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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2280-2289. Prepublished online as a Blood First Edition Paper on November 27, 2007; DOI 10.1182/blood-2007-07-100032. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-07-100032v1 111/4/2280    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lee, D. Y. Articles by Sugden, B. Search for Related Content PubMed PubMed Citation Articles by Lee, D. Y. Articles by Sugden, B. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis Dong Yun Lee1, and Bill Sugden1 1 McArdle Laboratory for Cancer Research, University of Wisconsin-Madison The oncogene latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) without a ligand drives proliferation of EBV-infected B cells. Its levels vary in cells of clonal populations by more than 100-fold, which leads to multiple distinct activities of the oncogene. At intermediate levels it drives proliferation, and at high levels it inhibits general protein synthesis by inducing phosphorylation of eukaryotic initiation factor 2 (eIF2). We have found that LMP1 activates PERK to induce phosphorylation of eIF2, which upregulates activating transcription factor 4 (ATF4) expression. ATF4, in turn, transactivates LMP1's own promoter. LMP1 activates not only PERK but also inositol requiring kinase 1 (IRE1) and ATF6, 3 pathways of the unfolded protein response (UPR). Increasing expression levels of LMP1 induced a dose-dependent increase in IRE1 activity, as measured by its "splicing" of XBP-1. These infected B cells secrete immunoglobins independent of the levels of LMP1, indicating that only a threshold level of XBP-1 is required for the secretion. These findings indicate that LMP1's activation of the UPR is a normal event in a continuum of LMP1's expression that leads both to stimulatory and inhibitory functions and regulates the physiology of EBV-infected B cells in multiple, unexpected modes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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