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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- ROS:
-
reactive oxygen species
- Casp2:
-
caspase-2
- FoxO:
-
forkhead box class O
- GSH-Px:
-
glutathione peroxidase
- MEF:
-
murine embryonic fibroblast
- 8-OHdG:
-
8-hydroxydeoxyguanosine
- Sesn:
-
sestrins
- SOD:
-
superoxide dismutase
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labelling
References
Kumar S . Caspase function in programmed cell death. Cell Death Differ 2007; 14: 32–43.
Kumar S . Caspase 2 in apoptosis, the DNA damage response and tumour suppression: enigma no more? Nat Rev Cancer 2009; 9: 897–903.
Kumar S, Kinoshita M, Noda M, Copeland NG, Jenkins NA . Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1 beta-converting enzyme. Genes Dev 1994; 8: 1613–1626.
Kumar S, Tomooka Y, Noda M . Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem Biophys Res Commun 1992; 185: 1155–1161.
Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A et al. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 1998; 12: 1304–1314.
O’Reilly LA, Ekert P, Harvey N, Marsden V, Cullen L, Vaux DL et al. Caspase-2 is not required for thymocyte or neuronal apoptosis even though cleavage of caspase-2 is dependent on both Apaf-1 and caspase-9. Cell Death Differ 2002; 9: 832–841.
Zhang Y, Padalecki SS, Chaudhuri AR, De Waal E, Goins BA, Grubbs B et al. Caspase-2 deficiency enhances aging-related traits in mice. Mech Ageing Dev 2007; 128: 213–221.
Ho LH, Taylor R, Dorstyn L, Cakouros D, Bouillet P, Kumar S . A tumor suppressor function for caspase-2. Proc Natl Acad Sci USA 2009; 106: 5336–5341.
Hoeijmakers JH . DNA damage, aging, and cancer. N Engl J Med 2009; 361: 1475–1485.
Kohen R, Nyska A . Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 2002; 30: 620–650.
Kenyon CJ . The genetics of ageing. Nature 2010; 464: 504–512.
Oliver TG, Meylan E, Chang GP, Xue W, Burke JR, Humpton TJ et al. Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell 2011; 43: 57–71.
Budanov AV . Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid Redox Signal 2011; 15: 1679–1690.
Greer EL, Brunet A . FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410–7425.
Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007; 6: 472–483.
Bouchard C, Lee S, Paulus-Hock V, Loddenkemper C, Eilers M, Schmitt CA . FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 2007; 21: 2775–2787.
Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 2008; 14: 458–470.
Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128: 325–339.
Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ . ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 2001; 276: 42462–42467.
Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T . DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 2009; 8: 311–323.
Kenyon J, Gerson SL . The role of DNA damage repair in aging of adult stem cells. Nucleic Acids Res 2007; 35: 7557–7565.
de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H et al. Premature aging in mice deficient in DNA repair and transcription. Science 2002; 296: 1276–1279.
Burtner CR, Kennedy BK . Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 2010; 11: 567–578.
Hinkal GW, Gatza CE, Parikh N, Donehower LA . Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging. Mech Ageing Dev 2009; 130: 262–271.
Rodier F, Campisi J, Bhaumik D . Two faces of p53: aging and tumor suppression. Nucleic Acids Res 2007; 35: 7475–7484.
Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM . The antioxidant function of the p53 tumor suppressor. Nat Med 2005; 11: 1306–1313.
van der Horst A, Burgering BM . Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 2007; 8: 440–450.
Kopnin PB, Agapova LS, Kopnin BP, Chumakov PM . Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability. Cancer Res 2007; 67: 4671–4678.
Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA et al. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 2010; 327: 1223–1228.
Nutt LK, Buchakjian MR, Gan E, Darbandi R, Yoon SY, Wu JQ et al. Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2. Dev Cell 2009; 16: 856–866.
Andersen JL, Thompson JW, Lindblom KR, Johnson ES, Yang CS, Lilley LR et al. A biotin switch-based proteomics approach identifies 14-3-3zeta as a target of sirt1 in the metabolic regulation of caspase-2. Mol Cell 2011; 43: 834–842.
Ho LH, Read SH, Dorstyn L, Lambrusco L, Kumar S . Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene 2008; 27: 3393–3404.
Lowe SW, Ruley HE, Jacks T, Housman DE . p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74: 957–967.
Acknowledgements
We thank David Vaux for caspase-2 knockout mice, Andreas Villunger for SV40 immortalized MEFs, David Huang for advice, Nancy Briggs (University of Adelaide) for statistical advice and staff at the SA Pathology animal facility for help in maintaining the mouse strains. This work was supported by the National Health and Medical Research Council of Australia project Grants (626905 and APP1021456) and a Senior Principal Research Fellowship (1002863) to SK.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Edited by G Melino
Supplementary Information accompanies the paper on Cell Death and Differentiation website
Rights and permissions
About this article
Cite this article
Shalini, S., Dorstyn, L., Wilson, C. et al. Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice. Cell Death Differ 19, 1370–1380 (2012). https://doi.org/10.1038/cdd.2012.13
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/cdd.2012.13
Keywords
This article is cited by
-
Selenium Effects on Oxidative Stress-Induced Calcium Signaling Pathways in Parkinson’s Disease
Indian Journal of Clinical Biochemistry (2022)
-
Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation
Cell Death & Differentiation (2020)
-
Trisomy 21 is Associated with Caspase-2 Upregulation in Cytotrophoblasts at the Maternal-Fetal Interface
Reproductive Sciences (2020)
-
Transcriptome profiling of caspase-2 deficient EμMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling
Cell Death & Disease (2019)
-
A caspase-2-RFXANK interaction and its implication for MHC class II expression
Cell Death & Disease (2018)
