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J. Biol. Chem., Vol. 283, Issue 7, 3791-3798, February 15, 2008

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Identification of Novel Direct Stat3 Target Genes for Control of Growth and Differentiation^*

From the Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021

Signal transducer and activator of transcription 3 (Stat3) is a key regulator of gene expression in response to signaling of the glycoprotein 130 (gp130) family cytokines, including interleukin 6, oncostatin M, and leukemia inhibitory factor. Many efforts have been made to identify Stat3 target genes and to understand the mechanism of how Stat3 regulates gene expression. Using the microarray technique, hundreds of genes have been documented to be potential Stat3 target genes in different cell types. However, only a small fraction of these genes have been proven to be true direct Stat3 target genes. Here we report the identification of novel direct Stat3 target genes using a genome-wide screening procedure based on the chromatin immunoprecipitation method. These novel Stat3 target genes are involved in a diverse array of biological processes such as oncogenesis, cell growth, and differentiation. We show that Stat3 can act as both a repressor and activator on its direct target genes. We further show that most of the novel Stat3 direct target genes are dependent on Stat3 for their transcriptional regulation. In addition, using a physiological cell system, we demonstrate that Stat3 is required for the transcriptional regulation of two of the newly identified direct Stat3 target genes important for muscle differentiation.

Received for publication, August 20, 2007 , and in revised form, December 6, 2007.

^* This work was supported by American Heart Association Grant 0455896T (to J. J. Z.) and National Institutes of Health Grant AG023202 (to X.-Y. H.). 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 Tables S1–S4.

¹ To whom correspondence should be addressed: Dept. of Physiology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Tel.: 212-746-4614; Fax: 212-746-6226; E-mail: jjz2002{at}med.cornell.edu.

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