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J. Biol. Chem., Vol. 280, Issue 48, 39795-39801, December 2, 2005

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TIS7 Regulation of the -Catenin/Tcf-4 Target Gene Osteopontin (OPN) Is Histone Deacetylase-dependent^*

Ilja Vietor, Robert Kurzbauer, Gerald Brosch¶, and Lukas A. Huber1

From the Biocenter, Division of Cell Biology, Medical University Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria, the Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria, and the ^¶Biocenter, Division of Molecular Biology, Medical University Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria

12-O-Tetradecanoylphorbol-13-acetate-induced sequence 7 (TIS7) acts as a transcriptional co-repressor interacting with SIN3, the histone deacetylase-containing complex. The overexpression of TIS7 down-regulates expression of a specific set of genes. Homozygous deletion of this gene in mice delays injury-induced muscle regeneration and inhibits muscle satellite cell differentiation and fusion of myoblasts in vitro. Osteopontin (OPN), a known -catenin/T cell factor-4 (Tcf-4) downstream target gene, is up-regulated in tumors and in cells with increased motility such as muscle cells. OPN promoter sequence contains binding sites for Sp1, glucocorticoid receptor, E-box-binding factors, octamer motif-binding protein, c-Myc, and other transcription factors. Previously we have shown that TIS7 regulates the OPN expression through the inhibition of the Sp1-activating effects. Here we show that TIS7 has the capacity to inhibit OPN expression also through Lef-1, the second identified OPN regulatory element. TIS7 has the capacity to down-regulate -catenin/Tcf-4 transcriptional activity. TIS7 homologous deletion in mouse embryonic fibroblasts increased not only the TOPflash reporter gene transcriptional activity but also the expression of c-Myc and OPN. Furthermore, we show that TIS7 overexpression leads to the -catenin interaction with enzymatically active histone deacetylases. We propose that TIS7 down-regulates the -catenin/Tcf-4 transcriptional activity via its interaction with histone deacetylase-containing complex thereby inhibiting the expression of -catenin downstream target genes such as c-Myc and OPN. We hypothesize that TIS7 as a negative regulator of transcriptional activity represses expression of OPN and -catenin/Tcf-4 target genes, which are involved in myogenesis, muscle maintenance, and regeneration in a histone deacetylase dependent manner.

Received for publication, September 7, 2005

^* This work was supported by the Jubiläumsfond of the Austrian National Bank Grant (no. 10224). Work in the Huber laboratory was supported by the Austrian Proteomics Platform (APP) within the Austrian Genome Program (GEN-AU), Vienna, Austria and the Special Research Program "Cell Proliferation and Cell Death in Tumors" (SFB021, Austrian Science Fund). 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 supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 43-512-507-3350; Fax: 43-512-507-9880; E-mail: Lukas.A.Huber{at}uibk.ac.at.

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