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J. Biol. Chem., Vol. 281, Issue 3, 1755-1764, January 20, 2006

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HIC-5 Is a Novel Repressor of Lymphoid Enhancer Factor/T-cell Factor-driven Transcription^*

From the Zoologisches Institut II, Universität Karlsruhe (Technische Hochschule), Kaiserstrasse 12, 76131 Karlsruhe, Germany

Activation of Wnt/-catenin target genes is regulated by a heterodimer of -catenin and the high mobility group box transcription factors of the lymphoid enhancer factor (LEF)/T-cell factor (TCF) family. In vertebrates, four LEF/TCF family members have been identified. They all contain a conserved -catenin-binding motif at the N terminus and a highly conserved high mobility group box for DNA binding. The core sequence between these motifs is less conserved and contributes to the specific properties of the individual family members. To identify interacting proteins that allocate specific functions to the individual LEF/TCF transcription factors, we performed a yeast two-hybrid screen using the less conserved core sequence as bait. We isolated the murine LIM protein HIC-5 (hydrogen peroxide-induced clone 5; also termed ARA-55 (androgen receptor activator of 55 kDa)) and cloned the highly conserved Xenopus homolog. In addition, we report that the LIM domain-containing C-terminal half of HIC-5 binds to a conserved alternatively spliced exon in LEF/TCF transcription factors. Our functional analyses revealed that HIC-5 acts as negative regulator of a subset of LEF/TCF family members, which have been characterized as activators in reporter gene analyses and in the Xenopus axis induction assay. In addition, we observed a repressive interference of LEF/TCF family members with HIC-5-mediated activation of glucocorticoid-driven transcription, which again could be allocated to specific LEF/TCF subtypes. With the characterization of HIC-5 as a binding partner of the alternatively spliced exon in LEF/TCF transcription factors, we identified a novel molecular mechanism in the dialog of steroid and canonical Wnt signaling that is LEF/TCF subtype-dependent.

Received for publication, May 31, 2005 , and in revised form, October 11, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY971603 [GenBank] .

^* This work was supported by Deutsche Forschungsgemeinschaft Grant DG 1802. 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.: 49-721-608-3988; Fax: 49-721-608-3992; E-mail: dietmar.gradl{at}zi2.uni-karlsruhe.de.

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