Caspase-2 is required for cell death induced by cytoskeletal disruption.
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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1Division of Haematology, Hanson Institute, IMVS, Adelaide, Australia.
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Dorstyn
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Lambrusco
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Kumar
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D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D053420:CRADD Signaling Adaptor Protein; D002352:Carrier Proteins; D053143:Caspase 2 / Q000502:physiology*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D045304:Cytochromes c / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004164:Diphosphonates / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000077211:Zoledronic Acid; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D050071:Bone Density Conservation Agents; D053420:CRADD Signaling Adaptor Protein; D002352:Carrier Proteins; C484481:Cradd protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004164:Diphosphonates; D007093:Imidazoles; C414729:Pidd1 protein, mouse; D051028:bcl-2-Associated X Protein; D000077211:Zoledronic Acid; D045304:Cytochromes c; D053143:Caspase 2