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J. Biol. Chem., Vol. 282, Issue 2, 1225-1237, January 12, 2007

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Wnt-mediated Down-regulation of Sp1 Target Genes by a Transcriptional Repressor Sp5^*

Naoko Fujimura, Tomas Vacik, Ondrej Machon, Cestmir Vlcek, Simone Scalabrin, Martin Speth^¶, Dzung Diep^¶, Stefan Krauss^¶, and Zbynek Kozmik¹

From the Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic, the Department of Mathematics and Computer Science, University of Udine, via delle Scienze 206, I-33100 Udine, Italy, and the ^¶Institute for Microbiology, Rikshospitalet, Gaustadalleen 21, 0349 Oslo, Norway

Wnt/-catenin signaling regulates many processes during vertebrate development. To study transcriptional targets of canonical Wnt signaling, we used the conditional Cre/loxP system in mouse to ectopically activate -catenin during central nervous system development. We show that the activation of Wnt/-catenin signaling in the embryonic mouse telencephalon results in the up-regulation of Sp5 gene, which encodes a member of the Sp1 transcription factor family. A proximal promoter of Sp5 gene is highly evolutionarily conserved and contains five TCF/LEF binding sites that mediate direct regulation of Sp5 expression by canonical Wnt signaling. We provide evidence that Sp5 works as a transcriptional repressor and has three independent repressor domains, called R1, R2, and R3, respectively. Furthermore, we show that the repression activity of R1 domain is mediated through direct interaction with a transcriptional corepressor mSin3a. Finally, our data strongly suggest that Sp5 has the same DNA binding specificity as Sp1 and represses Sp1 target genes such as p21. We conclude that Sp5 transcription factor mediates the downstream responses to Wnt/-catenin signaling by directly repressing Sp1 target genes.

Received for publication, June 19, 2006 , and in revised form, November 6, 2006.

^* This work was supported by the Grant Agency of the Czech Republic (Grant 204/04/1358), the Academy of Sciences of the Czech Republic (Grant AVZ50520514), and The Advanced Research Program of the Norwegian Research Council. 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. Tel.: 420-241-062-146; Fax: 420-241-062-110; E-mail: kozmik{at}img.cas.cz.

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