EBV-encoded LMP-I is absolutely required for EBV transformation of cells. Previous studies showed that LMP-I is responsible for mediating resistance to the anti- proliferative effects of TGF-beta that characterizes EBV-transformed cells. To clarify the mechanisms of resistance to TGF-beta by LMP-I, we examined the effect of expression of LMP-I on the activity of TGF-beta-responsive promoters. Interestingly, LMP-I inhibited TGF-beta-responsive promoters activity despite lack of direct interaction of LMP-I and Smad proteins, intracellular signaling molecules in the TGF-beta signal transduction pathway. Although TGF-beta treatment increased the expression of p15, TGF-beta-induced gene, this effect was counteracted by expression of LMP-1. The repressive effect was mapped to the NF-kappaB activation domains in the cytoplasmic carboxyl terminus of LMP-I. Furthermore, LMP-I-mediated inhibition of TGF-beta-responsive promoter was markedly restored after inhibition of NF-kappaB activity. LMP-I 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-I on the TGF-beta-responsive promoter. Our results suggest that LMP-I represses the TGF-beta signaling through the NF-kappaB 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.
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- DOI : 10.1002/ijc.11146
- ISSN : 0020-7136
- Web of Science ID : WOS:000183474000013