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Repression of Smad‐dependent transforming growth factor‐β signaling by Epstein‐Barr virus latent membrane protein 1 through nuclear factor‐κB
Author(s) -
Mori Naoki,
Morishita Mariko,
Tsukazaki Tomoo,
Yamamoto Naoki
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11146
Subject(s) - smad , signal transduction , biology , coactivator , transforming growth factor , microbiology and biotechnology , r smad , transcription factor , epstein–barr virus , psychological repression , gene expression , receptor , gene , growth factor , tgf alpha , virus , genetics
Abstract EBV‐encoded LMP‐1 is absolutely required for EBV transformation of cells. Previous studies showed that LMP‐1 is responsible for mediating resistance to the anti‐proliferative effects of TGF‐β that characterizes EBV‐transformed cells. To clarify the mechanisms of resistance to TGF‐β by LMP‐1, we examined the effect of expression of LMP‐1 on the activity of TGF‐β‐responsive promoters. Interestingly, LMP‐1 inhibited TGF‐β‐responsive promoters activity despite lack of direct interaction of LMP‐1 and Smad proteins, intracellular signaling molecules in the TGF‐β signal transduction pathway. Although TGF‐β treatment increased the expression of p15, TGF‐β‐induced gene, this effect was counteracted by expression of LMP‐1. The repressive effect was mapped to the NF‐κB activation domains in the cytoplasmic carboxyl terminus of LMP‐1. Furthermore, LMP‐1‐mediated inhibition of TGF‐β‐responsive promoter was markedly restored after inhibition of NF‐κB activity. LMP‐1 failed to affect receptor‐dependent formation of heteromers containing Smad proteins as well as the DNA‐binding activity of Smad proteins. Overexpression of the transcriptional coactivator CBP and p300 abrogated the inhibitory effect of LMP‐1 on the TGF‐β‐responsive promoter. Our results suggest that LMP‐1 represses the TGF‐β signaling through the NF‐κB signaling pathway at transcriptional level by competing for a limited pool of transcriptional coactivators. These results enhance our understanding of the molecular mechanisms of viral pathogenesis in EBV‐associated malignancies. © 2003 Wiley‐Liss, Inc.