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Kaposi's sarcoma-associated herpesvirus encodes a functional Bcl-2 homologue

Nature Medicine volume 3, pages 293–298 (1997)Cite this article

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpesvirus etiologically associated with Kaposi's sarcoma (KS) and two lymphoproliferative disorders. We describe a KSHV vbcl-2 gene with homology to the proto-oncogene bcl-2. It is expressed in KS lesions and in cell lines derived from primary effusion lymphomas. Using yeast and human cells we demonstrate the ability of KSHV vBcl-2 protein to suppress Bax toxicity. We show that KSHV vBcl-2 heterodimerizes with human Bcl-2 in a yeast two-hybrid system. These results suggest that KSHV vBcl-2 plays an anti-apoptotic role in virus infected cells.

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References

  1. Moore, P.S. et al. Primary characterization of a herpesvirus-like agent associated with Kaposi's sarcoma. J.Virol. 70, 549–558 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chang, Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 265, 1865–1869 (1994).

    Article  Google Scholar 

  3. Moore, P.S. & Chang, Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma lesions from persons with and without HIV infection. N. Eng. J. Med. 332, 1181–1185 (1995).

    Article  CAS  Google Scholar 

  4. Boshoff, C. et al. Kaposi's sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet 345, 1043–1044 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. de tellis, L. et al. Herpesvirus-like DNA sequences in non-AIDS Kaposi's sarcoma. J. Inf. Dis. 172, 1605–1607 (1995).

    Article  Google Scholar 

  6. Schalling, M., Ekman, M., Kaaya, E.E., Linde, A. & Biberfeld, P. A role for a new herpesvirus (KSHV) in different forms of Kaposi's sarcoma. Nature Med. 1, 707–708 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Chang, Y. et al. Kaposi's sarcoma-associated herpesvirus DNA sequences are present in African endemic and AIDS-associated Kaposi's sarcoma. Arch. Int. Med. 156, 202–204 (1996).

    Article  CAS  Google Scholar 

  8. Whitby, D. et al. Detection of Kaposi's sarcoma-associated herpesvirus (KSHV) in peripheral blood of HIV-infected individuals predicts progression to Kaposi's sarcoma. Lancet 364, 799–802 (1995).

    Article  Google Scholar 

  9. Moore, P.S. et al. KSHV infection prior to onset of Kaposi's sarcoma. AIDS 10, 175–180 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Miller, G. et al. Antibodies to butyrate inducible antigens of Kaposi's sarcoma-associated herpesvirus in HIV-1 infected patients. N. Eng. J. Med. 334, 1292–1297 (1996).

    Article  CAS  Google Scholar 

  11. Gao, S.-J. et al. KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nature Med. 2, 925–928 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Kedes, D.H. et al. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups for sexual transmission. Nature Med. 2, 918–924 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Gao, S.-J. et al. Seroconversion of antibodies to Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens prior to onset of Kaposi's sarcoma. N. Eng. J. Med. 335, 233–241 (1996).

    Article  CAS  Google Scholar 

  14. Cesarman, E., Chang, Y., Moore, P.S., Said, J.W. & Knowles, D.M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences are present in AIDS-related body cavity based lymphomas. N. Eng. J. Med. 332, 1186–1191 (1995).

    Article  CAS  Google Scholar 

  15. Soulier, J. et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86, 1276–1280 (1995).

    CAS  PubMed  Google Scholar 

  16. Frizzera, G., Peterson, B.A., Bayrd, E.D. & Goldman, A. A systemic lymphopro-liferative disorder with morphologic features of Castleman's disease: clinical findings and clinicopathologic correlations in 15 patients. J. Clin. Oncol. 3, 1202–1216 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. Strauchen, J.A. et al. Kaposi's sarcoma, Kaposi's sarcoma-associated herpesvirus, and body cavity-based malignant lymphoma in an HIV-negative man. Ann. Intern. Med. 125, 822–825 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. White, E. Regulation of apoptosis by the transforming genes of the DNA tumor virus adenovirus. [Review]. Proc. Soc. Exper. Biol. & Med. 204, 30–39 (1993).

    Article  CAS  Google Scholar 

  19. Gregory, C.D. et al. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature 349, 612–614 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Henderson, S. et al. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death:. Proc. Natl. Acad. Sci. U.S.A. 90, 8479–8483 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vaux, D.L., Haecker, G. & Strasser, A. An evolutionary perspective on apoptosis. Cell 76, 777–779 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Vaux, D.L., Cory, S. & Adams, J.M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Garcia, I., Martinou, I., Tsujimoto, Y. & Martinou, J.C. Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science 258, 302–304 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Tsujimoto, Y. & Croce, C.M. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Natl. Acad. Sci. U.S.A. 83, 5214–5218 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Geary, M.L., Smith, S.D. & Sklar, J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t (14;18) translocation. Cell 47, 19–28 (1986).

    Article  Google Scholar 

  26. Oltvai, Z.N., Milliman, C.L. & Korsmeyer, S.J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–619 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Sato, T. et al. Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system [published erratum appears in Proc.Natl.Acad. Sci.U.S.A. 92, 2016]. Proc. Natl. Acad. Sci. U.S.A. 91, 9238–9242 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Boyd, J.M. et al. Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 11, 1921–1928 (1995).

    CAS  PubMed  Google Scholar 

  29. Yang, E. et al. Bad, a heterodimeric partner for Bel-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Cesarman, E. et al. In vitro establishment and characterization of two AIDS-re-lated lymphoma cell lines containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DMA sequences. Blood 86, 2708–2714 (1995).

    CAS  PubMed  Google Scholar 

  31. Russo, J.J. et al. Nucleotide sequence of Kaposi's sarcoma-associated her-pesvirus (HHV8). Proc. Natl. Acad. Sci. U.S.A. 93, 14862–14867 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bankier, A.T., Weston, K.M. & Barrell, B.G. Random cloning and sequencing by the M13/dideoxynucleotide chain termination method. Methods in Enzymology 155, 51–93 (1987).

    Article  CAS  PubMed  Google Scholar 

  33. Altschul, S.F., Gish, W., Miller, M., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  PubMed  Google Scholar 

  34. Hanada, M., Aime'-Sempe', C., Sato, T. & Reed, J.C. Structure-function analysis of Bcl-2 protein. T. J. Biol. Chem. 270, 11962–11969 (1995).

    Article  CAS  Google Scholar 

  35. Bodrug, S.E. et al. Biochemical and functional comparisons of Mcl-1 and Bcl-2 proteins: evidence for a novel mechanism of regulating Bcl-2 family protein function. Death Differen. 2, 173–182 (1995).

    CAS  Google Scholar 

  36. Sato, T., Irie, S., Krajewski, S. & Reed, J.C. Cloning and sequencing of a cDNA encoding the rat Bcl-2 protein. Gene 140, 291–292 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Hunter, J. & Parslow, T. A peptide sequence from Bax that converts Bcl-2 into an activator of apoptosis. Biol. Chem. 271, 8521–8524 (1996).

    Article  CAS  Google Scholar 

  38. Miura, M., Zhu, H., Rotello, R., Hartwieg, E.A. & Yuan, J. Induction of apoptosis in fibroblasts by IL-1β-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75, 653–660 (1993).

    Article  CAS  PubMed  Google Scholar 

  39. Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R.D. & Korsmeyer, S.J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336 (1990).

    Article  CAS  PubMed  Google Scholar 

  40. Moore, P.S., Boshoff, C., Weiss, R.A. & Chang, Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 274, 1739–1744 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Nunez, G. et al. Growth-and tumor-promoting effects of deregulated BCL2 in human B-lymphoblastoid cells. Proc. Natl. Acad. Sci. U.S.A. 86, 4589–4593 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Szomolanyi, E., Medveczky, P. & Mulder, C. In vitro immortalization ofmarmoset cells with three subgroups of herpesvirus saimiri. J. Virol. 61, 3485–3490 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Miller, G. Epstein-Barr virus: Biology, pathogenesis and medical aspects, in Virology (eds. Fields, B. N. & Knipe, D. M.) 1921–1957 2nd edn. (Raven Press, New York, 1990).

    Google Scholar 

  45. Cesarman, E. et al. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J. Virol. 70, 8218–8223 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chang, Y. et al. KSHV encodes a functional cyclin. Nature 382, 410 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Nicholas Cameron, K.R. & Honess, R.W. Herpesvirus saimiri encodes homologues of G protein-coupled receptors and cyclins. Nature 355, 362–365 (1992).

    Article  Google Scholar 

  48. Sinclair, A.J., Palmero, I., Peters, G. & Farrell, P.J. EBNA-2 and EBNA-LP cooperate to cause GO to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. EMBO Journal 13, 3321–3328 (1994).

    Article  CAS  Google Scholar 

  49. Shen, Y. & Shenk, T.E. Viruses and apoptosis. [Review]. Curr. Opin. Gen. & Develop. 5, 105–111 (1995).

    Article  CAS  Google Scholar 

  50. Golemis, E.A., & Brent, R. Interaction trap/Two-hybrid system to identify interacting proteins. in Current Protocols in Molecular Biology 13.14.1–13.14.17 (John Wiley and Sons, New York, 1994).

    Google Scholar 

  51. Neilan, J.G. et al. An African swine fever virus gene with similarity to the proto-oncogene bcl-2 and the Epstein-Barr virus gene BHRF1. Journal of Virology 67, 4391–4394 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Smith, R.F. & Smith, T.F. Pattern-induced multiple sequence alignment (PIMA) algorithm employing secondary structure-dependent gap penalties for use in comparative protein modeling. Protein Eng. 5, 35–41 (1992).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Columbia University College of Physicians & Surgeons,

    Ronit Sarid, Takaaki Sato, Roy A. Bohenzky & Yuan Chang

  2. Department of Otolaryngology, Columbia University College of Physicians & Surgeons,

    Takaaki Sato

  3. Columbia Genome Center, Columbia University, 630 West 168th Street, New York, New York, 10032

    James J. Russo

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Sarid, R., Sato, T., Bohenzky, R. et al. Kaposi's sarcoma-associated herpesvirus encodes a functional Bcl-2 homologue. Nat Med 3, 293–298 (1997). https://doi.org/10.1038/nm0397-293

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