title: Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice.
abstract: Caspase-2 has been implicated in apoptosis and in non-apoptotic processes such as cell cycle regulation, tumor suppression and ageing. Using caspase-2 knockout (casp2(-/-)) mice, we show here that the putative anti-ageing role of this caspase is due in part to its involvement in the stress response pathway. The old casp2(-/-) mice show increased cellular levels of oxidized proteins, lipid peroxides and DNA damage, suggesting enhanced oxidative stress. Furthermore, murine embryonic fibroblasts from casp2(-/-) mice showed increased reactive oxygen species generation when challenged with pro-oxidants. Reduced activities of antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were observed in the old casp2(-/-) mice. Interestingly, in the old casp2(-/-) animals expression of FoxO1 and FoxO3a was significantly reduced, whereas p21 levels and the number of senescent hepatocytes were elevated. In contrast to young wild-type mice, the casp2(-/-) animals fed an on ethanol-based diet failed to show enhanced GSH-Px and SOD activities. Thus, caspase-2, most likely via FoxO transcription factors, regulates the oxidative stress response in vivo.
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Shalini
authors.forename: L
authors.initials: L
authors.lastname: Dorstyn
authors.forename: C
authors.initials: C
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: Puccini
authors.forename: L
authors.initials: L
authors.lastname: Ho
authors.forename: S
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000367:Age Factors; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D053143:Caspase 2 / Q000172:deficiency* / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D004249:DNA Damage; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D005979:Glutathione Peroxidase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000975:Antioxidants; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C090208:Casp2 protein, mouse; D053143:Caspase 2