Involvement of a small GTP-binding protein (G protein) regulator, small G protein GDP dissociation stimulator, in antiapoptotic cell survival signaling

Small GTP-binding protein GDP dissociation stimulator (Smg GDS) regulates G DP/GTP exchange reaction of Ki-Ras and the Rho and Rap1 family members and inhibits their binding to membranes. In fibroblasts, Smg GDS shows mitogeni c and transforming activities in cooperation with Ki-Ras. However, the phys iological function of Smg GDS remains unknown. Here we show that mice lacki ng Smg GDS died of heart failure shortly after birth, not resulting from de velopmental heart defects but from enhanced apoptosis of cardiomyocytes tri ggered by cardiovascular overload. Furthermore, neonatal thymocytes and dev eloping neuronal cells underwent apoptotic cell death. Smg GDS-/- thymocyte s were susceptible to apoptotic inducers, such as etoposide and UV irradiat ion. Smg GDS-/- thymocytes were protected from etoposide-induced cell death by ex vivo transduction of the Smg GDS cDNA. These phenotypes partly coinc ide with those observed in Ki-Ras-deficient mice, suggesting that Smg GDS i s involved in antiapoptotic cell survival, signaling through Ki-Ras.