Epstein-Barr virus represses the FoxO1 transcription factor through latent membrane protein 1 and latent membrane protein 2A.
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.
Shore
Angharad M
AM
Medical Biochemistry and Immunology, Henry Wellcome Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom. brennanp@cardiff.ac.uk
White
Paul C
PC
Hui
Rosaline C-Y
RC
Essafi
Abdelkader
A
Lam
Eric W-F
EW
Rowe
Martin
M
Brennan
Paul
P
D002051:Burkitt Lymphoma / Q000821:virology; D045744:Cell Line, Tumor; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis / Q000302:isolation & purification; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013223:Statistics as Topic; D014763:Viral Matrix Proteins / Q000502:physiology*
C084103:BCL6 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D014763:Viral Matrix Proteins; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases