Specificity in transforming growth factor beta-induced transcription of the plasminogen activator inhibitor-1 gene: interactions of promoter DNA, transcription factor muE3, and Smad proteins

Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13130-5. doi: 10.1073/pnas.96.23.13130.


Transforming growth factor beta (TGF-beta) regulates a broad range of biological processes, including cell growth, development, differentiation, and immunity. TGF-beta signals through its cell surface receptor serine kinases that phosphorylate Smad2 or Smad3 proteins. Because Smad3 and its partner Smad4 bind to only 4-bp Smad binding elements (SBEs) in DNA, a central question is how specificity of TGF-beta-induced transcription is achieved. We show that Smad3 selectively binds to two of the three SBEs in PE2.1, a TGF-beta-inducible fragment of the plasminogen activator inhibitor-1 promoter, to mediate TGF-beta-induced transcription; moreover, a precise 3-bp spacer between one SBE and the E-box, a binding site for transcription factor muE3 (TFE3), is essential for TGF-beta-induced transcription. Whereas an isolated Smad3 MH1 domain binds to TFE3, TGF-beta receptor-mediated phosphorylation of full-length Smad3 enhances its binding to TFE3. Together, these studies elucidate an important mechanism for specificity in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Binding Sites
  • Cell Line
  • DNA / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Phosphorylation
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Promoter Regions, Genetic*
  • Smad3 Protein
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transforming Growth Factor beta / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Plasminogen Activator Inhibitor 1
  • SMAD3 protein, human
  • Smad3 Protein
  • TFE3 protein, human
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • DNA