Transforming growth factor beta-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells

Ohgushi, M; Kuroki, S; Fukamachi, H; O&#39;Reilly, LA; Kuida, K; Strasser, A; Yonehara, S

Author(s): Ohgushi, M; Kuroki, S; Fukamachi, H; O'Reilly, LA; Kuida, K; Strasser, A; Yonehara, S;
Details: Publication Year 2005-11,Volume 25,Issue #22,Page 10017-10028
Journal Title: MOLECULAR AND CELLULAR BIOLOGY
Publication Type: Journal Article
Abstract: Transforming growth factor beta (TGF-beta) has been implicated in the maintenance of homeostasis in various organs, including the gastric epithelium. In particular, TGF-beta-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-beta-induced apoptosis was analyzed in a human gastric epithelial cell line, SNU16, as an in vitro model. Expression of Smad7 and Bcl-X-L, but not viral FLIP, was shown to prevent TGF-beta-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-beta induced binding of Bim, a proapoptotic Bcl-2 homology domain 3 (BH3)-only protein, to Bcl-X-L which is dependent on the activation of Smad, and reduction in the expression of Bim by RNA interference decreased the sensitivity to TGF-beta-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-beta is involved in the physiological loss of gastric epithelial cells by activating apoptosis mediated by Smad, Bim, and caspase-9.
Publisher: AMER SOC MICROBIOLOGY
Keywords: BCL-2 FAMILY-MEMBER; BH3-ONLY PROTEIN BIM; TGF-BETA; CANCER CELLS; RECEPTOR GENE; EXPRESSION; DEATH; MICE; MECHANISMS; TGF-BETA-1
Publisher's Version: https://doi.org/10.1128/MCB.25.22.10017-10028.2005
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Creation Date: 2005-11-01 12:00:00