Expression of the anti-apoptotic bfl-1/A1 gene is regulated by the Epstein Barr virus nuclear antigen 2(EBNA2)
Pegman, Pamela Mary
(2003)
Expression of the anti-apoptotic bfl-1/A1 gene is regulated by the Epstein Barr virus nuclear antigen 2(EBNA2).
PhD thesis, Dublin City University.
The ubiquitous and oncogenic human herpesvirus Epstein-Barr virus (EBV) establishes a latent infection and promotes the long-term survival of the infected host cell by targeting the molecular machinery that controls cell fate decisions (apoptosis, proliferation and differentiation). These host-virus interactions are likely to play a crucial role in the development of EBV-associated malignancies mcludmg African endemic Burkitf s lymphoma, nasopharyngeal carcinoma, Hodgkin’s disease and lymphoprohferative disorders in immunodeficient individuals We have previously shown that (1) EBVmfected Burkitt’s lymphoma cell lines exhibit elevated levels of expression of the antiapoptotic bfl-\ gene (also known as A l) compared to their uninfected counterparts, (11) ectopic expression of Bfl-1 can protect a Burkitt’s lymphoma (BL) cell line from apoptosis induced by serum deprivation (D’Souza, B , Rowe, M and Walls, D 2000 J Virol, 74, 6652) and (m) the EBV Latent Membrane Protein 1 (LMP1) stimulates bfl-1 promoter activity through interactions with components of the cellular Tumour Necrosis Factor Receptor (TNFR/CD40)-signallmg pathway by a mechanism which includes an essential role for the transcription factor NFkB (D’Souza et al, submitted) Bfl-1 is an anti-apoptotic protein of the Bcl-2 family, whose preferential expression in hematopoietic and endothelial cells is controlled by inflammatory stimuli. This study reports the novel finding that the EBV nuclear antigen 2 (EBNA2), a second major effector of phenotypic change m EBV-infected cells, can independently upregulate bfl-1 mRNA levels m BL cell lines. This thesis presents the novel finding that EBNA2 regulates bfl-1 promoter activity through interactions with components of the cellular Notch signalling pathway EBNA2-mediated /ram-activation of bfl-1 is dependent upon its ability to bind CBF1 (a nuclear component of the Notch signalling pathway) and involves a novel CBF-l-hke binding site on the bfl-1 promoter This EBNA2-mediated effect on bfl-1 is modulated by other EBV latent proteins that are known to co-operate with EBNA2 (EBNA-LP) or which have been shown to interact with the CBF1 -co-repressor complex (EBNA3A, 3B, 3C and RPMS) These findings are relevant to our understanding of EBV persistence, its role m malignant disease, and the B cell developmental process