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Journal of Virology, February 2004, p. 1800-1816, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1800-1816.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nuclear Factor B-Dependent Activation of the Antiapoptotic bfl-1 Gene by the Epstein-Barr Virus Latent Membrane Protein 1 and Activated CD40 Receptor

Brendan N. D'Souza,^1, Leonard C. Edelstein,^2, Pamela M. Pegman,¹ Sinéad M. Smith,¹ Sinéad T. Loughran,¹ Ann Clarke,^1, Anja Mehl,^3,|| Martin Rowe,³ Céline Gélinas,² and Dermot Walls^1*

School of Biotechnology and National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland,¹ Department of Biochemistry, Centre for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,² Section of Infection and Immunity, University of Wales College of Medicine, Cardiff CF14 4XX, United Kingdom³

Received 20 August 2003/ Accepted 16 October 2003

Suppression of the cellular apoptotic program by the oncogenic herpesvirus Epstein-Barr virus (EBV) is central to both the establishment of latent infection and the development of EBV-associated malignancies. We have previously shown that expression of the EBV latent membrane protein 1 (LMP1) in Burkitt's lymphoma cell lines leads to increased mRNA levels from the cellular antiapoptotic bfl-1 gene (also known as A1). Furthermore, ectopic expression of Bfl-1 in an EBV-positive cell line exhibiting a latency type 1 infection protects against apoptosis induced by growth factor deprivation (B. N. D'Souza, M. Rowe, and D. Walls, J. Virol. 74:6652-6658, 2000). We now report that LMP1 drives bfl-1 promoter activity through interactions with components of the tumor necrosis factor receptor (TNFR)/CD40 signaling pathway. We present evidence that this process is NF-B dependent, involves the recruitment of TNFR-associated factor 2, and is mediated to a greater extent by the carboxyl-terminal activating region 2 (CTAR2) relative to the CTAR1 domain of LMP1. Activation of CD40 receptor also led to increased bfl-1 mRNA levels and an NF-B-dependent increase in bfl-1 promoter activity in Burkitt's lymphoma-derived cell lines. We have delineated a 95-bp region of the promoter that functions as an LMP1-dependent transcriptional enhancer in this cellular context. This sequence contains a novel NF-B-like binding motif that is essential for transactivation of bfl-1 by LMP1, CD40, and the NF-B subunit protein p65. These findings highlight the role of LMP1 as a mediator of EBV-host cell interactions and may indicate an important route by which it exerts its cellular growth transforming properties.

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

Present address: Department of Pathology, Children's Hospital, Harvard Medical School, Boston, MA 02115.

Present address: Schering-Plough (Brinny) Co., Innishannon, County Cork, Ireland.

^|| Present address: Max Delbrueck Center, Berlin, Germany.

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