Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Cell Division / drug effects
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Cell Line
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Genes, Reporter
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Humans
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Mice
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Mutation / genetics
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Nuclear Proteins / analysis
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Protein Binding
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Proto-Oncogene Proteins c-fos*
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Response Elements / genetics
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Smad3 Protein
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Smad4 Protein
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Smad7 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factor AP-1 / metabolism*
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Transcriptional Activation / drug effects
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Transfection
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
Substances
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Bacterial Proteins
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DNA-Binding Proteins
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FOSB protein, human
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Fosb protein, mouse
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Nuclear Proteins
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Proto-Oncogene Proteins c-fos
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Proto-Oncogene Proteins c-jun
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SMAD3 protein, human
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SMAD4 protein, human
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SMAD7 protein, human
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Smad3 Protein
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Smad3 protein, mouse
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Smad4 Protein
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Smad4 protein, mouse
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Smad7 Protein
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Smad7 protein, mouse
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Trans-Activators
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Transcription Factor AP-1
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Transforming Growth Factor beta
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Transforming Growth Factor beta1