Skip to main content
SpringerLink
Log in

The Epstein—Barr Virus Gene BHRF1, a Homologue of the Cellular Oncogene Bcl-2, Inhibits Apoptosis Induced by Gamma Radiation and Chemotherapeutic Drugs

  • Chapter
Mechanisms of Lymphocyte Activation and Immune Regulation VI

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 406))

Abstract

Analysis of apoptosis, active and controllable cell death, has demonstrated that the size of a cell population can be regulated by changes in the cell death rate as well as in the rates of proliferation and differentiation. Factors which alter the rate of cell death, such as expression of the proto-oncogene bc1-2, can therefore directly affect the number of cells within a population. Bc1-2 has been. shown to suppress apoptosis in response to a variety of stimuli and to act as a complementary survival signal for the random acquisition of other oncogenic mutations, such as deregulated c-myc.

The Epstein Barr virus (EBV) gene BHRF1 was the first of a family of bc1-2 homologues now being identified. BHRF1 and bc1-2 share 25% primary amino acid sequence homology. Here we show that γ radiation and several cytotoxic anticancer agents induce apoptosis in Burkitt’s lymphoma (BL) cell lines, as has been found in several other systems. Using gene transfection studies we have also shown that expression of either BHRF 1 or bc1-2 in BL cell lines significantly suppresses apoptosis in response to a variety of anticancer treatments. This has confirmed that BHRF 1 is functionally homologous to bcl-2 in B-cells and suggests that BHRF1 may act to prevent apoptosis during EBV infection, maximising virus particle production, as has been suggested for other human and insect viral genes. Suppression of chemotherapeutic drug induced cell death by bcl-2 and BHRF1, as demonstrated in this cell system, results in resistance to a variety of different agents and may represent an alternative mechanism by which multidrug resistance arises during chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. M.J. Arends and Wyllie, A., Apoptosis: mechanisms and roles in pathology. Int. Rev. Exp. Pathol., 32, 223–254 (1991).

    PubMed  CAS  Google Scholar 

  2. G.T.Williams, Smith, C.A., McCarthy, N.J. and Grimes, E.A., Apoptosis: Final control point in cell biology. Trends Cell. Biol., 2: 263–267 (1992).

    Article  PubMed  CAS  Google Scholar 

  3. A.J. Hale, Smith, C.A., Sutherland, L.C., Stoneman, V.E.A., Longthorne, V.L., Culhane, A.C. and Williams, G.T., Apoptosis: molecular regulation of cell death. Eur. J. Biochem. 1996 (in the press).

    Google Scholar 

  4. C.A.Smith, Gimes, E.A., McCarthy, N.J. and Williams, G.T., Multiple gene regulation of apoptosis: Significance in immunology and oncology. In:L.D. Tomei and F.O. Cope (eds.), Apoptosis. The molecular basis of cell death II,Cold Spring Harbour Laboratory Press, Cold Spring Harbour, NY. (in press) (1994).

    Google Scholar 

  5. P. Golstein, Ojcius, D.M. and Young, J.D-E., Cell death mechanisms and the immune system. Immunol. Rev., 121: 29–65 (1991).

    Article  PubMed  CAS  Google Scholar 

  6. G.T.Williams. Apoptosis in the immune system. J. Pathol., 173: 1–4 (1994).

    Article  PubMed  CAS  Google Scholar 

  7. C.A. Smith, Williams, G.T., Kingston, R, Jenkinson, E.J. and Owen, J.J.T., Antibodies to the CD3/T-cell receptor complex induce death by apoptosis in immature T-cells in thymic cultures. Nature, 337: 181–184 (1989).

    Article  PubMed  CAS  Google Scholar 

  8. Y. Shi, Sahai, B.M. and Green, D.R., Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymoccytes. Nature, 339: 625–626 (1989).

    Article  PubMed  CAS  Google Scholar 

  9. Y.J.Liu, Cairns, J.A, Holder, M.J., Abbot, S.J., Jansen, K.U., Bonnefoy, J.Y., Gordon, J. and MacLennan, I.C.M.. Recombinant 25 kDa CD23 and interleukin la promote the survival of germinal centre B cells: evidence for bifurcation in the development of centrocytes rescued from apoptosis. Eur. J. Immunol. 21, 1107–1114 (1991).

    Article  PubMed  CAS  Google Scholar 

  10. G.J.V.Nossal. The molecular and cellular basis of affinity maturation in the antibody response. Cell, 68: 1–2 (1992).

    Google Scholar 

  11. G.T.Williams, Smith, C. A., Spooncer, E., Dexter, T.M and Taylor, D. R., Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature, 343: 76–79 (1990).

    Article  PubMed  CAS  Google Scholar 

  12. M.J.Koury and Bondurant, M.C., Control of red cell prodcution: the roles of programmed cell death (apoptosis) and erythropoietin. Transfusion, 30: 673–674 (1990).

    Article  PubMed  CAS  Google Scholar 

  13. D.L.Vaux, Cory, S. and Adams, J.M.. Bc1–2 gene promotes haemopoietic cell survival and co-operates with c-myc to immortalize pre-B cells. Nature, 335: 440–42 (1988).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Y.Tsujimoto, Stress resistance conferred by high level of Bcl-2a protein in human B-lymphoblastoid cell. Oncogene, 4: 1331–1336 (1989).

    PubMed  CAS  Google Scholar 

  16. N.J.McCarthy, Smith, C.A. and Williams, G.T., Apoptosis in the development of the immune system: Growth factors, clonal selection and bd-2. Cancer Metastasis Rev., 11: 157–178 (1992).

    Article  Google Scholar 

  17. M.L.Cleary, Smith, S.D. and Sklar J., Cloning and structural analysis of cDNAs for bc1–2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell, 47: 19–28 (1986).

    Article  Google Scholar 

  18. G.T.Williams, Programmed cell death: Apoptosis and oncogenesis. Cell, 65: 1097–1098 (1991).

    Article  Google Scholar 

  19. S.A.Henderson, Huen, D., Rowe, M., Dawson, C., Johnson, G. and Rickinson, A., Epstein-Barr virus coded BHRF 1 protein, a viral homologue of bc1–2, protects human B cells from programmed cell death. Proc. Natl. Acad. Sci. U.S.A., 90: 8479–8483 (1993).

    Article  Google Scholar 

  20. 20. T.Hickish, Robertson, D., Clarke, P., Hill, M., di Stefano, F., Clarke, C. and Cunnigham, D., Ultrastructural localisation of BHRF I: an Epstein-Barr virus gene product which has homology with bc1–2. Cancer Res. 54, 2808–2811.

    Google Scholar 

  21. J.W.Gratama, Oosterveer, M.A.P., Zwann, F.E., Lepoutre, J., Klein, G. and Ernberg, I., Eradication of Epstein Barr virus by allogenic bone marrow transplantation: implcations for sites of vital latency. Proc. Natl. Acad. Sci. USA, 85: 8693–8696 (1988).

    Article  Google Scholar 

  22. Q.Y.Yao, Ogan, P., Rowe, M., Wood, M. and Rickinson, A.B., Epstein Barr virus infected B cells persist in the cirulation of acyclovir-treated virus carriers. Int. J. Cancer, 43: 67–71 (1989).

    Article  Google Scholar 

  23. C.D.Gregory, Dive, C., Henderson, S.A., Smith, C.A., Williams, G.T., Gordon, J and Rickinson, A. B., Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature, 349: 612–614 (1991).

    Article  Google Scholar 

  24. S.A.Henderson, Rowe, M., Gregory, C., Croom-Carter, D., Wang, F., Longnecker, R., Kieff, E. and Rickinson, A., Induction of bc1–2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell, 65: 1107–1115 (1991).

    Article  Google Scholar 

  25. E.White, Sabbatini, P. Debbas, M., Wold, W.S.M., Kusher, D. I. and Gooding L.R., The 19-Kilodalton Adenovirus Elb transforming protein inhibits programmed cell death and prevents cytolysis by tumour necrosis factor a. Mol. Cell. Biol., 12: 2570–2580.

    Google Scholar 

  26. J.L.Cleveland, Dean, M., Rosenberg, N., Wang, J.Y.J. and Rapp, U.R., Tyrosine kinase oncogenes abrogate interleukin 3 dependence of murine myeloid cells through signalling pathways involving c-myc: conditional regulation ofc-myc transcription by temperature sensitive v-abl. Mol. Cell Biol., 9:5685–5695 (1989).

    Google Scholar 

  27. R.J.Clem, Fechheimer, M. and Miller L. K., Prevention of apoptosis by a Baculovirus gene during infection of insect cells. Science, 254: 1388–1390 (1991).

    Article  Google Scholar 

  28. N.E.Crook, Clem, R.J. and Miller, L.K., An apoptosis inhibiting Baculovirus gene with a zinc finger like motif. J. Virol., 67: 2168–2174 (1993).

    Google Scholar 

  29. M.Hummel, and Kieff, E., Epstein Barr virus RNA VIII. Viral RNA in permissively infected B95–8 cells. J. Virol., 43: 262–272 (1982).

    Google Scholar 

  30. M.Hummel, and Kieff, E., Mapping of polypeptides encoded by the Epstein Barr virus genome in productive infection. Proc. Natl. Acad. Sci. U.S.A., 79: 5698–5702 (1982).

    Article  Google Scholar 

  31. T.J.McDonnell, Deane, N., Platt, F.M, Nunez, G., Jaeger, U., McKearn, J.P. and Korsmeyer S. J., Bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell: 57: 79–88 (1989).

    Article  Google Scholar 

  32. T.J.McDonnell and Korsmeyer, S. J., Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature, 349: 254–256 (1991).

    Article  Google Scholar 

  33. J.J.Oudejans, van den Brule, A.J., Jiwa, N.M., de Bruin, P.C., Ossenkoppele, G.J., van der Valk, P., Walboomers, J.M. and Meijer, C.J., BHRF1, the Epstein-Barr virus (EBV) homologue of the Bc1–2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes. Blood, 86: 1893–1902 (1995).

    Google Scholar 

  34. T.Yamada, and Ohyama, H. Radiation-induced interphase death of rat thymocytes is internally programmed. Int. J. Radiat. Biol.,53: 65–75 (1988).

    Google Scholar 

  35. M.A.Barry, Behnke, C.A. and Eastman, A., Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem. Pharmacol., 40: 2353–2362 (1990).

    Article  Google Scholar 

  36. C.A.Evans, Owen-Lynch, P.J., Whetton, A.O. and Dive, C., Activation of the ableson tyrosine kinase activity is associated with suppression of apoptosis in haemopoietic cells. Cancer Res., 53: 1735–1738 (1993).

    Google Scholar 

  37. C.A.Dive and Hickman, J.A., Drug-target interactions: only the first step in a commitment to a programmed cell death. Br. J. Cancer, 64: 192–196 (1991).

    Article  Google Scholar 

  38. M.K.L.Collins, Marvel, J., Malde, P. and Lopez-Rivas, A., Interleukin 3 protects murine bone marrow cells from apoptosis induced by DNA damaging agents. J. Exp. Med., 176: 1043–1051 (1992).

    Article  Google Scholar 

  39. T.Miyashita, and Reed, J.C., Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a leukaemia cell line. Blood, 81: 151–157 (1993).

    Google Scholar 

  40. A.H.Wyllie. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature, 284: 555–556 (1980).

    Article  Google Scholar 

  41. D.J.McConkey, Hartzell, P., Nicotera, P. and Orrenius, S., Calcium-activated DNA fragmentation kills immature thymocytes. FASEB J., 3: 1843–1849 (1989).

    Google Scholar 

  42. K.S.Sellins, and Cohen, J.J., Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J.Immunol., 139: 3199–3206 (1987).

    Google Scholar 

  43. A.J.Levine, Momand J. and Finlay, C.A., The p53 tumour suppressor gene. Nature, 351: 453–456 (1991).

    Article  Google Scholar 

  44. S.J.Baker, Fearon, E.R., Nigro, J.M., Hamilton, S.R., Preisinger, A.C., Jessup, J.M., vanTuinen, P., Ledbetter, D.H., Barker, D.F., Nakamura, Y., White, R. and Vogelstein, B., Chromosome 17 deletions and p53 gene mutations in colosectal carcinoma. Science, 244: 217–221 (1989).

    Article  Google Scholar 

  45. S.W.Lowe, Schmitt, E.M., Smith, S.W., Osborne, B.A. and Jacks, T., p53 is required for radiation induced apoptosis in mouse thymocytes. Nature, 362, 847–849 (1993).

    Article  Google Scholar 

  46. A.R.Clarke, Purdie, C.A., Harrison, D.J., Morris, R.G., Bird, C.C., Hooper, M.L. and Wyllie, A.H., Thymocyte apoptosis induced by p53 dependent and independent pathways. Nature, 362: 849–852 (1993).

    Article  Google Scholar 

  47. G.I.Evan, Wyllie, A. H., Gilbert, C. S., Littlewood, T. D., Land, H., Brooks, M, Waters, C.M. and Hancock, D. C., Induction of apoptosis in fibroblasts by c-myc protein. Cell, 63: 119–128 (1992).

    Google Scholar 

  48. L.H.Boise, Gonzalez-Garcia, M., Postema, C.E., Ding, L., Lindsten, T., Turka, L.A., Mao, X., Nunez, G. and Thompson, C.B., bcl-x, a bc1–2 related gene that functions as a dominant regulator of apoptotíc cell death. Cell, 74: 597–609 (1993).

    Article  Google Scholar 

  49. Z.N.Oltvai, Milliman, C.L. & Korsmeyer, S.J., Bc1–2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell, 74: 609–619 (1993).

    Article  Google Scholar 

  50. D.L.Vaux, Weissman, I.L. and Kim, S.K., Prevention of programmed cell death in Caenorhabditis elegans by human bcl-2. Science, 258: 1955–1957 (1992).

    Google Scholar 

  51. M.O.Hengartner, and Horvitz, H.R. C.elegans cell survival gene ced-9 encodes a functional homologue of the mammalian proto-oncogene bc1–2. Cell, 76: 665–676 (1994).

    Google Scholar 

  52. G.T. Williams, and Smith, C.A., Molecular regulation of apoptosis: Genetic controls on cell death. Cell, 74: 777–779 (1993).

    Article  PubMed  CAS  Google Scholar 

  53. J.G.Neilan, Lu, Z., Afonso, C.L., Kutish, G.F., Sussman, M.D. and Rock, D.L., An African swine fever virus gene with similarity to the proto-oncogene bc1–2 and the Epstein-Barr virus gene BHRF1. J Viral., 67: 4391–4394 (1993).

    Google Scholar 

  54. G.R.Pearson, Luka, J., Petti, L., Sample, J., Birkenbach, M., Braun, D. and Keiff, E., Identification of an Epstein Barr virus early gene encoding a second comonent of the restricted early antigen complex. Virology, 160: 151–161 (1987).

    Article  Google Scholar 

  55. B.Tarodi, Subramanian, T. and Chinnadurai, G., Epstein-Barr virus BHRF1 protein protects against cell death induced by DNA-damaging agents and heterologous viral infection. Virology, 201: 404–407 (1994).

    Article  Google Scholar 

  56. C.W.Dawson, Eliopoulos, A.G., Dawson, J. and Young, L.S., BHRF1, a viral homologue of the BCL-2 oncogene, disturbs epithelial cell differentiation. Oncogene, 10: 69–77 (1995).

    Google Scholar 

  57. R.Dalla-Favera, Martinotti, S., Gallo, R.C., Erikson, J. and Croce, C.M., Science, 219: 963–967 (1983).

    Article  Google Scholar 

  58. F.Cavalli, Chemothreapy of non-Hodgkin’s lymphoma. Bailliere’s Clinical Haematology, 4: 157–179 (1991).

    Article  Google Scholar 

  59. R.Juliano, and Ling, V., J. Supramol. Strut., 4: 521–526 (1976).

    Article  Google Scholar 

  60. V.Ling. P-glycoprotein and resistance to anticancer drugs. Cancer, 69: 2603–2609 (1992).

    Article  Google Scholar 

  61. P.F.Juranka, Zastawny, R.L. and Ling, V., P-glycoprotein multidrug-resistance and a super family of membrane-associated transport proteins. FASEB J., 3: 2583–2592 (1989).

    Google Scholar 

  62. G.H.Mickisch, Merlino, G.T., Galski, H., Gottesman, M.M. and Pastan, I. Transgenic mice that express the human multidrug resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proc. Natl. Acad. Sci. USA., 88: 547–551 (1991).

    Article  Google Scholar 

  63. T.C.Fisher, Milner, A.E., Gregory, C.D., Jackman, A., Aherne, G.W., Hartley, J.A., Dive, C. and Hickman, J.A., bc1–2 modulation of apoptosis induced by anticancer drugs: Resistance to thymidylate stress is independent of classical resistance pathways. Cancer Res., 53: 3321–3326 (1993).

    Google Scholar 

  64. M.I.Walton, Whysong, D., O’Connor, P.M., Hockenbery, D., Korsmeyer, S.J. and Kohn, K.W., Constitutive expression of human bc1–2 modulates nitrogen mustard and camptothecin induced apoptosis. Cancer Res., 53: 1853–1861 (1993).

    PubMed  CAS  Google Scholar 

  65. J.Lotem and Sachs, L. Regulation by bc12-, c-myc and p53 of susceptibility to induction of apoptosis by heat shock and cancer chemotherapy compounds in differentiation competent and defective myeloid leukaemic cells. Cell Growth Diff., 4: 41–47 (1993).

    PubMed  CAS  Google Scholar 

  66. C.M.Rooney, Gregory, C.D., Rowe, M., Finerty, S., Edwards, C., Rupani, H. and Rickinson, A.B., Endemic Burkitt’s lymphoma: phenotypic analysis of Burkitt’s lymphoma biopsy cell and of the derived tumour cell lines. J.Natl. Cancer Inst., 77: 681–687 (1986).

    PubMed  CAS  Google Scholar 

  67. K.Takada and Ono. Y., Synchronous and sequential activation of latently infected Epstein-Barr virus genomes. J.Virol., 63: 445–449 (1989).

    PubMed  CAS  Google Scholar 

  68. L.Rymo, Lindahl, T., Povey, S. and Klien, G., Anaylsis of restriction endonuclease fragments of intracellular Epstein-Barr virus type A (EBNA 2A) and type B (EBNA 2B) isolates extends to the EBNA 3 family of proteins. Virology, 115: 115–124 (1981).

    Article  PubMed  CAS  Google Scholar 

  69. A.H.Wyllie, Morris, R.G., Smith, A.L. and Dunlop, D., Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis. J. Pathol., 142: 67–77 (1984).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Author notes

  1. N. J. McCarthy

    Present address: ICRF Laboratories, P.O.Box 123, Lincoln’s Inn Fields, London, WC2A 3PX, UK

Authors and Affiliations

  1. Department of Biological Sciences, Keele University, Keele, Staffordshire, ST5 5BG, UK

    N. J. McCarthy, S. A. Hazlewood & G. T. Williams

  2. Department of Anatomy, UK

    N. J. McCarthy & G. T. Williams

  3. CRC Laboratories, Department of Cancer Studies, University of Birmingham Medical School, Vincent Drive, Birmingham, B15 2TT, UK

    S. A. Hazlewood, D. S. Huen & A. B. Rickinson

Authors
  1. N. J. McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. A. Hazlewood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. S. Huen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. B. Rickinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. T. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of California, Irvine, Irvine, California, USA

    Sudhir Gupta

  2. University of Colorado Health Sciences Center, Denver, Colorado, USA

    J. John Cohen

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer Science+Business Media New York

About this chapter

Cite this chapter

McCarthy, N.J., Hazlewood, S.A., Huen, D.S., Rickinson, A.B., Williams, G.T. (1996). The Epstein—Barr Virus Gene BHRF1, a Homologue of the Cellular Oncogene Bcl-2, Inhibits Apoptosis Induced by Gamma Radiation and Chemotherapeutic Drugs. In: Gupta, S., Cohen, J.J. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation VI. Advances in Experimental Medicine and Biology, vol 406. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0274-0_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4899-0274-0_9

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-0276-4

  • Online ISBN: 978-1-4899-0274-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation