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.
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.
Hua
X
X
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Miller
Z A
ZA
Wu
G
G
Shi
Y
Y
Lodish
H F
HF
D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C069203:TFE3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA