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J. Biol. Chem., Vol. 281, Issue 40, 29479-29490, October 6, 2006

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Requirement of Smad3 and CREB-1 in Mediating Transforming Growth Factor- (TGF) Induction of TGF3 Secretion^*

From the Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania 17033

Because increased transforming growth factor- (TGF) production by tumor cells contributes to cancer progression through paracrine mechanisms, identification of critical points that can be targeted to block TGF production is important. Previous studies have identified the precise signaling components and promoter elements required for TGF induction of TGF1 expression in epithelial cells (Yue, J., and Mulder, K. M. (2000) J. Biol. Chem. 275, 30765–30773). To determine how regulation of TGF3 expression differs from that of TGF1, we identified the precise signaling pathways and transcription factor-binding sites that are required for TGF3 gene expression. By using mutational analysis in electrophoresis mobility shift assays (EMSAs), we demonstrated that the c-AMP-responsive element (CRE) site in the TGF3 promoter was required for TGF-inducible TGF3 expression. Electrophoresis mobility supershift assays indicated that CRE-binding protein 1 (CREB1) and Smad3 were the major components present in this TGF-inducible complex. Furthermore, by using chromatin immunoprecipitation assays, we demonstrated that CREB-1, ATF-2, and c-Jun bound constitutively at the TGF3 promoter (–100 to +1), whereas Smad3 bound at this site only after TGF stimulation. In addition, inhibition of JNK and p38 suppressed TGF induction of TGF3 transactivation, whereas inhibition of ERK and protein kinase A had no effect. Small interfering RNA-CREB1 and small interfering RNA-Smad3 significantly inhibited TGF stimulation of TGF3 promoter reporter activity and TGF3 production. Our results indicate that TGF activation of the TGF3 promoter CRE site, which leads to TGF3 production, is required for TGFRII, JNK, p38, and Smad3 but was independent of protein kinase A, ERK, and Smad4.

Received for publication, January 19, 2006 , and in revised form, August 2, 2006.

^* This work was supported by National Institutes of Health Grants CA90765, CA92889, and CA100239 and Department of Defense Award DAMD17-03-1-0287 (to K. M. M.). 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: Dept. of Pharmacology, Penn State College of Medicine, 500 University Dr., Hershey, PA 17033. Tel.: 717-531-6789; Fax: 717-531-5013; E-mail: kmm15{at}psu.edu.

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