Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1.

Research paper by Tamara T Alliston, Tien C TC Ko, Yanna Y Cao, Yao-Yun YY Liang, Xin-Hua XH Feng, Chenbei C Chang, Rik R Derynck

Indexed on: 26 Apr '05Published on: 26 Apr '05Published in: Journal of Biological Chemistry


Smads, key effectors of transforming growth factor (TGF)-beta, activin, and bone morphogenetic protein (BMP) signaling, regulate gene expression and interact with coactivators and corepressors that modulate Smad activity. The corepressor Evi-1 exerts its oncogenic effects by repressing TGF-beta/Smad3-mediated transcription, thereby blocking TGF-beta-induced growth arrest. Because Evi-1 interacts with the highly conserved MH2 domain of Smad3, we investigated the physical and functional interaction of Evi-1 with Smad1 and Smad2, downstream targets of BMP and activin signaling, respectively. Evi-1 interacted with and repressed the receptor-activated transcription through Smad1 and Smad2, similarly to Smad3. In addition, Evi-1 repressed BMP/Smad1- and activin/Smad2-mediated induction of endogenous Xenopus gene expression, suggesting a role of repression of BMP and activin signals by Evi-1 in vertebrate embryogenesis. Evi-1 also repressed the induction of endogenous Smad7 expression by TGF-beta family ligands. In the course of these studies, we observed Evi-1 repression of Smad transactivation even when Smad binding to DNA was kept constant. We therefore explored the mechanism of Evi-1 repression of TGF-beta family-inducible transcription. Evi-1 repression did not result from displacement of Smad binding to DNA or to CREB-binding protein but from the recruitment of Evi-1 by Smad3 and CREB-binding protein to DNA. Following TGF-beta stimulation, Evi-1 and the associated corepressor CtBP were recruited to the endogenous Smad7 promoter. Evi-1 recruitment to the promoter decreased TGF-beta-induced histone acetylation, coincident with its repression of Smad7 gene expression. In this way, Evi-1 acts as a general Smad corepressor to inhibit TGF-beta-, activin-, and BMP-inducible transcription.