Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene.
Members of the TGF-beta superfamily influence a broad range of biological activities including stimulation of wound healing and inhibition of cell growth. TGF-beta signals through type I and II receptor serine/ threonine kinases and induces transcription of many genes including plasminogen activator inhibitor-1 (PAI-1). To identify proteins that participate in TGF-beta-induced gene expression, we developed a novel retrovirus-mediated expression cloning strategy; and using this approach, we established that transcription factor microE3 (TFE3) is involved in TGF-beta-induced activation of the PAI-1 promoter. We showed that TFE3 binds to an E-box sequence in PE2, a 56-bp promoter fragment of the PAI-1 promoter, and that mutation of this sequence abolishes both TFE3 binding as well as TGF-beta-dependent activation. TFE3 and Smad3 synergistically activate the PE2 promoter and phosphorylated Smad3 and Smad4 bind to a sequence adjacent to the TFE3-binding site in this promoter. Binding of both TFE3 and the Smad proteins to their cognate sequences is indispensable for TGF-beta-inducible activation of the PE2 promoter. Hence, TFE3 is an important transcription factor in at least one TGF-beta-activated signal transduction pathway.
The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
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D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002460:Cell Line; D002999:Clone Cells; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D016350:Leucine Zippers; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012190:Retroviridae; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; C069203:TFE3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA