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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-beta -dependent Apoptosis*

Yasuko YamamuraDagger §, Xianxin HuaDagger ||, Svetlana BergelsonDagger , and Harvey F. LodishDagger **

From the Dagger  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

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

* This work was supported in part by National Institutes of Health Grant CA63260 (to H. F. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the Research Training Program of the National Cancer Institute of the United States of America and the Japanese Foundation for Cancer Research of Japan. To whom correspondence should be addressed: Dept. of Retroviral Regulation, Tokyo Medical and Dental University Medical Research Division, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Tel.: 81-3-5803-5161; Fax: 81-3-3814-7172; E-mail: yama.mbch@med.tmd.ac.jp.

|| Recipient of the Howard Temin Award and Burroughs Wellcome Career Development Award.

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

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