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Two Epstein–Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma

Oncogene volume 27, pages 421–433 (2008)Cite this article

Abstract

Epstein–Barr virus (EBV) contributes to the development of several human cancers including the endemic form of Burkitt's lymphoma (BL). In culture, EBV induces the continuous proliferation of primary B cells as lymphoblastoid cell lines (LCLs) and if EBV-negative BL-derived cells are infected with EBV, latency-associated viral factors confer resistance to various inducers of apoptosis. Nuclear proteins EBNA3A and EBNA3C (but not EBNA3B) are necessary to establish LCLs and their expression may be involved in the resistance of BL cells to cytotoxic agents. We have therefore created recombinant EBVs from which each of the EBNA3 genes has been independently deleted, and revertant viruses in which the genes have been re-introduced into the viral genome. Infection of EBV-negative BL cells with this panel of EBVs and challenge with various cytotoxic drugs showed that EBNA3A and EBNA3C cooperate as the main determinants of both drug resistance and the downregulation of the proapoptotic Bcl-2-family member Bcl-2-interacting mediator of cell death (Bim). The regulation of Bim is predominantly at the level of RNA, with little evidence of post-translational Bim stabilization by EBV. In the absence of Bim, EBNA3A and EBNA3C appear to provide no survival advantage. The level of Bim is a critical regulator of B cell survival and reduced expression is a major determinant of lymphoproliferative disease in mice and humans; moreover, Bim is uniquely important in the pathogenesis of BL. By targeting this tumour-suppressor for repression, EBV significantly increases the likelihood of B lymphomagenesis in general, and BL in particular. Our results may also explain the selection pressure that gives rise to a subset of BL that retain expression of the EBNA3 proteins.

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Abbreviations

BL:

Burkitt's lymphoma

EBNA:

Epstein–Barr virus nuclear antigen

LCL:

lymphoblastoid cell line

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Acknowledgements

We thank the Wellcome Trust and the Medical Research Council, UK, for financial support of this research.

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Authors and Affiliations

  1. Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London, UK

    E Anderton, J Yee, R E White & M J Allday

  2. The Institute of Cancer Research/Breakthrough, Toby Robins Breast Cancer Research Centre, Fulham Road, London, UK

    P Smith & T Crook

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  1. E Anderton
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Correspondence to M J Allday.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Anderton, E., Yee, J., Smith, P. et al. Two Epstein–Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma. Oncogene 27, 421–433 (2008). https://doi.org/10.1038/sj.onc.1210668

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