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.
Portis
Toni
T
Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Longnecker
Richard
R
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000821:virology; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D016283:Proto-Oncogene Proteins p21(ras); D014763:Viral Matrix Proteins; D051020:bcl-X Protein; D048490:raf Kinases; C494812:Bcl2l1 protein, mouse; C037662:EBV-associated membrane antigen, Epstein-Barr virus