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Papers In Press, published online ahead of print August 4, 2006
Pharmacology, Pennsylvania State College of Medicine, Hershey, PA 17033
Corresponding Author: kmm15{at}psu.edu
Since increased TGF
J. Biol. Chem, 10.1074/jbc.M600579200
Submitted on January 19, 2006
Revised on August 2, 2006
Accepted on August 4, 2006
Requirement of Smad3 and CREB-1 in mediating TGF
induction of TGF3 secretion
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 (J. Biol. Chem. 275, 30765-30773, 2000). In order 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. 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. EMSA supershift assays indicated that CRE binding protein 1 (CREB1) and Smad3 were the major components present in this TGF-inducible complex. Further, using chromatin immunoprecipitation (ChIP) 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 Jun N-terminal kinase (JNK) and p38 suppressed TGF induction of TGF3 transactivation, while inhibition of extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) had no effect. Small interfering RNA (siRNA)-CREB1 and siRNA-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 TGFRII, JNK, p38, and Smad3, but was independent of PKA, ERK, and Smad4.
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