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Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins

Nature volume 390, pages 184–187 (1997)Cite this article

Abstract

The passage of mammalian cells through the restriction point into the S phase of the cell cycle is regulated by the activities of Cdk4 and Cdk6 complexed with the D-type cyclins and by cyclin E/Cdk2 (refs 1,2,3). The activities of these holoenzymes are constrained by CDK inhibitory proteins4,5. The importance of the restriction point is illustrated by its deregulation in many tumour cells6,7 and upon infection with DNA tumour viruses8. Here we describe the properties of cyclins encoded by two herpesviruses, herpesvirus saimiri (HVS) which can transform blood lymphocytes9 and induce malignancies of lymphoid origin in New World primates9,10, and human herpesvirus 8 (HHV8) implicated as a causative agent of Kaposi's sarcoma and body cavity lymphomas11,12. Both viral cyclins form active kinase complexes with Cdk6 that are resistant to inhibition by the CDK inhibitors p16Ink4a, p21Cip1and p27Kip1. Furthermore, ectopic expression of a viral cyclin prevents G1 arrest imposed by each inhibitor and stimulates cell-cycle progression in quiescent fibroblasts. These results suggest a new mechanism for deregulation of the cell cycle and indicate that the viral cyclins may contribute to the oncogenic nature of these viruses.

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Figure 1: Lack of inhibition of V-cyclin/Cdk6 and K-cyclin/Cdk6 complexes by p21Cip1, p27Kip1and p16Ink4a.
Figure 2: Co-precipitation of cyclins with p21Cip1, p27Kip1and Cdk6.
Figure 3: Stimulation of quiescent cells by expression of K-cyclin.

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References

  1. Sherr, C. J. Mammalian G1 cyclins. Cell 73, 1059–1065 (1993).

    Article  CAS  Google Scholar 

  2. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    Article  CAS  Google Scholar 

  3. Sherr, C. J. Cancer cell cycles. Science 274, 1672–1677 (1996).

    Article  ADS  CAS  Google Scholar 

  4. Sherr, C. J. & Roberts, J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9, 1149–1163 (1995).

    Article  CAS  Google Scholar 

  5. Harper, J. W. & Elledge, S. J. Cdk inhibitors in development and cancer. Curr. Opin. Genet. Dev. 6, 56–64 (1996).

    Article  CAS  Google Scholar 

  6. Hall, M. & Peters, G. Genetic alterations of cyclins, cyclin-dependent kinases, and cdk inhibitors in human cancer. Adv. Cancer Res. 68, 67–108 (1996).

    Article  CAS  Google Scholar 

  7. Strauss, M., Lukas, J. & Bartek, J. Unrestricted cell cycling and cancer. Nature Med. 1, 1245–1246 (1996).

    Article  Google Scholar 

  8. Nevins, J. R. Cell cycle targets of the DNA tumor viruses. Curr. Opin. Genet. Dev. 4, 130–134 (1994).

    Article  CAS  Google Scholar 

  9. Biesinger, B. et al. Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc. Natl Acad. Sci. USA 89, 3116–3119 (1992).

    Article  ADS  CAS  Google Scholar 

  10. Fleckenstein, B. & Desrosiers, R. C. in The herpesviruses Vol. 1(ed. Roizman, B.) 252–332 (Plenum, New York, (1982)).

    Google Scholar 

  11. Chang, Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869 (1994).

    Article  ADS  CAS  Google Scholar 

  12. Cesarmen, E. et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N. Engl. J. Med. 332, 1186–1191 (1995).

    Article  Google Scholar 

  13. Jung, J. U., Stager, M. & Desrosiers, R. C. Virus encoded cyclin. Mol. Cell. Biol. 14, 7235–7244 (1994).

    Article  CAS  Google Scholar 

  14. Chang, Y. et al. Cyclin encoded by KS herpesvirus. Nature 382, 410 (1996).

    Article  ADS  CAS  Google Scholar 

  15. Meyerson, M. & Harlow, E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol. Cell. Biol. 14, 2077–2086 (1994).

    Article  CAS  Google Scholar 

  16. Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 (1994).

    Article  CAS  Google Scholar 

  17. Hall, M., Bates, S. & Peters, G. Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins. Oncogene 11, 1581–1588 (1995).

    CAS  Google Scholar 

  18. Chen, J. et al. Cyclin binding motifs are essential for the function of p21Cip1. Mol. Cell. Biol. 16, 4673–4682 (1996).

    Article  CAS  Google Scholar 

  19. Lin, J., Reichner, C., Wu, X. & Levine, A. J. Analysis of wild-type and mutant p21 WAF-1 gene activities. Mol. Cell. Biol. 16, 1786–1793 (1996).

    Article  CAS  Google Scholar 

  20. Russo, A. A., Jeffrey, P. D., Patten, A. K., Massague, J. & Pavletich, N. P. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382, 325–331 (1996).

    Article  ADS  CAS  Google Scholar 

  21. Resnitzky, D. & Reed, S. I. Different roles for cyclin D1 and E in regulation of the G1-to-S transition. Mol. Cell. Biol. 15, 3463–3469 (1995).

    Article  CAS  Google Scholar 

  22. Mann, D. J. & Jones, N. E2F-1 but not E2F-4 can overcome p16-induced cell cycle arrest. Curr. Biol. 6, 474–483 (1996).

    Article  CAS  Google Scholar 

  23. Ohtsubo, M. et al. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol. Cell. Biol. 15, 2612–2624 (1995).

    Article  CAS  Google Scholar 

  24. Roussel, R. et al. Rescue of defective mitogenic signalling by D-type cyclins. Proc. Natl Acad. Sci. USA 92, 6837–6841 (1995).

    Article  ADS  CAS  Google Scholar 

  25. Kato, J. M. et al. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 7, 331–342 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Sherr and M. Meyerson for gifts of baculovirus recombinants. We thank M. Hall for technical advice on the cyclin-inhibitor binding assay and for providing purified inhibitor proteins. We also thank D. Davies and C. Hughes for help with FACS analysis, G. Clark and A.Davies for sequencing analysis, and G. Card and N. McDonald for advice and encouragement throughout the study. This study was funded by the Imperial Cancer Research Fund. C.S. is supported by University College London Medical School and F.N. by the ‘Deutsche Krebsforschungstifftung founded by Mildred Scheel’ foundation.

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  1. Imperial Cancer Research Fund, PO Box 123, Lincoln's Inn Fields, WC2A 3PXM, London, UK

    Charles Swanton, David J. Mann, Gordon Peters & Nic Jones

  2. Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität, Loschgestrasse 7, Erlangen, D-8520, Germany

    Bernhard Fleckenstein & Frank Neipel

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  1. Charles Swanton
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Correspondence to Nic Jones.

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Swanton, C., Mann, D., Fleckenstein, B. et al. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature 390, 184–187 (1997). https://doi.org/10.1038/36606

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