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

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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.