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J. Biol. Chem. 275 (46): 36295-36302

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Critical Role of Smads and AP-1 Complex in Transforming Growth Factor-β-dependent Apoptosis*

Yasuko Yamamura{ddagger}§, Xianxin Hua{ddagger}||, Svetlana Bergelson{ddagger}, , and Harvey F. Lodish{ddagger}**

From the {ddagger}Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, the **Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and the §Department of Retroviral Regulation, Tokyo Medical and Dental University Medical Research Division, Tokyo 113-8519, Japan

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Abstract: Transforming growth factor-β1 (TGF-β1) 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-β1-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-β1 signaling for apoptosis. Overexpression of a dominant-negative Smad3 mutant or Smad7, both of which impair Smad-mediated signal transduction, inhibits TGF-β1-dependent apoptosis. Only the JunD·FosB form of the AP-1 complex is markedly activated during TGF-β1-dependent apoptosis. FosB substantially enhances Smad3·Smad4-dependent transcription, and dominant-negative FosB blocks TGF-β1-dependent apoptosis but not growth inhibition. Expression of JunD·FosB enhances induction of apoptosis by TGF-β1. 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-β1-dependent apoptosis.


Received for publication July 8, 2000. Revision received August 6, 2000.

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