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J. Biol. Chem., Vol. 283, Issue 38, 25988-25999, September 19, 2008

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Silencing Mediator for Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Attenuate Transcriptional Activation by the β-Catenin-TCF4 Complex^*

From the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032

β-Catenin is a multifunctional mediator of cellular signaling and an oncogene. Nuclear β-catenin, when complexed with members of the T-cell factor (TCF)/leukocyte enhancer factor family of DNA-binding proteins, mediates transcriptional activation important for embryonic development and adult cell homeostasis. Deregulation of intracellular levels of β-catenin is an early event in the development of a variety of cancers. We observed that the proteins silencing mediator for retinoid and thyroid hormone receptor (SMRT) and the nuclear receptor corepressor (NCoR) are negative regulators of transcription induced by the β-catenin-TCF4 complex. Overexpression of SMRT and NCoR attenuated the transcription of β-catenin-TCF4-specific reporter gene and of CCND1, an endogenous β-catenin target gene. Knockdown of endogenous SMRT or NCoR by short interfering RNA augmented the β-catenin-TCF4-mediated reporter gene expression. Glutathione S-transferase pulldown experiments showed there was a direct physical association of SMRT and NCoR with both β-catenin and TCF4. DNA-protein interaction studies revealed that the interactions between either SMRT or NCoR and β-catenin or TCF4 occurred at the promoter regions of CCND1 and other target genes. These findings demonstrate an important role for corepressors SMRT and NCoR in the regulation of β-catenin-TCF4-mediated gene transcription.

Received for publication, January 14, 2008 , and in revised form, May 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA96854 from the USPHS (to E. P. G.). 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center MHB 6N-435, New York, NY 10032. Tel.: 212-305-8602; Fax: 212-305-3035; E-mail: gelmanne{at}columbia.edu.

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