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

Oncogene volume 23, pages 8619–8628 (2004)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Roger Perlmutter for kindly letting us use the dominant-negative Ras transgenic mice generated in his laboratory. We also thank members of the Longnecker laboratory for help with these studies. In particular, we thank Lori Lev for researching and selecting inhibitors for our experiments and Dr Michelle Swanson-Mungerson for helpful discussions and ideas to improve the manuscript. RL is a Stohlman Scholar of the Leukemia and Lymphoma Society of America and supported by the Public Health Service Grants CA62234, CA73507, and CA93444 from the National Cancer Institute and DE13127 from the National Institute of Dental and Craniofacial Research. TP is a Special Fellow of the Leukemia and Lymphoma Society of America.

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  1. Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Toni Portis & Richard Longnecker

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Correspondence to Richard Longnecker.

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Portis, T., Longnecker, R. Epstein–Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene 23, 8619–8628 (2004). https://doi.org/10.1038/sj.onc.1207905

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