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J. Biol. Chem., Vol. 278, Issue 51, 51673-51684, December 19, 2003

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DACH1 Inhibits Transforming Growth Factor- Signaling through Binding Smad4^*

Kongming Wu, Ying Yang, Chenguang Wang, Maria A. Davoli, Mark D'Amico, Anping Li, Kveta Cveklova, Zbynek Kozmik¶, Michael P. Lisanti||, Robert G. Russell, Ales Cvekl**, and Richard G. Pestell

From the Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, D. C. 20057, the Department of Ophthalmology and Visual Sciences and Molecular Genetics, the ^||Deparment of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, and the ^¶Institute of Molecular Genetics, 166 37 Prague 6, Czech Republic

The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit transforming growth factor- (TGF-)-induced apoptosis. DACH1 repressed TGF- induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF--responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dotlike structures. NCoR enhanced DACH1 repression, and the repression of TGF--induced AP-1 or Smad signaling by DACH1 required the DACH1 DS domain. The DS domain of DACH was sufficient for NCoR binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF- signaling by interacting with NCoR and Smad4.

Received for publication, September 9, 2003 , and in revised form, September 29, 2003.

^* This work was supported in part by Susan Komen Breast Cancer Foundation, Breast Cancer Alliance Inc., Grants R01CA70896, R01CA75503, R01CA86072, and R01CA86071 (to R. G. P.). This work was also supported by National Institutes of Health (NIH) Grant EY12200 (to A. C.) and grants from the Center for Integrated Genomics (to Z. K.). Work conducted at the Lombardi Cancer Center was supported by the NIH Cancer Center Core grant. 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.

The on-line version of this article (available at http://www.jbc.org) contains six additional figures.

^** Supported by a Research to Prevent Blindness Career Development Award and an American Cancer Society Junior Faculty Institutional Award.

Recipient of the Irma T. Hirschl and Weil Caulier award and the Diane Belfer Faculty Scholar in Cancer Research. To whom correspondence should be addressed: Dept. of Oncology, Lombardi Cancer Center, Georgetown University, Research Bldg. Rm. E501, 3970 Reservoir Rd. NW, Box 571468, Washington, D. C. 20057-1468. Tel.: 202-687-2110; Fax: 202-687-6402; E-mail: pestell{at}georgetown.edu.

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