Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Sep;96(3):1548–1555. doi: 10.1172/JCI118193

Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells.

X Xu 1, S H Kang 1, O Heidenreich 1, M Okerholm 1, J J O'Shea 1, M I Nerenberg 1
PMCID: PMC185780  PMID: 7657825

Abstract

HTLV-1 infection causes an adult T cell leukemia in humans. The viral encoded protein tax, is thought to play an important role in oncogenesis. Our previous data obtained from a tax transgenic mouse model revealed that tax transforms mouse fibroblasts but not thymocytes, despite comparable levels of tax expression in both tissues. Constitutive tyrosine phosphorylation of a 130-kD protein(s) was observed in the tax transformed fibroblast B line and in HTLV-1 transformed human lymphoid lines, but not in thymocytes from Thy-tax transgenic mice. Phosphotyrosine immunoprecipitation followed by Western blot analysis with a set of Jak kinase specific antibodies, identified p130 as Jak2 in the tax transformed mouse fibroblastic cell line and Jak3 in HTLV-1 transformed human T cell lines. Phosphorylation of Jak2 in tax transformed cells resulted from high expression of IL-6. Tyrosine phosphorylation of this protein could also be induced in Balb/c3T3 cells using a supernatant from the B line, which was associated with induction of cell proliferation. Both phosphorylation and proliferation were inhibited by IL-6 neutralizing antibodies. Constitutive phosphorylation of Jak kinases may facilitate tumor growth in both HTLV-1 infected human T cells and the transgenic mouse model.

Full text

PDF
1548

Images in this article

1549Image
on p.1549
1549Image
on p.1549
1549Image
on p.1549
1550Image
on p.1550
1550Image
on p.1550
1550Image
on p.1550
1551Image
on p.1551
1551Image
on p.1551
1551Image
on p.1551
1552Image
on p.1552
1553Image
on p.1553
1553Image
on p.1553
1553Image
on p.1553
1553Image
on p.1553

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 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]
  2. Boulton T. G., Stahl N., Yancopoulos G. D. Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J Biol Chem. 1994 Apr 15;269(15):11648–11655. [PubMed] [Google Scholar]
  3. Boussiotis V. A., Barber D. L., Nakarai T., Freeman G. J., Gribben J. G., Bernstein G. M., D'Andrea A. D., Ritz J., Nadler L. M. Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor. Science. 1994 Nov 11;266(5187):1039–1042. doi: 10.1126/science.7973657. [DOI] [PubMed] [Google Scholar]
  4. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  5. Dendorfer U., Oettgen P., Libermann T. A. Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Cell Biol. 1994 Jul;14(7):4443–4454. doi: 10.1128/mcb.14.7.4443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Franchini G., Mulloy J. C., Koralnik I. J., Lo Monico A., Sparkowski J. J., Andresson T., Goldstein D. J., Schlegel R. The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. J Virol. 1993 Dec;67(12):7701–7704. doi: 10.1128/jvi.67.12.7701-7704.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  8. Giri J. G., Ahdieh M., Eisenman J., Shanebeck K., Grabstein K., Kumaki S., Namen A., Park L. S., Cosman D., Anderson D. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J. 1994 Jun 15;13(12):2822–2830. doi: 10.1002/j.1460-2075.1994.tb06576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  10. Johnston J. A., Kawamura M., Kirken R. A., Chen Y. Q., Blake T. B., Shibuya K., Ortaldo J. R., McVicar D. W., O'Shea J. J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151–153. doi: 10.1038/370151a0. [DOI] [PubMed] [Google Scholar]
  11. Kawamura M., McVicar D. W., Johnston J. A., Blake T. B., Chen Y. Q., Lal B. K., Lloyd A. R., Kelvin D. J., Staples J. E., Ortaldo J. R. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6374–6378. doi: 10.1073/pnas.91.14.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kitajima I., Shinohara T., Bilakovics J., Brown D. A., Xu X., Nerenberg M. Ablation of transplanted HTLV-I Tax-transformed tumors in mice by antisense inhibition of NF-kappa B. Science. 1992 Dec 11;258(5089):1792–1795. doi: 10.1126/science.1299224. [DOI] [PubMed] [Google Scholar]
  13. Kitajima I., Shinohara T., Minor T., Bibbs L., Bilakovics J., Nerenberg M. Human T-cell leukemia virus type I tax transformation is associated with increased uptake of oligodeoxynucleotides in vitro and in vivo. J Biol Chem. 1992 Dec 25;267(36):25881–25888. [PubMed] [Google Scholar]
  14. Koralnik I. J., Fullen J., Franchini G. The p12I, p13II, and p30II proteins encoded by human T-cell leukemia/lymphotropic virus type I open reading frames I and II are localized in three different cellular compartments. J Virol. 1993 Apr;67(4):2360–2366. doi: 10.1128/jvi.67.4.2360-2366.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Leonard W. J., Depper J. M., Robb R. J., Waldmann T. A., Greene W. C. Characterization of the human receptor for T-cell growth factor. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6957–6961. doi: 10.1073/pnas.80.22.6957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lütticken C., Wegenka U. M., Yuan J., Buschmann J., Schindler C., Ziemiecki A., Harpur A. G., Wilks A. F., Yasukawa K., Taga T. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994 Jan 7;263(5143):89–92. doi: 10.1126/science.8272872. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Matsuda T., Yamanaka Y., Hirano T. Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells. Biochem Biophys Res Commun. 1994 Apr 29;200(2):821–828. doi: 10.1006/bbrc.1994.1525. [DOI] [PubMed] [Google Scholar]
  19. Miyazaki T., Kawahara A., Fujii H., Nakagawa Y., Minami Y., Liu Z. J., Oishi I., Silvennoinen O., Witthuhn B. A., Ihle J. N. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994 Nov 11;266(5187):1045–1047. doi: 10.1126/science.7973659. [DOI] [PubMed] [Google Scholar]
  20. Miyoshi I., Kubonishi I., Yoshimoto S., Akagi T., Ohtsuki Y., Shiraishi Y., Nagata K., Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981 Dec 24;294(5843):770–771. doi: 10.1038/294770a0. [DOI] [PubMed] [Google Scholar]
  21. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  22. Nerenberg M. I., Minor T., Price J., Ernst D. N., Shinohara T., Schwarz H. Transgenic thymocytes are refractory to transformation by the human T-cell leukemia virus type I tax gene. J Virol. 1991 Jun;65(6):3349–3353. doi: 10.1128/jvi.65.6.3349-3353.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Noma T., Nakakubo H., Sugita M., Kumagai S., Maeda M., Shimizu A., Honjo T. Expression of different combinations of interleukins by human T cell leukemic cell lines that are clonally related. J Exp Med. 1989 May 1;169(5):1853–1858. doi: 10.1084/jem.169.5.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  26. Poiesz B. J., Ruscetti F. W., Reitz M. S., Kalyanaraman V. S., Gallo R. C. Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sézary T-cell leukaemia. Nature. 1981 Nov 19;294(5838):268–271. doi: 10.1038/294268a0. [DOI] [PubMed] [Google Scholar]
  27. Quelle F. W., Sato N., Witthuhn B. A., Inhorn R. C., Eder M., Miyajima A., Griffin J. D., Ihle J. N. JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol. 1994 Jul;14(7):4335–4341. doi: 10.1128/mcb.14.7.4335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Russell S. M., Johnston J. A., Noguchi M., Kawamura M., Bacon C. M., Friedmann M., Berg M., McVicar D. W., Witthuhn B. A., Silvennoinen O. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994 Nov 11;266(5187):1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar]
  31. Suzuki T., Fujisawa J. I., Toita M., Yoshida M. The trans-activator tax of human T-cell leukemia virus type 1 (HTLV-1) interacts with cAMP-responsive element (CRE) binding and CRE modulator proteins that bind to the 21-base-pair enhancer of HTLV-1. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):610–614. doi: 10.1073/pnas.90.2.610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Taniguchi T. Regulation of cytokine gene expression. Annu Rev Immunol. 1988;6:439–464. doi: 10.1146/annurev.iy.06.040188.002255. [DOI] [PubMed] [Google Scholar]
  33. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  34. Villiger P. M., Cronin M. T., Amenomori T., Wachsman W., Lotz M. IL-6 production by human T lymphocytes. Expression in HTLV-1-infected but not in normal T cells. J Immunol. 1991 Jan 15;146(2):550–559. [PubMed] [Google Scholar]
  35. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  36. Xu X., Brown D. A., Kitajima I., Bilakovics J., Fey L. W., Nerenberg M. I. Transcriptional suppression of the human T-cell leukemia virus type I long terminal repeat occurs by an unconventional interaction of a CREB factor with the R region. Mol Cell Biol. 1994 Aug;14(8):5371–5383. doi: 10.1128/mcb.14.8.5371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zhuang H., Patel S. V., He T. C., Sonsteby S. K., Niu Z., Wojchowski D. M. Inhibition of erythropoietin-induced mitogenesis by a kinase-deficient form of Jak2. J Biol Chem. 1994 Aug 26;269(34):21411–21414. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES