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Journal of Virology, August 2006, p. 8133-8144, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00278-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Nuclear Antigen 2 trans-Activates the Cellular Antiapoptotic bfl-1 Gene by a CBF1/RBPJ-Dependent Pathway

Pamela M. Pegman,^1, Sinéad M. Smith,¹ Brendan N. D'Souza,^1, Sinéad T. Loughran,¹ Sabine Maier,³ Bettina Kempkes,³ Paul A. Cahill,² Matthew J. Simmons,⁴ Céline Gélinas,⁴ and Dermot Walls^1*

School of Biotechnology and National Centre for Sensor Research,¹ Vascular Health Research Centre, Faculty of Science and Health, Dublin City University, Dublin 9, Ireland,² Institut fur Klinische Molekularbiologie und Tumorgenetik, GSF-Forschungszentrum fur Umwelt und Gesundheit, Marchioninistrasse 25, D-81377 Munchen, Germany,³ Centre for Advanced Biotechnology and Medicine and Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854⁴

Received 7 February 2006/ Accepted 18 May 2006

The human herpesvirus Epstein-Barr virus (EBV) establishes latency and promotes the long-term survival of its host B cell by targeting the molecular machinery controlling cell fate decisions. The cellular antiapoptotic bfl-1 gene confers protection from apoptosis under conditions of growth factor deprivation when expressed ectopically in an EBV-negative Burkitt's lymphoma-derived cell line (B. D'Souza, M. Rowe, and D. Walls, J. Virol. 74:6652-6658, 2000), and the EBV latent membrane protein 1 (LMP1) and its cellular functional homologue CD40 can both drive bfl-1 via an NF-B-dependent enhancer element in the bfl-1 promoter (B. N. D'Souza, L. C. Edelstein, P. M. Pegman, S. M. Smith, S. T. Loughran, A. Clarke, A. Mehl, M. Rowe, C. Gélinas, and D. Walls, J. Virol. 78:1800-1816, 2004). Here we show that the EBV nuclear antigen 2 (EBNA2) also upregulates bfl-1. EBNA2 trans-activation of bfl-1 requires CBF1 (or RBP-J), a nuclear component of the Notch signaling pathway, and there is an essential role for a core consensus CBF1-binding site on the bfl-1 promoter. trans-activation is dependent on the EBNA2-CBF1 interaction, is modulated by other EBV gene products known to interact with the CBF1 corepressor complex, and does not involve activation of NF-B. bfl-1 expression is induced and maintained at high levels by the EBV growth program in a lymphoblastoid cell line, and withdrawal of either EBNA2 or LMP1 does not lead to a reduction in bfl-1 mRNA levels in this context, whereas the simultaneous loss of both EBV proteins results in a major decrease in bfl-1 expression. These findings are relevant to our understanding of EBV persistence, its role in malignant disease, and the B-cell developmental process.

Present address: GlaxoSmithKline Research and Development, South Eden Park Road, Beckenham, Kent BR3 3BS, United Kingdom.

Present address: Department of Biological Chemistry, UCLA School of Medicine, UCLA, Los Angeles, CA 90095-1737.