Repression of Bone Morphogenetic Protein and Activin-inducible Transcription by Evi-1

• Published in: The Journal of biological chemistry 2005-06, Vol.280 (25), p.24227-24237
• Main Authors: Alliston, Tamara, Ko, Tien C., Cao, Yanna, Liang, Yao-Yun, Feng, Xin-Hua, Chang, Chenbei, Derynck, Rik
• Format: Article
• Language: English
• Subjects: Acetylation; Activins - physiology; Animals; Bone Morphogenetic Proteins - physiology; Cell Line; CREB-Binding Protein; DNA - metabolism; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Gene Expression Regulation, Developmental - physiology; Histones - metabolism; Humans; MDS1 and EVI1 Complex Locus Protein; Nuclear Proteins - physiology; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein Binding; Proto-Oncogenes - physiology; Smad3 Protein; Trans-Activators - physiology; Transcription Factors - metabolism; Transcription Factors - physiology; Transcription, Genetic - physiology; Transforming Growth Factor beta - physiology; Xenopus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M414305200

Smads, key effectors of transforming growth factor (TGF)-β, 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-β/Smad3-mediated transcription, thereby blocking TGF-β-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-β 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-β 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-β stimulation, Evi-1 and the associated corepressor CtBP were recruited to the endogenous Smad7 promoter. Evi-1 recruitment to the promoter decreased TGF-β-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-β-, activin-, and BMP-inducible transcription.