title: Caspase-3 protects stressed organs against cell death.
abstract: The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response.
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Hadi
authors.initials: H
authors.lastname: Khalil
authors.forename: Nieves
authors.initials: N
authors.lastname: Peltzer
authors.forename: Joël
authors.initials: J
authors.lastname: Walicki
authors.forename: Jiang-Yan
authors.initials: JY
authors.lastname: Yang
authors.forename: Gilles
authors.initials: G
authors.lastname: Dubuis
authors.forename: Noémie
authors.initials: N
authors.lastname: Gardiol
authors.forename: Werner
authors.initials: W
authors.lastname: Held
authors.forename: Paul
authors.initials: P
authors.lastname: Bigliardi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Marsland
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D053148:Caspase 3 / Q000172:deficiency / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D016264:Dextran Sulfate; D004317:Doxorubicin; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006439:Hemodynamics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013312:Stress, Physiological; D013471:Sunburn / Q000201:enzymology* / Q000235:genetics; D014466:Ultraviolet Rays; D020729:p120 GTPase Activating Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D020729:p120 GTPase Activating Protein; D004317:Doxorubicin; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt; C505409:Casp3 protein, mouse; D053148:Caspase 3