Mediator Is a Transducer of Wnt/β-Catenin Signaling*
- ‡Department of Molecular Medicine and the Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245-3207 and the §Institut für Molekulare Medizin und Zellforschung, Universität Freiburg, D-79104 Freiburg, Germany
- 1 To whom correspondence should be addressed: Dept. of Molecular Medicine, University of Texas Health Science Center, 15355 Lambda Dr., San Antonio, TX 78245-3207. Tel.: 210-567-7258; Fax: 210-567-7247; E-mail: boyer{at}uthscsa.edu.
Abstract
Signal transduction within the canonical Wnt/β-catenin pathway drives development and carcinogenesis through programmed or unprogrammed changes in gene transcription. Although the upstream events linked to signal-induced activation of β-catenin in the cytoplasm have been deciphered in considerable detail, much less is known regarding the mechanism by which β-catenin stimulates target gene transcription in the nucleus. Here, we show that β-catenin physically and functionally targets the MED12 subunit in Mediator to activate transcription. The β-catenin transactivation domain bound directly to isolated MED12 and intact Mediator both in vitro and in vivo, and Mediator was recruited to Wnt-responsive genes in a β-catenin-dependent manner. Disruption of the β-catenin/MED12 interaction through dominant-negative interference- or RNA interference-mediated MED12 suppression inhibited β-catenin transactivation in response to Wnt signaling. This study thus identifies the MED12 interface within Mediator as a new component and a potential therapeutic target in the Wnt/β-catenin pathway.
Footnotes
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↵2 The abbreviations used are: TCF, T cell factor; LEF, lymphoid enhancer factor; CBP, cAMP-responsive element-binding protein-binding protein; ChIP, chromatin immunoprecipitation; OPA, opposite paired; RNAi, RNA interference; siRNA, small interfering RNA; GST, glutathione S-transferase; DSP, dithiobis(succinimidyl propionate); RT, reverse transcription; TBEs, TCF-binding elements.
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↵3 A. J. Berk and J. L. Stevens, personal communication.
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↵* This work was supported by Career Development Award DAMD17-02-1-0584 and IDEA Award DAMD17-03-1-0272 from the United States Army Department of Defense Breast Cancer Research Program (to T. G. B.) and by United States Public Health Service Grant CA-098301 from NCI, National Institutes of Health (to T. G. B.). 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.
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- Received March 22, 2006.
- The American Society for Biochemistry and Molecular Biology, Inc.
