SYNERGISTIC COOPERATION OF TFE3 AND SMAD PROTEINS IN TGF-BETA-INDUCEDTRANSCRIPTION OF THE PLASMINOGEN-ACTIVATOR INHIBITOR-1 GENE

Members of the TGF-beta superfamily influence a broad range of biologi cal activities including stimulation of wound healing and inhibition o f cell growth. TGF-beta signals through type I and II receptor serine/ threonine kinases and induces transcription of many genes including pl asminogen activator inhibitor-1 (PAI-1). To identify proteins that par ticipate in TGF-beta-induced gene expression, we developed a novel ret rovirus-mediated expression cloning strategy; and using this approach, we established that transcription factor mu E3 (TFE3) is involved in TGF-beta-induced activation of the PAI-1 promoter. We showed that TEE3 binds to an E-box sequence in PE2, a 56-bp promoter fragment of the P AI-1 promoter, and that mutation of this sequence abolishes both TFE3 binding as well as TGF-beta-dependent activation. TFE3 and Smad3 syner gistically activate the PE2 promoter and phosphorylated Smad3 and Smad 4 bind to a sequence adjacent to the TFE3-binding site in this promote r. Binding of both TFE3 and the Smad proteins to their cognate sequenc es is indispensable for TGF-beta-inducible activation of the PE2 promo ter. Hence, TFE3 is an important transcription factor in at least one TGF-beta-activated signal transduction pathway.