Published online before print October 13, 2005, doi: 10.1161/01.RES.0000190604.90049.71
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Submitted on April 25, 2005
Revised on September 27, 2005
Accepted on September 30, 2005
Myocardin Enhances Smad3-Mediated Transforming Growth Factor-
1 Signaling in a CArG Box-Independent Manner. Smad-Binding Element Is a Critical cis Element for SM22
Transcription In Vivo
Ping Qiu ;
From the Department of Internal Medicine (P.Q., R.R., Z.F., J.C., L.L.) and Center for Molecular Medicine and Genetics (P.Q., R.R., L.L.), Wayne State University, Detroit, Mich; Carolina Cardiovascular Biology Center (D.C., D.-Z.W.), Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill; Center for Cardiovascular Research in the Aab Institute of Biomedical Sciences (J.M.M.), University of Rochester School of Medicine, New York; and the Molecular Cardiology Research Institute (H.J.L.), Tufts University School of Medicine, Boston, Mass.
* To whom correspondence should be addressed. E-mail: lili{at}med.wayne.edu.
Transforming growth factor (TGF)-
1 is an important cytokine involved in various diseases. However, the molecular mechanism whereby TGF-1 signaling modulates the regulatory network for smooth muscle gene transcription remains largely unknown. To address this question, we previously identified a Smad-binding element (SBE) in the SM22
promoter as one of the TGF-1 response elements. Here, we show that mutation of the SBE greatly diminishes the activation of a SM22 promoter in transgenic mice during embryogenesis. Chromatin immunoprecipitation assays reveal that TGF-1 induces Smad3 binding to the SM22 promoter in vivo. A multimerized SBE promoter responsive to TGF-1 signaling is highly activated by Smad3 but not by the closely related Smad2. Intriguingly, myocardin (Myocd), a known CArG box-dependent serum response factor coactivator, participates in Smad3-mediated TGF-1 signaling and synergistically stimulates Smad3-induced SBE promoter activity independent of the CArG box; no such synergy is seen with Smad2. Importantly, Myocd cooperates with Smad3 to activate the wild-type SM22, SM-myosin heavy chain, and SM-actin promoters; they also activate the CArG box-mutated SM22 promoter as well as the CArG box-independent ACLP promoter. Immunopreciptiation assays reveal that Myocd and Smad3 directly interact both in vitro and in vivo. Mutagenesis studies indicate that the C-terminal transactivation domains of Myocd and Smad3 are required for their functional synergy. These results reveal a novel regulatory mechanism whereby Myocd participates in TGF-1 signal pathway through direct interaction with Smad3, which binds to the SBEs. This is the first demonstration that Myocd can act as a transcriptional coactivator of the smooth muscle regulatory network in a CArG box-independent manner.
Key words: myocardin • SM22
or transgelin •
Smad-binding site (SBE) •
Smad3 •
transforming growth factor-1 •
smooth muscle transcription
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