Y. Yamamura et al., Critical role of Smads and AP-1 complex in transforming growth factor-beta-dependent apoptosis, J BIOL CHEM, 275(46), 2000, pp. 36295-36302
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.