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Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo.

Transforming growth factor (TGF)-beta1 is an important cytokine involved in various diseases. However, the molecular mechanism whereby TGF-beta1 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 SM22alpha promoter as one of the TGF-beta1 response elements. Here, we show that mutation of the SBE reduces the activation potential of a SM22alpha promoter in transgenic mice during embryogenesis. Chromatin immunoprecipitation assays reveal that TGF-beta1 induces Smad3 binding to the SM22alpha promoter in vivo. A multimerized SBE promoter responsive to TGF-beta1 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-beta1 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 SM22alpha, SM myosin heavy chain, and SMalpha-actin promoters; they also activate the CArG box-mutated SM22alpha promoter as well as the CArG box-independent aortic carboxypeptidase-like protein 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-beta1 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.

Pubmed ID: 16224064


  • Qiu P
  • Ritchie RP
  • Fu Z
  • Cao D
  • Cumming J
  • Miano JM
  • Wang DZ
  • Li HJ
  • Li L


Circulation research

Publication Data

November 11, 2005

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL075251
  • Agency: NHLBI NIH HHS, Id: HL58916
  • Agency: NHLBI NIH HHS, Id: HL62572

Mesh Terms

  • Animals
  • Binding Sites
  • Gene Expression Regulation
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins
  • Muscle Proteins
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Response Elements
  • Serum Response Factor
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators
  • Transcription, Genetic
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1