Critical role of Smads and AP-1 complex in transforming growth factor-beta-dependent apoptosis

Transforming growth factor-beta1 (TGF-beta1) induces not only cell growth i nhibition but also apoptosis in hepatocytes, myeloid cells, and epithelial cells. Although Smad proteins are identified as key signal transducers in T GF-beta1 dependent growth inhibition, their roles in the induction of apopt osis are unclear. We show here that both Smad proteins and AP-1 complex are involved in TGF-beta1 signaling for apoptosis. Overexpression of a dominan t-negative Smad3 mutant or Smad7, both of which impair Smad-mediated signal transduction, inhibits TGF-beta1-dependent apoptosis. Only the JunD-FosB f orm of the AP-1 complex is markedly activated during TGF-beta1-dependent ap optosis, FosB substantially enhances Smad3.Smad4-dependent transcription, a nd dominant-negative FosB blocks TGF-beta1-dependent apoptosis but not grow th inhibition. Expression of JunD.FosB enhances induction of apoptosis by T GF-beta1. Moreover, JunD.FosB binds to the 12-O-tetradecanoyl-13-acetate-re sponsive gene promoter element and recruits Smad3.Smad4 to form a multicomp onent complex. These results suggest that Smad proteins and AP-1 complex sy nergize to mediate TGF-beta1-dependent apoptosis.