Smad2 and Smad3 positively and negatively regulate TGF beta-dependent transcription through the forkhead DNA-binding protein FAST2.
We identify a mammalian forkhead domain protein, FAST2, that is required for induction of the goosecoid (gsc) promoter by TGF beta or activin signaling. FAST2 binds to a sequence in the gsc promoter, but efficient transcriptional activation and assembly of a DNA-binding complex of FAST2, Smad2, and Smad4 requires an adjacent Smad4 site. Smad3 is closely related to Smad2 but suppresses activation of the gsc promoter. Inhibitory activity is conferred by the MH1 domain, which unlike that of Smad2, binds to the Smad4 site. Through competition for this shared site, Smad3 may prevent transcription by altering the conformation of the DNA-binding complex. Thus, we describe a mechanism whereby Smad2 and Smad3 positively and negatively regulate a TGF beta/activin target gene.
Department of Anatomy and Cell Biology, University of Toronto, Ontario, Canada.
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Labbé
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Silvestri
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Hoodless
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Wrana
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Attisano
D028341:Activins; D000595:Amino Acid Sequence; D000818:Animals; D004274:DNA, Recombinant / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000502:physiology*; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000502:physiology*; D051956:Goosecoid Protein; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007265:Inhibins / Q000502:physiology; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry; D014158:Transcription, Genetic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000235:genetics
D004274:DNA, Recombinant; D004268:DNA-Binding Proteins; C102067:FOXH1 protein, Xenopus; C510350:FOXH1 protein, human; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; C497992:GSC protein, human; D051956:Goosecoid Protein; C497993:Gsc protein, mouse; D018398:Homeodomain Proteins; D046911:Macromolecular Substances; D012097:Repressor Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D028341:Activins; D007265:Inhibins