SMAD4 DPC4 AND SMAD3 MEDIATE TRANSFORMING-GROWTH-FACTOR-BETA (TGF-BETA) SIGNALING THROUGH DIRECT BINDING TO A NOVEL TGF-BETA-RESPONSIVE ELEMENT IN THE HUMAN PLASMINOGEN-ACTIVATOR INHIBITOR-1 PROMOTER/

The transforming growth factor-beta (TGF-beta) family of cytokines med iates multiple biological effects by regulating the expression of targ et genes. The Smad family proteins function as intracellular signal tr ansducers downstream of the receptors to transmit the TGF-beta signal from cell membrane to nucleus. The mechanisms by which Smads mediate t ranscriptional activation of target genes is largely unknown. Here we report the identification of a novel TGF-beta-responsive element in th e human type 1 plasminogen activator inhibitor promoter that is requir ed for mediating strong transcriptional activation of this gene by TGF -beta. Smad3 and Smad4 are incorporated into a TGF-beta inducible comp lex formed on this element following TGF-beta stimulation of human hep atoma cells. Both Smads and Smad4 bind directly to this TGF-beta-respo nsive element through their conserved MH1 domains. These results indic ate that Smad3 and Smad4 mediate TGF-beta signaling by directly intera cting with a specific response element in a physiological target gene.