This Article Full Text (PDF) Other Versions of this Article: JVI.00125-08v1 82/11/5486    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Kung, C.-P. Articles by Raab-Traub, N. PubMed PubMed Citation Articles by Kung, C.-P. Articles by Raab-Traub, N.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.00125-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Epstein-Barr Virus Latent Membrane Protein 1 Induces Expression of the Epidermal Growth Factor Receptor Through Effects on Bcl-3 and STAT3

Department of Microbiology-Immunology, University of North Carolina at Chapel Hill, Chapel Hill NC 27599; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill NC 27599

^* To whom correspondence should be addressed. Email: nrt{at}med.unc.edu.

	Abstract

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) activates multiple signaling pathways. Two regions, CTAR1 and CTAR2, have been identified within the cytoplasmic carboxy terminal domain that activates NF-B. C-terminal activating region 2 (CTAR2) activates the canonical NF-B pathway which includes p50/p65 complexes. C-terminal activating region 1 (CTAR1) can activate both the canonical and noncanonical pathways to produce multiple distinct NF-B dimers, including p52/p50, p52/p65, and p50/p50. CTAR1 also uniquely upregulates the epidermal growth factor receptor (EGFR) in epithelial cells. Increased p50-Bcl-3 complexes have been detected by chromatin precipitation on the NF-B consensus motifs within the egfr promoter in CTAR1-expressing epithelial cells and NPC cells. In this study, the mechanism responsible for the increased Bcl-3 has been further investigated. The data indicate that LMP1-CTAR1 induces Bcl-3 mRNA and increases the nuclear translocation of both Bcl-3 and p50. LMP1-CTAR1 constitutively activates STAT3 and this activation was not due to induction of IL-6. In LMP1-CTAR1-expressing cells, increased levels of activated STAT3 were detected by chromatin immunoprecipitation on STAT-binding sites located within both the promoter and second intron of Bcl-3. A STAT3 inhibitor significantly reduced the activation of STAT3, as well as the CTAR1-mediated upregulation of Bcl-3 and EGFR. These data suggest that LMP1 activates distinct forms of NF-B through multiple pathways. In addition to the canonical and noncanonical pathways, LMP1-CTAR1 constitutively activates STAT3 and increases Bcl-3. The increased nuclear Bcl-3 and p50 homodimer complexes positively regulate EGFR expression. These results indicate that LMP1 likely regulates distinct cellular genes by activating specific NF-B pathways.