Specificity in transforming growth factor β-induced transcription of the plasminogen activator inhibitor-1 gene: Interactions of promoter DNA, transcription factor μE3, and Smad proteins
- *Whitehead Institute for Biomedical Research, Cambridge, MA 02142; †Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and ‡Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, NJ 08544
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Contributed by Harvey F. Lodish
Abstract
Transforming growth factor β (TGF-β) regulates a broad range of biological processes, including cell growth, development, differentiation, and immunity. TGF-β 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-β-induced transcription is achieved. We show that Smad3 selectively binds to two of the three SBEs in PE2.1, a TGF-β-inducible fragment of the plasminogen activator inhibitor-1 promoter, to mediate TGF-β-induced transcription; moreover, a precise 3-bp spacer between one SBE and the E-box, a binding site for transcription factor μE3 (TFE3), is essential for TGF-β-induced transcription. Whereas an isolated Smad3 MH1 domain binds to TFE3, TGF-β receptor-mediated phosphorylation of full-length Smad3 enhances its binding to TFE3. Together, these studies elucidate an important mechanism for specificity in TGF-β-induced transcription of the plasminogen activator inhibitor-1 gene.
Footnotes
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↵ § To whom reprint requests should be addressed. E-mail: lodish{at}wi.mit.edu.
- Abbreviations:
- PAI-1,
- plasminogen activator inhibitor-1;
- TFE3,
- transcription factor μE3;
- SBE,
- Smad binding element;
- TGF-β,
- transforming growth factor β;
- GST,
- glutathione S-transferase
- Copyright © 1999, The National Academy of Sciences
