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 inhibition but also apoptosis in hepatocytes, myeloid cells, and epithelial cells. Although Smad proteins are identified as key signal transducers in TGF-beta1-dependent growth inhibition, their roles in the induction of apoptosis are unclear. We show here that both Smad proteins and AP-1 complex are involved in TGF-beta1 signaling for apoptosis. Overexpression of a dominant-negative Smad3 mutant or Smad7, both of which impair Smad-mediated signal transduction, inhibits TGF-beta1-dependent apoptosis. Only the JunD. FosB form of the AP-1 complex is markedly activated during TGF-beta1-dependent apoptosis. FosB substantially enhances Smad3. Smad4-dependent transcription, and dominant-negative FosB blocks TGF-beta1-dependent apoptosis but not growth inhibition. Expression of JunD.FosB enhances induction of apoptosis by TGF-beta1. Moreover, JunD.FosB binds to the 12-O-tetradecanoyl-13-acetate-responsive gene promoter element and recruits Smad3.Smad4 to form a multicomponent complex. These results suggest that Smad proteins and AP-1 complex synergize to mediate TGF-beta1-dependent apoptosis.
Yamamura
Y
Y
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. yama.mbch@med.tmd.ac.jp
Hua
X
X
Bergelson
S
S
Lodish
H F
HF
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D051900:Smad3 Protein; D051901:Smad4 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C064269:FOSB protein, human; C483819:Fosb protein, mouse; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1