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J. Biol. Chem., Vol. 281, Issue 29, 20357-20367, July 21, 2006

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Smad6 Represses Dlx3 Transcriptional Activity through Inhibition of DNA Binding^*

From the Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853

Dlx3 (Distal-less 3) is a homeobox-containing transcription factor required for normal placental development in mice. Here we demonstrate that Dlx3 interacts with Smad6, a member of a larger family of transcriptional regulators generally thought to regulate transforming growth factor /bone morphogenetic protein signaling. Immunocytochemical and immunoprecipitation studies demonstrate overlapping nuclear localization and physical interaction between Dlx3 and Smad6 in human choriocarcinoma cells and in differentiated trophoblasts from human placenta. In vitro protein interaction studies mapped the Smad6 interaction domain within Dlx3 to residues 80-163, a region of Dlx3 that includes a portion of the homeodomain. Dlx3 and Dlx4 share homology within this region, and Dlx4 was also found to bind Smad6. Using the Esx1 gene promoter as a model for a Dlx3-responsive gene, studies demonstrate two near consensus Dlx3 binding sites within the proximal 2.3 kb of the transcription start site. Interestingly, binding of Dlx3 to one of these two sites was inhibited by interaction with Smad6. Consistent with this result, expression of an Esx1 promoter luciferase reporter was increased by overexpression of Dlx3; this effect was reversed with co-expression of Smad6. Further, small interference RNA-mediated knockdown of endogenous Smad6 increased Dlx3-dependent expression of the Esx1 gene promoter. Thus, Smad6 appears to functionally interact with Dlx3, altering the ability of Dlx3 to bind target gene promoters. Smad6 appears to play a modulatory role in the regulation of Dlx3-dependent gene transcription within placental trophoblasts.

Received for publication, March 30, 2006 , and in revised form, May 8, 2006.

^* This work was supported by NICHD, National Institutes of Health, Grant R01 HD 39354 (to M. S. R.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: T3-004d Veterinary Research Tower, Dept. of Biomedical Sciences, Cornell University, Ithaca, NY 14853. Tel.: 607-253-3469; Fax: 607-253-3851; E-mail: msr14{at}cornell.edu.

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