1887

Abstract

Human herpesvirus-8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, encodes a protein, referred to as HHV8-Vcyc, with sequence similarity to human G1 cyclins, in particular of the D type. HHV8-Vcyc is expressed in Kaposi’s sarcoma and functional analysis suggests that it can activate cyclin-dependent kinases (cdk) and thereby trigger inactivation of the retinoblastoma protein (pRb), indicating that HHV8-Vcyc may contribute to the oncogenic potential of HHV-8. We show here that HHV8-Vcyc can activate transcription of the human cyclin A gene in quiescent cells, a property shared with known transforming oncogenes. Transcriptional activation by HHV8-Vcyc depends on an E2F-binding site in the cyclin A promoter, and cdk6 kinase activity is required. The ability of HHV8-Vcyc to activate cyclin A gene expression is shared by D-type cyclins and cyclin E. Unlike D-type cyclins, HHV8-Vcyc is unable to trigger phosphorylation of the pRb-related protein p107 and fails to induce dissociation of p107 from E2F. Unlike cyclin E, HHV8-Vcyc fails to interact physically with E2F complexes on the cyclin A promoter. These results provide additional evidence for the notion that the HHV-8-encoded cyclin differs in several properties from cellular G1 cyclins.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-80-3-549
1999-03-01
2021-09-24
Loading full text...

Full text loading...

/deliver/fulltext/jgv/80/3/0800549a.html?itemId=/content/journal/jgv/10.1099/0022-1317-80-3-549&mimeType=html&fmt=ahah

References

  1. Beijersbergen R. L., Carlee L., Kerkhoven R. M., Bernards R. 1995; Regulat ion of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes & Development 9:1340–1353
    [Google Scholar]
  2. Bodrug S. E., Warner B. J., Bath M. L., Lindeman G. J., Harris A. W., Adams J. M. 1994; Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO Journal 13:2124–2130
    [Google Scholar]
  3. Cao L., Faha B., Dembski M., Tsai L. H., Harlow E., Dyson N. 1992; Independent binding of the retinoblastoma protein and p107 to the transcription factor E2F. Nature 355:176–179
    [Google Scholar]
  4. Cesarman E., Nador R. G., Bai F., Bohenzky R. A., Russo J. J., Moore P. S., Chang Y., Knowles D. M. 1996; Kaposi’s sarcomaassociated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi′s sarcoma and malignant lymphoma. Journal of Virology 70:8218–8223
    [Google Scholar]
  5. Chang Y., Moore P. S., Talbot S. J., Boshoff C. H., Zarkowska T., Godden-Kent D., Paterson H., Weiss R. A., Mittnacht S. 1996; Cyclin encoded by KS herpesvirus. Nature 382:410
    [Google Scholar]
  6. Davis M. A., Sturzl M. A., Blasig C., Schreier A., Guo H. G., Reitz M., Opalenik S. R., Browning P. J. 1997; Expression of human herpesvirus 8-encoded cyclin D in Kaposi’s sarcoma spindle cells. Journal of the National Cancer Institute 89:1868–1874
    [Google Scholar]
  7. Devoto S. H., Mudryj M., Pines J., Hunter T., Nevins J. R. 1992; A cyclin A-protein kinase complex possesses sequence-specific DNA binding activity: p33cdk2 is a component of the E2F–cyclin A complex. Cell 68:167–176
    [Google Scholar]
  8. Ginsberg D., Vairo G., Chittenden T., Xiao Z. X., Xu G. F., Wydner K. L., Decaprio J. A., Lawrence J. B., Livingston D. M. 1994; E2F-4, a new member of the E2F transcription factor family, interacts with p107. Genes & Development 8:2665–2679
    [Google Scholar]
  9. Godden-Kent D., Talbot S. J., Boshoff C., Chang Y., Moore P., Weiss R. A., Mittnacht S. 1997; The cyclin encoded by Kaposi’s sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. Journal of Virology 71:4193–4198
    [Google Scholar]
  10. Guadagno T., Ohtsubo M., Roberts J. M., Assoian R. K. 1993; A link between cyclin A expression and adhesion-dependent cell cycle progression. Science 262:1572–1575
    [Google Scholar]
  11. Herrera R. E., Chen F., Weinberg R. A. 1996; Increased histone H1 phosphorylation and relaxed chromatin structure in Rb-deficient fibroblasts. Proceedings of the National Academy of Sciences, USA 93:11510–11515
    [Google Scholar]
  12. Hinds P. W., Dowdy S. F., Eaton E. N., Arnold A., Weinberg R. A. 1994; Function of a human cyclin gene as an oncogene. Proceedings of the National Academy of Sciences, USA 91:709–713
    [Google Scholar]
  13. La Thangue N. B. 1996; E2F and the molecular mechanisms of early cell-cycle control. Biochemical Society Transactions 24:54–59
    [Google Scholar]
  14. Li M. T., Lee H. R., Yoon D. W., Albrecht J. C., Fleckenstein B., Neipel F., Jung J. U. 1997; Kaposi’s sarcoma-associated herpesvirus encodes a functional cyclin. Journal of Virology 71:1984–1991
    [Google Scholar]
  15. Moberg K., Starz M. A., Lees J. A. 1996; E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Molecular and Cellular Biology 16:1436–1449
    [Google Scholar]
  16. Moore P. S., Chang Y. 1998; Kaposi’s sarcoma-associated herpes-virus-encoded oncogenes and oncogenesis. Journal of the National Cancer Institute Monographs 1998:65–71
    [Google Scholar]
  17. Neipel F., Albrecht J. C., Fleckenstein B. 1997; Cell-homologous genes in the Kaposi’s sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity?. Journal of Virology 71:4187–4192
    [Google Scholar]
  18. Pagano M., Draetta G., Jansen-Durr P. 1992a; Association of cdk2 kinase with the transcription factor E2F during S phase. Science 255:1144–1147
    [Google Scholar]
  19. Pagano M., Pepperkok R., Verde F., Ansorge W., Draetta G. 1992b; Cyclin A is required at two points in the human cell cycle. EMBO Journal 11:961–971
    [Google Scholar]
  20. Reed J. A., Nador R. G., Spaulding D., Tani Y., Cesarman E., Knowles D. M. 1998; Demonstration of Kaposi’s sarcoma-associated herpes virus cyclin D homolog in cutaneous Kaposi’s sarcoma by colorimetric in situ hybridization using a catalysed signal amplification system. Blood 91:3825–3832
    [Google Scholar]
  21. Schulze A., ZerfaB K., Spitkovsky D., Middendorp S., Berges J., Helin K., Jansen-Durr P., Henglein B. 1995; Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proceedings of the National Academy of Sciences, USA 92:11264–11268
    [Google Scholar]
  22. Schulze A., ZerfaB-Thome K., Berges J., Middendorp S., Jansen-Durr P., Henglein B. 1996; Anchorage-dependent transcription of the cyclin A gene. Molecular and Cellular Biology 16:4632–4638
    [Google Scholar]
  23. Schulze A., Mannhardt B., Zerfaß-Thome K., Zwerschke W., Jansen-Durr P. 1998; Anchorage-independent transcription of the cyclin A gene induced by the E7 oncoprotein of human papillomavirus type 16. Journal of Virology 72:2323–2334
    [Google Scholar]
  24. Spitkovsky D., Schulze A., Boye B., Jansen-Durr P. 1997; Downregulation of cyclin A gene expression upon genotoxic stress correlates with reduced binding of free E2F to the promoter. Cell Growth & Differentiation 8:699–710
    [Google Scholar]
  25. Swanton C., Mann D. J., Fleckenstein B., Neipel F., Peters G., Jones N. 1997; Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature 390:184–187
    [Google Scholar]
  26. Wang T. C., Cardiff R. D., Zukerberg L., Lees E., Arnold A., Schmidt E. V. 1994; Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669–671
    [Google Scholar]
  27. Won K.-A., Xiong Y., Beach D., Gilman M. Z. 1992; Growth-regulated expression of D-type cyclin genes in human diploid fibroblasts. Proceedings of the National Academy of Sciences, USA 89:9910–9914
    [Google Scholar]
  28. Zerfaß K., Schulze A., Spitkovsky D., Friedman V., Henglein B., Jansen-Dürr P. 1995; Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. Journal of Virology 69:6389–6399
    [Google Scholar]
  29. Zerfaß K., Spitkovsky D., Schulze A., Joswig S., Henglein B., Jansen-Dürr P. 1996; Adenovirus E1A activates cyclin A gene transcription in the absence of growth factors through interaction with p107. Journal of Virology 70:2637–2642
    [Google Scholar]
  30. Zerfaß-Thome K., Schulze A., Zwerschke W., Vogt B., Helin K., Bartek J., Henglein B., Jansen-Durr P. 1997; p27KIP1 blocks cyclin E-dependent transactivation of cyclin A gene expression. Molecular and Cellular Biology 17:407–415
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-80-3-549
Loading
/content/journal/jgv/10.1099/0022-1317-80-3-549
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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