Activated Notch1 Modulates Gene Expression in B Cells Similarly to Epstein-Barr Viral Nuclear Antigen 2

Abstract

Epstein-Barr virus (EBV), a human herpesvirus, is associated with several human malignancies, including Burkitt's lymphoma, nasopharyngeal carcinoma, T-cell lymphoma, gastric carcinoma, Hodgkin lymphoma, and immunoblastic lymphoma in immunocompromised individuals. The virus has the ability to immortalize primary B cells in vitro. In these immortalized lymphoblastoid cell lines, only a few viral genes are expressed, coding for six nuclear proteins (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, and EBNA-LP) and three latent membrane proteins (LMP1, LMP2A, and LMP2B) (for a review, see reference 35). Five of the nuclear antigens (EBNA1, -2, -3A, and -3C seem to be absolutely required for B-cell immortalization (10,23,32,68), whereas EBNA-LP and LMP2A seem to affect the efficiency of the process (6,23,47).EBNA2 plays a pivotal role in B-cell immortalization, since a natural occurring EBV mutant, the P3HR1 strain, carrying a deletion of the EBNA2 gene, has lost the ability to transform primary B cells. Reintroduction of the EBNA2 gene in the viral genome by homologous recombination or complementation can restore the immortalizing capacity of the virus (23). EBNA2 contributes to B-cell immortalization most likely by its ability to act as transcriptional modulator of cellular and viral gene expression. It activates the transcription of the B-cell activation markers CD21 and CD23 (9,11,70) and the tyrosine kinase c-Fgr (37) and downregulates the expression of the immunoglobulin heavy-chain locus (Ig) (30). In addition, EBNA2 transactivates the viral promoters of the three latent membrane proteins LMP1, LMP2A, and LMP2B and the Cp promoter, which regulates the transcription of the EBNA genes (17,64,75,76). EBNA2 does not bind to DNA directly (45, 77) but is recruited to EBNA2-responsive elements by interacting with the transcriptional factors 25,69,78) and PU

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

“…CBF1 transcription factor is bound by ICN under normal conditions, which recruits co-activators to form a transcriptional complex containing p300, CBP and P/CAF histone acetyltransferases. This complex activates various genes including c-myc and LMP1 that are both involved in activation of telomerase [37,38] (Figure 4). …”

“…Under normal cellular conditions, CBF1 transcription factor is bound by intracellular Notch (ICN) -a product of enzymatic cleavage of membrane-bound Notch, and in the presence of ICN, the CBF1 complex recruits co-activators (such as mastermind-like proteins) to become part of a transcriptional activation complex containing p300, CBP and P/CAF histone acetyltransferases. This complex activates various targets including the LMP1 promoter [37,38]. The EBNA2/CBF1 complex can similarly activate gene transcription by recruiting several components of gene transcription machinery using the EBNA2 C-terminal acidic activation domain [38].…”

Epstein–Barr virus EBNA2 blocks Nur77- mediated apoptosis

“…In its transcriptional role, EBNA2 mimics the effects of activated Notch (13,14). Notch is an evolutionarily conserved, surface receptor that mediates cell-cell signaling to influence developmental and cell fate decisions (15,16).…”

Potential Therapeutic Molecular Targets for Nasopharyngeal Carcinoma

“…The carboxy-terminal acidic activation domain of EBNA2 is required for direct interaction with the CSL family of DNA-binding protein (CBF1) and participates in EBNA2-mediated gene transcription (306). EBNA2 has been shown to be able to functionally replace the intracellular region of Notch in the regulation of gene expression of B cells by targeting CBF1 and localizing the coactivators p300, PCAF, and CBP to the promoter (109,122,250,280,306,321). In normal cells, CBF-1 is bound by Notch to regulate the expression of cellular genes involved in cell proliferation (14,187).…”