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J. Biol. Chem., Vol. 280, Issue 25, 24227-24237, June 24, 2005

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

Tamara Alliston, Tien C. Ko¶, Yanna Cao¶, Yao-Yun Liang||, Xin-Hua Feng||**, Chenbei Chang, and Rik Derynck

From the Departments of Cell and Tissue Biology and Anatomy, University of California at San Francisco, San Francisco, California 94143-0512, the ^¶Department of Surgery, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-0542, the ^||Michael E. DeBakey Department of Surgery, Department of Molecular and Cellular Biology, Biology of Inflammation Center, and Baylor College of Medicine Cancer Center, Baylor College of Medicine, Houston, Texas 77030, and the Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294

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

Received for publication, December 20, 2004 , and in revised form, April 1, 2005.

^* This research was supported by a Hulda Irene Duggan Arthritis Investigator career development award from the Arthritis Foundation (to T. A.) and National Institutes of Health Grants RO1-GM63773 and RO1-CA108454 (to X.-H. F.), RO1-DK60105, P01-DK35608 and K08-CA64191 (to T. C. K.), RO1-HD43345 (to C. C.), and RO1-CA63101 and P60 DE13058 (to R. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** A Leukemia and Lymphoma Society Scholar.

To whom correspondence should be addressed: Dept. of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143-0512. Tel.: 415-476-7322; Fax: 415-502-7338; E-mail: derynck{at}itsa.ucsf.edu.

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