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Molecular and Cellular Biology, November 2005, p. 10017-10028, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10017-10028.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß-Dependent Sequential Activation of Smad, Bim, and Caspase-9 Mediates Physiological Apoptosis in Gastric Epithelial Cells{dagger}

Masatoshi Ohgushi,1 Shunsuke Kuroki,1 Hiroshi Fukamachi,2 Lorraine A. O'Reilly,3 Keisuke Kuida,4 Andreas Strasser,3 and Shin Yonehara1*

Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan,1 Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan,2 Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 3050 Victoria, Australia,3 Department of Biology, Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 021394

Received 29 April 2005/ Returned for modification 26 June 2005/ Accepted 2 September 2005

Transforming growth factor ß (TGF-ß) has been implicated in the maintenance of homeostasis in various organs, including the gastric epithelium. In particular, TGF-ß-induced signaling was shown to be required for the differentiation-associated physiological apoptosis of gastric epithelial cells, but its mechanism has not been well understood. In this study, the molecular mechanism of TGF-ß-induced apoptosis was analyzed in a human gastric epithelial cell line, SNU16, as an in vitro model. Expression of Smad7 and Bcl-XL, but not viral FLIP, was shown to prevent TGF-ß-induced apoptosis, indicating an exclusive requirement of the activation of Smad signaling pathway and mitochondrial dysfunction followed by activation of caspase-9. In addition, treatment with TGF-ß induced binding of Bim, a proapoptotic Bcl-2 homology domain 3 (BH3)-only protein, to Bcl-XL, which is dependent on the activation of Smad, and reduction in the expression of Bim by RNA interference decreased the sensitivity to TGF-ß-induced apoptosis. Moreover, we found abnormalities in the gastric epithelium of both Bim and caspase-9 knockout mice; these abnormalities were associated with a defect of physiological apoptosis in gastric epithelial cells. These results indicate for the first time that TGF-ß is involved in the physiological loss of gastric epithelial cells by activating apoptosis mediated by Smad, Bim, and caspase-9.

* Corresponding author. Mailing address: Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, SCRB/Building G, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81 75 753 9234. Fax: 81 75 753 9235. E-mail: yonehara{at}lif.kyoto-u.ac.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2005, p. 10017-10028, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10017-10028.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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