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Journal of Virology, November 2006, p. 11191-11199, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00983-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Represses the FoxO1 Transcription Factor through Latent Membrane Protein 1 and Latent Membrane Protein 2A{triangledown}

Angharad M. Shore,1 Paul C. White,1 Rosaline C.-Y. Hui,2 Abdelkader Essafi,2 Eric W.-F. Lam,2 Martin Rowe,3 and Paul Brennan1*

Medical Biochemistry and Immunology, Henry Wellcome Research Building, Cardiff University, Heath Park, Cardiff CF14 4XX, United Kingdom,1 Cancer Research UK Labs and Department of Oncology, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom,2 CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston B15 2TJ, United Kingdom3

Received 12 May 2006/ Accepted 23 August 2006

Epstein-Barr virus (EBV) infection is associated with the development of many B-cell lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease. The virus alters a diverse range of cellular molecules, which leads to B-cell growth and immortalization. This study was initiated to investigate the interplay between EBV and a proapoptotic transcription factor target, FoxO1. In this report, we show that EBV infection of B cells leads to the downregulation of FoxO1 expression by phosphatidylinositol 3-kinase-mediated nuclear export, by inhibition of FoxO1 mRNA expression, and by alteration of posttranslational modifications. This repression directly correlates with the expression of the FoxO1 target gene Bcl-6 and inversely correlates with the FoxO1-regulated gene Cyclin D2. Expression of the EBV genes for latent membrane protein 1 and latent membrane protein 2A decreases FoxO1 expression. Thus, our data elucidate distinct mechanisms for the regulation of the proapoptotic transcription factor FoxO1 by EBV.

* Corresponding author. Mailing address: Medical Biochemistry and Immunology, Henry Wellcome Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom. Phone: 44 29 20744517. Fax: 44 29 2074 4905. E-mail: brennanp{at}cardiff.ac.uk.

{triangledown} Published ahead of print on 30 August 2006.

Journal of Virology, November 2006, p. 11191-11199, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00983-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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