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Epstein–Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K

Oncogene volume 24, pages 6917–6924 (2005)Cite this article

Abstract

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus associated with a variety of malignancies including nasopharyngeal carcinoma. The EBV-encoded latent membrane protein 1 (LMP1) is considered the EBV oncogene as it is necessary for EBV-induced B-lymphocyte transformation and has been shown to transform rodent fibroblasts. LMP1 contains two signaling domains, the carboxy-terminal activating region 1 and 2 (CTAR1 and CTAR2), by which NF-κB, phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase, and c-Jun N-terminal kinase are activated. In this study, the role of CTAR1 and CTAR2 in LMP1-mediated transformation of rodent fibroblasts was analysed. CTAR1 was found to be necessary for rodent fibroblast transformation, whereas CTAR2 was dispensable. The activation of the PI3K pathway in Rat-1 cells by LMP1 and LMP1-CTAR1 in transformed cells resulted in phosphorylated Akt and phosphorylated glycogen synthase kinase 3β. The role of PI3K and NF-κB activation in LMP1-mediated transformation was further analysed using the chemical inhibitors LY294002 and BAY 11-7085. LY294002 inhibited CTAR1-induced focus formation and anchorage-independent growth, whereas BAY 11-7085 did not inhibit focus formation or anchorage-independent growth. Similar studies in human fibroblasts confirmed that LMP1-CTAR1 also mediates aberrant growth, phosphorylation of Akt, and decreased levels of p27. These findings indicate that LMP1-mediated rodent fibroblast transformation is dependent upon activation of PI3K and Akt and is independent of activation of NF-κB.

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Acknowledgements

We would like to thank Dr Eng-Shang Huang's lab for the HEL cells. This work was supported by NIH Grants CA 32979 and CA 19014 to NRT.

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Authors and Affiliations

  1. Department of Microbiology-Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    Bernardo A Mainou & Nancy Raab-Traub

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    David N Everly Jr & Nancy Raab-Traub

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  1. Bernardo A Mainou
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  2. David N Everly Jr
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Correspondence to Nancy Raab-Traub.

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Mainou, B., Everly, D. & Raab-Traub, N. Epstein–Barr virus latent membrane protein 1 CTAR1 mediates rodent and human fibroblast transformation through activation of PI3K. Oncogene 24, 6917–6924 (2005). https://doi.org/10.1038/sj.onc.1208846

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