Nuclear factor kappa B-dependent activation of the antiapoptotic bfl-1 gene by the Epstein-Barr virus latent membrane protein 1 and activated CD40 receptor.
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-kappa 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-kappa 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-kappa B-like binding motif that is essential for transactivation of bfl-1 by LMP1, CD40, and the NF-kappa 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.
D'Souza
Brendan N
BN
School of Biotechnology and National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland.
Edelstein
Leonard C
LC
Pegman
Pamela M
PM
Smith
Sinéad M
SM
Loughran
Sinéad T
ST
Clarke
Ann
A
Mehl
Anja
A
Rowe
Martin
M
Gélinas
Céline
C
Walls
Dermot
D
D000818:Animals; D001402:B-Lymphocytes; D002051:Burkitt Lymphoma; D019013:CD40 Antigens / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007739:L Cells; D051379:Mice; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism*
C096816:BCL2-related protein A1; D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014763:Viral Matrix Proteins