Repression of Smad‐dependent transforming growth factor‐β signaling by Epstein‐Barr virus latent membrane protein 1 through nuclear factor‐κB

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 exam...

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Bibliographic Details
Published in:International journal of cancer 2003-07, Vol.105 (5), p.661-668
Main Authors: Mori, Naoki, Morishita, Mariko, Tsukazaki, Tomoo, Yamamoto, Naoki
Format: Article
Language:English
Subjects:
Epstein‐Barr virus
LMP‐1
NF‐κB
Smad
TGF‐β
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Summary: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.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.11146