Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta

Transcriptional regulation by transforming growth factor beta (TGF-beta) is a complex process which is likely to involve cross talk between different DNA responsive elements and transcription factors to achieve maximal promot er activation and specificity. Here, me describe a concurrent requirement f or two discrete responsive elements in the regulation of the c-Jun promoter , one a binding site for a Smad3-Smad4 complex and the other an AP-1 bindin g site. The two elements are located 120 bp apart in the proximal c-Jun pro moter, and each was able to independently bind its corresponding transcript ion factor complex. The effects of independently mutating each of these ele ments were nonadditive; disruption of either sequence resulted in complete or severe reductions in TGF-beta responsiveness. This simultaneous requirem ent for two distinct and independent DNA binding elements suggests that Sma d and AP-1 complexes function synergistically to mediate TGF-beta-induced t ranscriptional activation of the c-Jun promoter.