Oxidative stress induces neuronal death by recruiting a protease and phosphatase-gated mechanism.
Reactive oxygen species (ROS) cause death of cerebellar granule neurons. Here, a 15-min pulse of H(2)O(2) (100 microm) induced an active process of neuronal death distinct from apoptosis. Oxidative stress activated a caspase-independent but calpain-dependent decline of calcium/calmodulin-dependent protein kinase IV and cAMP- responsive element-binding protein (CREB). Calpain inhibitors restored calcium/calmodulin-dependent protein kinase IV and CREB but did not influence phosphorylated CREB levels or survival, indicating recruitment of an additional dephosphorylation process. Co-treatment with calpain and serine/threonine phosphatase inhibitors restored pCREB levels and rescued neurons. This phosphatase-activated signaling pathway was shown to be dependent on de novo protein synthesis. Further, gene transfer studies revealed that CREB is a common final effector of both apoptosis and ROS-induced death. Our data indicate that dephosphorylation and proteolytic signaling mechanisms underlie ROS-induced programmed cell death.
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Université Louis Pasteur, Faculty of Medicine, E. A. Molecular Signaling and Neurodegeneration, 11 rue Humann, Strasbourg 67000, France.
Loeffler
J P
JP
D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis; D002154:Calpain / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D009336:Necrosis; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012694:Serine / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D012694:Serine; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002154:Calpain; D020169:Caspases