;8(8):2275–2281. [PubMed] [Google Scholar]
  38. Naumann M., Wulczyn F. G., Scheidereit C. The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B. EMBO J. 1993 Jan;12(1):213–222. doi: 10.1002/j.1460-2075.1993.tb05647.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nerenberg M., Hinrichs S. H., Reynolds R. K., Khoury G., Jay G. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science. 1987 Sep 11;237(4820):1324–1329. doi: 10.1126/science.2888190. [DOI] [PubMed] [Google Scholar]
  40. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. 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. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pozzatti R., Vogel J., Jay G. The human T-lymphotropic virus type I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. Mol Cell Biol. 1990 Jan;10(1):413–417. doi: 10.1128/mcb.10.1.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rice N. R., Ernst M. K. In vivo control of NF-kappa B activation by I kappa B alpha. EMBO J. 1993 Dec;12(12):4685–4695. doi: 10.1002/j.1460-2075.1993.tb06157.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rice N. R., MacKichan M. L., Israël A. The precursor of NF-kappa B p50 has I kappa B-like functions. Cell. 1992 Oct 16;71(2):243–253. doi: 10.1016/0092-8674(92)90353-e. [DOI] [PubMed] [Google Scholar]
  44. Ruben S., Poteat H., Tan T. H., Kawakami K., Roeder R., Haseltine W., Rosen C. A. Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product. Science. 1988 Jul 1;241(4861):89–92. doi: 10.1126/science.2838905. [DOI] [PubMed] [Google Scholar]
  45. Salahuddin S. Z., Markham P. D., Wong-Staal F., Franchini G., Kalyanaraman V. S., Gallo R. C. Restricted expression of human T-cell leukemia--lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. Virology. 1983 Aug;129(1):51–64. doi: 10.1016/0042-6822(83)90395-1. [DOI] [PubMed] [Google Scholar]
  46. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Siebenlist U., Franzoso G., Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. doi: 10.1146/annurev.cb.10.110194.002201. [DOI] [PubMed] [Google Scholar]
  48. Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Smith M. R., Greene W. C. Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. J Clin Invest. 1991 Mar;87(3):761–766. doi: 10.1172/JCI115078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Smith M. R., Greene W. C. Type I human T cell leukemia virus tax protein transforms rat fibroblasts through the cyclic adenosine monophosphate response element binding protein/activating transcription factor pathway. J Clin Invest. 1991 Sep;88(3):1038–1042. doi: 10.1172/JCI115364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sun S. C., Elwood J., Béraud C., Greene W. C. Human T-cell leukemia virus type I Tax activation of NF-kappa B/Rel involves phosphorylation and degradation of I kappa B alpha and RelA (p65)-mediated induction of the c-rel gene. Mol Cell Biol. 1994 Nov;14(11):7377–7384. doi: 10.1128/mcb.14.11.7377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sun S. C., Ganchi P. A., Ballard D. W., Greene W. C. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science. 1993 Mar 26;259(5103):1912–1915. doi: 10.1126/science.8096091. [DOI] [PubMed] [Google Scholar]
  53. Sun S. C., Ganchi P. A., Béraud C., Ballard D. W., Greene W. C. Autoregulation of the NF-kappa B transactivator RelA (p65) by multiple cytoplasmic inhibitors containing ankyrin motifs. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1346–1350. doi: 10.1073/pnas.91.4.1346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Suzuki T., Hirai H., Murakami T., Yoshida M. Tax protein of HTLV-1 destabilizes the complexes of NF-kappa B and I kappa B-alpha and induces nuclear translocation of NF-kappa B for transcriptional activation. Oncogene. 1995 Mar 16;10(6):1199–1207. [PubMed] [Google Scholar]
  55. Suzuki T., Hirai H., Yoshida M. Tax protein of HTLV-1 interacts with the Rel homology domain of NF-kappa B p65 and c-Rel proteins bound to the NF-kappa B binding site and activates transcription. Oncogene. 1994 Nov;9(11):3099–3105. [PubMed] [Google Scholar]
  56. Tanaka A., Takahashi C., Yamaoka S., Nosaka T., Maki M., Hatanaka M. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1071–1075. doi: 10.1073/pnas.87.3.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Thompson J. E., Phillips R. J., Erdjument-Bromage H., Tempst P., Ghosh S. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell. 1995 Feb 24;80(4):573–582. doi: 10.1016/0092-8674(95)90511-1. [DOI] [PubMed] [Google Scholar]
  58. Watanabe M., Muramatsu M., Hirai H., Suzuki T., Fujisawa J., Yoshida M., Arai K., Arai N. HTLV-I encoded Tax in association with NF-kappa B precursor p105 enhances nuclear localization of NF-kappa B p50 and p65 in transfected cells. Oncogene. 1993 Nov;8(11):2949–2958. [PubMed] [Google Scholar]
  59. Watanabe M., Muramatsu M., Tsuboi A., Arai K. Differential response of NF-kappa B1 p105 and NF-kappa B2 p100 to HTLV-I encoded Tax. FEBS Lett. 1994 Apr 4;342(2):115–118. doi: 10.1016/0014-5793(94)80483-4. [DOI] [PubMed] [Google Scholar]
  60. Yoshida M., Miyoshi I., Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031–2035. doi: 10.1073/pnas.79.6.2031. [DOI] [PMC free article] [PubMed] [Google Scholar]

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