Vol. 11, Issue 5, 1875-1886, May 2000

Involvement of a Small GTP-binding Protein (G Protein) Regulator, Small G Protein GDP Dissociation Stimulator, in Antiapoptotic Cell Survival Signaling

Ayumi Takakura,^* Jun Miyoshi,^* Hiroyoshi Ishizaki,^* Miki Tanaka,^* Atsushi Togawa,^* Yasuko Nishizawa, Hisahiro Yoshida, Shin-ichi Nishikawa, and Yoshimi Takai^*§

 ^*Takai Biotimer Project, Exploratory Research in Advanced Technology, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals, Kobe 651-2241, Japan;  Department of Experimental Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan;  Department of Molecular Genetics, Faculty of Medicine, Kyoto University, Kyoto 606-8502, Japan; and  ^§Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Osaka 565-0871, Japan

Small GTP-binding protein GDP dissociation stimulator (Smg GDS) regulates GDP/GTP exchange reaction of Ki-Ras and the Rho and Rap1 family members and inhibits their binding to membranes. In fibroblasts, Smg GDS shows mitogenic and transforming activities in cooperation with Ki-Ras. However, the physiological function of Smg GDS remains unknown. Here we show that mice lacking Smg GDS died of heart failure shortly after birth, not resulting from developmental heart defects but from enhanced apoptosis of cardiomyocytes triggered by cardiovascular overload. Furthermore, neonatal thymocytes and developing neuronal cells underwent apoptotic cell death. Smg GDS/ thymocytes were susceptible to apoptotic inducers, such as etoposide and UV irradiation. Smg GDS/ thymocytes were protected from etoposide-induced cell death by ex vivo transduction of the Smg GDS cDNA. These phenotypes partly coincide with those observed in Ki-Ras-deficient mice, suggesting that Smg GDS is involved in antiapoptotic cell survival signaling through Ki-Ras.