Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway

Epstein-Barr virus (EBV) establishes a lifelong latent infection in host B cells and is associated with the development of a variety of malignancies. The viral LMP2A protein mediates viral latency by mimicking a constitutively activated B-cell receptor (BCR). In vivo LMP2A provides developmental and survival signals to BCR-negative B cells, allowing them to survive in peripheral lymphoid organs. In this study, we have demonstrated that Ras is constitutively active in peripheral, BCR-negative B cells from LMP2A transgenic mice. Furthermore, increased expression of activated Ras correlated with elevated levels of Bcl-xL expression and a slower migrating, band-shifted form of Bcl-2. B cells from LMP2A transgenic mice were sensitive to apoptosis induction in the presence of specific inhibitors of Ras, phosphatidylinositol 3-kinase (PI3K), and Akt, indicating that LMP2A activates the Ras/PI3K/Akt pathway to mediate B-cell survival. Increased B-cell apoptosis correlated with reduced expression of Bcl-xL, suggesting that this Bcl-2 family member may be involved in apoptosis inhibition mediated by LMP2A. The ability of LMP2A to activate constitutively the Ras pathway, a common event during tumorigenesis, suggests that this viral protein plays an active role in the development of EBV-associated malignancies.