Abstract
Caspase-2 is one of the most conserved caspases, yet its biological function remains a matter of controversy. In the present article we analysed mouse embryonic fibroblasts (MEFs) from caspase-2 knockout mice for their sensitivity to various apoptosis inducing agents. We found that cell death induced by drugs that disrupt cytoskeleton is significantly inhibited in Casp2−/− MEFs. These drugs included zoledronic acid, vincristine, cytochalasin D and paclitaxel. We demonstrate that MEFs lacking Casp2 show clonogenic survival following drug treatment, whereas all Casp2+/+ MEFs die, indicating that caspase-2 is required for apoptosis induced by cytoskeletal disruption. We further found that caspase-2 mediates apoptosis via Piddosome, Bid and Bax activation, and cytochrome c release. In the absence of caspase-2, Bid and Bax activation, and cytochrome c release are significantly delayed following drug treatment. Our data provide strong support for a context-dependent function of caspase-2 in apoptosis.
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Abbreviations
- Casp2:
-
caspase-2
- cyto D:
-
cytochalasin D
- KO:
-
knockout
- MEFs:
-
mouse embryonic fibroblasts
- MOMP:
-
mitochondrial outer membrane permeabilization
- Pacl:
-
paclitaxel
- Vinc:
-
vincristine
- ZA:
-
zoledronic acid
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Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia and the Cancer Council of South Australia. LD is a Royal Adelaide Hospital Florey Research Fellow.
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Ho, L., Read, S., Dorstyn, L. et al. Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene 27, 3393–3404 (2008). https://doi.org/10.1038/sj.onc.1211005
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DOI: https://doi.org/10.1038/sj.onc.1211005
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