Suppression of Ras-induced apoptosis by the Rac GTPase.
Ras is an essential component of signal transduction pathways that control cell proliferation, differentiation, and survival. In this study we have examined the cellular responses to high-intensity Ras signaling. Expression of increasing amounts of the oncogenic form of human HRas, HRasV12, results in a dose-dependent induction of apoptosis in both primary and immortalized cells. The induction of apoptosis by HRasV12 is blocked by activated Rac and potentiated by dominant interfering Rac. The ability of Rac to suppress Ras-induced apoptosis is dependent on effector pathway(s) controlled by the insert region and is linked to the activation of NF-kappaB. The apoptotic effect of HRasV12 requires the activation of both the ERK and JNK mitogen-activated protein kinase cascade and is independent of p53. These results demonstrate a role for Rac in controlling signals that are necessary for cell survival, and suggest a mechanism by which Rac activity can confer growth advantage to cells transformed by the ras oncogene.
Joneson
T
T
Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794-5222, USA.
Bar-Sagi
D
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins; D015870:Gene Expression; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; D006133:Growth Substances; D016328:NF-kappa B; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D020703:ras GTPase-Activating Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein; D018631:ras Proteins