Human T-cell leukemia virus type 1 Tax releases cell cycle arrest induced by p16INK4a (original) (raw)

Abstract

The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein causes cellular transformation by deregulating important cellular processes such as DNA repair, transcription, signal transduction, proliferation, and growth. Although it is clear that normal cell cycle control is deregulated during HTLV-1-induced cellular transformation, the effects of Tax on cell cycle control are not well understood. Flow cytometric analyses of human T cells indicate that cell cycle arrest in late G1, at or before the G1/S restriction point, by p16INK4a is relieved by Tax. Furthermore, Tax-dependent stimulation of 5-bromo-2'-deoxyuridine incorporation and transcriptional activation is inhibited by p16INK4a. This result suggests that p16INK4a is able to block Tax-dependent stimulation of DNA synthesis and cell cycle progression into S phase. In vitro binding assays with recombinant glutathione S-transferase fusion proteins and [35S]methionine-labeled proteins indicate that Tax binds specifically with p16INK4a but not with either p21cip1 or p27kip1. Furthermore, sequential immunoprecipitation assays with specific antisera and [35S]methionine-labeled cell lysates subsequent to coexpression with Tax and p16INK4a indicate that the two proteins form complexes in vivo. Immunocomplex kinase assays with cyclin-dependent kinase 4 antiserum indicate that Tax blocks the inhibition of cdk4 kinase activity by p16INK4a. This study identifies p16INK4a as a novel cellular target for Tax and suggests that the inactivation of p16INK4a function is a mechanism of cell cycle deregulation by Tax.

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Selected References

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  1. Adya N., Zhao L. J., Huang W., Boros I., Giam C. Z. 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. 1994 Jun 7;91(12):5642–5646. doi: 10.1073/pnas.91.12.5642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson M. G., Dynan W. S. Quantitative studies of the effect of HTLV-I Tax protein on CREB protein--DNA binding. Nucleic Acids Res. 1994 Aug 11;22(15):3194–3201. doi: 10.1093/nar/22.15.3194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  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. Baranger A. M., Palmer C. R., Hamm M. K., Giebler H. A., Brauweiler A., Nyborg J. K., Schepartz A. Mechanism of DNA-binding enhancement by the human T-cell leukaemia virus transactivator Tax. Nature. 1995 Aug 17;376(6541):606–608. doi: 10.1038/376606a0. [DOI] [PubMed] [Google Scholar]
  6. Caron C., Rousset R., Béraud C., Moncollin V., Egly J. M., Jalinot P. Functional and biochemical interaction of the HTLV-I Tax1 transactivator with TBP. EMBO J. 1993 Nov;12(11):4269–4278. doi: 10.1002/j.1460-2075.1993.tb06111.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Elroy-Stein O., Fuerst T. R., Moss B. Cap-independent translation of mRNA conferred by encephalomyocarditis virus 5' sequence improves the performance of the vaccinia virus/bacteriophage T7 hybrid expression system. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6126–6130. doi: 10.1073/pnas.86.16.6126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Franklin A. A., Kubik M. F., Uittenbogaard M. N., Brauweiler A., Utaisincharoen P., Matthews M. A., Dynan W. S., Hoeffler J. P., Nyborg J. K. Transactivation by the human T-cell leukemia virus Tax protein is mediated through enhanced binding of activating transcription factor-2 (ATF-2) ATF-2 response and cAMP element-binding protein (CREB). J Biol Chem. 1993 Oct 5;268(28):21225–21231. [PubMed] [Google Scholar]
  9. Fujii M., Tsuchiya H., Chuhjo T., Akizawa T., Seiki M. Interaction of HTLV-1 Tax1 with p67SRF causes the aberrant induction of cellular immediate early genes through CArG boxes. Genes Dev. 1992 Nov;6(11):2066–2076. doi: 10.1101/gad.6.11.2066. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
  12. Jeang K. T., Widen S. G., Semmes O. J., 4th, Wilson S. H. HTLV-I trans-activator protein, tax, is a trans-repressor of the human beta-polymerase gene. Science. 1990 Mar 2;247(4946):1082–1084. doi: 10.1126/science.2309119. [DOI] [PubMed] [Google Scholar]
  13. Joshi J. B., Dave H. P. Transactivation of the proenkephalin gene promoter by the Tax1 protein of human T-cell lymphotropic virus type I. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1006–1010. doi: 10.1073/pnas.89.3.1006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kadison P., Poteat H. T., Klein K. M., Faller D. V. Role of protein kinase A in tax transactivation of the human T-cell leukemia virus type I long terminal repeat. J Virol. 1990 May;64(5):2141–2148. doi: 10.1128/jvi.64.5.2141-2148.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Koh J., Enders G. H., Dynlacht B. D., Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature. 1995 Jun 8;375(6531):506–510. doi: 10.1038/375506a0. [DOI] [PubMed] [Google Scholar]
  17. Kwok R. P., Laurance M. E., Lundblad J. R., Goldman P. S., Shih H., Connor L. M., Marriott S. J., Goodman R. H. Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature. 1996 Apr 18;380(6575):642–646. doi: 10.1038/380642a0. [DOI] [PubMed] [Google Scholar]
  18. Leung K., Nabel G. J. HTLV-1 transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor. Nature. 1988 Jun 23;333(6175):776–778. doi: 10.1038/333776a0. [DOI] [PubMed] [Google Scholar]
  19. Low K. G., Chu H. M., Schwartz P. M., Daniels G. M., Melner M. H., Comb M. J. Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. Mol Cell Biol. 1994 Jul;14(7):4958–4974. doi: 10.1128/mcb.14.7.4958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503–506. doi: 10.1038/375503a0. [DOI] [PubMed] [Google Scholar]
  21. Mal A., Poon R. Y., Howe P. H., Toyoshima H., Hunter T., Harter M. L. Inactivation of p27Kip1 by the viral E1A oncoprotein in TGFbeta-treated cells. Nature. 1996 Mar 21;380(6571):262–265. doi: 10.1038/380262a0. [DOI] [PubMed] [Google Scholar]
  22. Matsushime H., Quelle D. E., Shurtleff S. A., Shibuya M., Sherr C. J., Kato J. Y. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. 1994 Mar;14(3):2066–2076. doi: 10.1128/mcb.14.3.2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Morgan D. O. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131–134. doi: 10.1038/374131a0. [DOI] [PubMed] [Google Scholar]
  24. Moss B., Elroy-Stein O., Mizukami T., Alexander W. A., Fuerst T. R. Product review. New mammalian expression vectors. Nature. 1990 Nov 1;348(6296):91–92. doi: 10.1038/348091a0. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Peter M., Herskowitz I. Joining the complex: cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell. 1994 Oct 21;79(2):181–184. doi: 10.1016/0092-8674(94)90186-4. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Serrano M., Gómez-Lahoz E., DePinho R. A., Beach D., Bar-Sagi D. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science. 1995 Jan 13;267(5195):249–252. doi: 10.1126/science.7809631. [DOI] [PubMed] [Google Scholar]
  30. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  31. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  32. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
  33. Shih C., Weinberg R. A. Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell. 1982 May;29(1):161–169. doi: 10.1016/0092-8674(82)90100-3. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Suzuki T., Kitao S., Matsushime H., Yoshida M. HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4. EMBO J. 1996 Apr 1;15(7):1607–1614. [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Uchiumi F., Semba K., Yamanashi Y., Fujisawa J., Yoshida M., Inoue K., Toyoshima K., Yamamoto T. Characterization of the promoter region of the src family gene lyn and its trans activation by human T-cell leukemia virus type I-encoded p40tax. Mol Cell Biol. 1992 Sep;12(9):3784–3795. doi: 10.1128/mcb.12.9.3784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wagner S., Green M. R. HTLV-I Tax protein stimulation of DNA binding of bZIP proteins by enhancing dimerization. Science. 1993 Oct 15;262(5132):395–399. doi: 10.1126/science.8211160. [DOI] [PubMed] [Google Scholar]
  39. Zhao L. J., Giam C. Z. Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7070–7074. doi: 10.1073/pnas.89.15.7070. [DOI] [PMC free article] [PubMed] [Google Scholar]