p16-independence of Epstein–Barr virus-induced cell proliferation and virus latency Free

Abstract

Epstein–Barr virus (EBV) has the ability to promote cell cycle progression following the initial infection of primary resting B-lymphocytes and to cause cell cycle arrest at the onset of the viral replicative cycle. Various mechanisms have been proposed for the proliferative effects, including the up-regulation of cyclin D2 by the viral EBNA-2 and EBNA-LP proteins, direct binding of EBNA3C to the retinoblastoma protein (pRb), and down-regulation of the p16 tumour suppressor by the viral LMP1 product. To try to gain insight into the relative importance of these mechanisms, the ability of EBV to immortalize lymphocytes from an individual who is genetically deficient for p16 was examined. From detailed analyses of the resultant lymphoblastoid cell lines it is concluded that p16 status has little bearing on EBV's ability to manipulate the cell cycle machinery and a model to accommodate the previously proposed routes taken by EBV to bypass the restriction point is presented.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.79831-0
2004-06-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/85/6/vir851381.html?itemId=/content/journal/jgv/10.1099/vir.0.79831-0&mimeType=html&fmt=ahah

References

  1. Alcorta D. A., Xiong Y., Phelps D., Hannon G., Beach D., Barrett J. C. 1996; Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 93:13742–13747 [CrossRef]
    [Google Scholar]
  2. Andoh T. 2000; Signal transduction pathways leading to cell cycle arrest and apoptosis induced by DNA topoisomerase poisons. Cell Biochem Biophys 33:181–188 [CrossRef]
    [Google Scholar]
  3. Baer R., Bankier A. T., Biggin M. D. 9 other authors 1984; DNA sequence and expression of the B95-8 Epstein–Barr virus genome. Nature 310:207–211 [CrossRef]
    [Google Scholar]
  4. Bringold F., Serrano M. 2000; Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol 35:317–329 [CrossRef]
    [Google Scholar]
  5. Brookes S., Rowe J., Ruas M. 12 other authors 2002; INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J 21:2936–2945 [CrossRef]
    [Google Scholar]
  6. Cannell E. J., Farrell P. J., Sinclair A. J. 1996; Epstein–Barr virus exploits the normal cell pathway to regulate Rb activity during the immortalisation of primary B-cells. Oncogene 13:1413–1421
    [Google Scholar]
  7. Cannell E. J., Farrell P. J., Sinclair A. J. 1998; Cell cycle arrest following exposure of EBV-immortalised B-cells to gamma irradiation correlates with inhibition of cdk2 activity. FEBS Lett 439:297–301 [CrossRef]
    [Google Scholar]
  8. Chin L., Pomerantz J., DePinho R. A. 1998; The INK4a/ARF tumor suppressor: one gene–two products–two pathways. Trends Biochem Sci 23:291–296 [CrossRef]
    [Google Scholar]
  9. Classon M., Harlow E. 2002; The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2:910–917 [CrossRef]
    [Google Scholar]
  10. Flemington E. K. 2001; Herpesvirus lytic replication and the cell cycle: arresting new developments. J Virol 75:4475–4481 [CrossRef]
    [Google Scholar]
  11. Frost V., Sinclair A. J. 2000; p27KIP1 is down-regulated by two different mechanisms in human lymphoid cells undergoing apoptosis. Oncogene 19:3115–3120 [CrossRef]
    [Google Scholar]
  12. Gruis N. A., Vandervelden P. A., Sandkuijl L. A., Prins D. E., Weaverfeldhaus J., Kamb A., Bergman W., Frants R. R. 1995; Homozygotes for Cdkn2 (P16) germline mutation in Dutch familial melanoma kindreds. Nat Genet 10:351–353 [CrossRef]
    [Google Scholar]
  13. Hara E., Smith R., Parry D., Tahara H., Stone S., Peters G. 1996; Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol 16:859–867
    [Google Scholar]
  14. Jansen-Durr P. 1996; How viral oncogenes make the cell cycle. Trends Genet 12:270–275 [CrossRef]
    [Google Scholar]
  15. Kempkes B., Spitkovsky D., Jansendurr P., Ellwart J. W., Kremmer E., Delecluse H. J., Rottenberger C., Bornkamm G. W., Hammerschmidt W. 1995; B-cell proliferation and induction of early G1-regulating proteins by Epstein–Barr virus mutants conditional for EBNA2. EMBO J 14:88–96
    [Google Scholar]
  16. King K. L., Cidlowski J. A. 1998; Cell cycle regulation and apoptosis. Annu Rev Physiol 60:601–617 [CrossRef]
    [Google Scholar]
  17. Koh J., Enders G. H., Dynlacht B. D., Harlow E. 1995; Tumor-derived P16 alleles encoding proteins defective in cell-cycle inhibition. Nature 375:506–510 [CrossRef]
    [Google Scholar]
  18. Loughran O., Malliri A., Owens D., Gallimore P. H., Stanley M. A., Ozanne B., Frame M. C., Parkinson E. K. 1996; Association of CDKN2A/p16INK4A with human head and neck keratinocyte replicative senescence: relationship of dysfunction to immortality and neoplasia. Oncogene 13:561–568
    [Google Scholar]
  19. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. 1995; Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor-suppressor P16. Nature 375:503–506 [CrossRef]
    [Google Scholar]
  20. Meikrantz W., Schlegel R. 1995; Apoptosis and the cell cycle. J Cell Biochem 58:160–174 [CrossRef]
    [Google Scholar]
  21. Ohtani N., Brennan P., Gaubatz S., Sanij E., Hertzog P., Wolvetang E., Ghysdael J., Rowe M., Hara E. 2003; Epstein–Barr virus LMP1 blocks p16INK4a-RB pathway by promoting nuclear export of E2F4/5. J Cell Biol 162:173–183 [CrossRef]
    [Google Scholar]
  22. Palmero I., Peters G. 1996; Perturbation of cell cycle regulators in human cancer. Cancer Surv 27:351–367
    [Google Scholar]
  23. Palmero I., McConnell B., Parry D., Brookes S., Hara E., Bates S., Jat P., Peters G. 1997; Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status. Oncogene 15:495–503 [CrossRef]
    [Google Scholar]
  24. Parker G. A., Crook T., Bain M., Sara E. A., Farrell P. J., Allday M. J. 1996; Epstein–Barr virus nuclear antigen (EBNA)3C is an immortalizing oncoprotein with similar properties to adenovirus EIA and papillomavirus E7. Oncogene 13:2541–2549
    [Google Scholar]
  25. Parry D., Bates S., Mann D. J., Peters G. 1995; Lack of cyclin D–Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J 14:503–511
    [Google Scholar]
  26. Reznikoff C. A., Yeager T. R., Belair C. D., Savelieva E., Puthenveettil J. A., Stadler W. M. 1996; Elevated p16 at senescence and loss of p16 at immortalization in human papillomavirus 16 E6, but not E7, transformed human uroepithelial cells. Cancer Res 56:2886–2890
    [Google Scholar]
  27. Rickinson A. 2002; Epstein–Barr virus. Virus Res 82:109–113
    [Google Scholar]
  28. Ruas M., Peters G. 1998; The p16(INK4a)/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta - Reviews On Cancer 1378F115–177 [CrossRef]
    [Google Scholar]
  29. Serrano M., Hannon G. J., Beach D. 1993; A new regulatory motif in cell-cycle control causing specific-inhibition of cyclin-D/Cdk4. Nature 366:704–707 [CrossRef]
    [Google Scholar]
  30. Sinclair A. J. 2003; bZIP proteins of human gammaherpesviruses. J Gen Virol 84:1941–1949 [CrossRef]
    [Google Scholar]
  31. Sinclair A. J., Farrell P. J. 1995a; Host-cell requirements for efficient infection of quiescent primary B-lymphocytes by Epstein–Barr virus. J Virol 69:5461–5468
    [Google Scholar]
  32. Sinclair A. J., Farrell P. J. 1995b; Methods to study Epstein–Barr virus and p53 status in human cells. In Methods in Molecular Genetics pp  89–100 Edited by Aldolph K. W. New York: Academic Press;
    [Google Scholar]
  33. Sinclair A. J., Palmero I., Peters G., Farrell P. J. 1994; EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein–Barr virus. EMBO J 13:3321–3328
    [Google Scholar]
  34. Sinclair A. J., Fenton M., Delikat S. 1998; Interactions between Epstein–Barr virus and the cell cycle control machinery. Histol Histopathol 13:461–467
    [Google Scholar]
  35. Wang T. H., Wang H. S., Soong Y. K. 2000; Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 88:2619–2628 [CrossRef]
    [Google Scholar]
  36. Yang X. H., He Z. M., Xin B. Z., Cao L. 2000; LMP1 of Epstein–Barr virus suppresses cellular senescence associated with the inhibition of p16INK4a expression. Oncogene 19:2002–2013 [CrossRef]
    [Google Scholar]
  37. Young L. S., Lau R., Rowe M. other authors 1991; Differentiation-associated expression of the Epstein–Barr virus BZLF1 transactivator protein in oral hairy leukoplakia. J Virol 65:2868–2874
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.79831-0
Loading
/content/journal/jgv/10.1099/vir.0.79831-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed