Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1.
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.
Alliston
Tamara
T
Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, California 94143-0512, USA.
Ko
Tien C
TC
Cao
Yanna
Y
Liang
Yao-Yun
YY
Feng
Xin-Hua
XH
Chang
Chenbei
C
Derynck
Rik
R
D000107:Acetylation; D028341:Activins / Q000502:physiology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D050882:CREB-Binding Protein; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D009687:Nuclear Proteins / Q000502:physiology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011519:Proto-Oncogenes / Q000502:physiology*; D051900:Smad3 Protein; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014981:Xenopus
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D009687:Nuclear Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D028341:Activins; D004247:DNA; D050882:CREB-Binding Protein; C494363:CREBBP protein, human