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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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BH3 Interacting Domain Death Agonist Protein / metabolism
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Bone Density Conservation Agents / pharmacology
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CRADD Signaling Adaptor Protein
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Carrier Proteins
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Caspase 2 / physiology*
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Cells, Cultured
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Colony-Forming Units Assay
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Cytochromes c / metabolism
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Cytoskeleton / metabolism*
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Death Domain Receptor Signaling Adaptor Proteins
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Diphosphonates / pharmacology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Imidazoles / pharmacology
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Immunoblotting
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Immunoenzyme Techniques
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / drug effects
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Mitochondria / metabolism
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Zoledronic Acid
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bcl-2-Associated X Protein / metabolism
Substances
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BH3 Interacting Domain Death Agonist Protein
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Bax protein, mouse
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Bid protein, mouse
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Bone Density Conservation Agents
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CRADD Signaling Adaptor Protein
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Carrier Proteins
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Cradd protein, mouse
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Death Domain Receptor Signaling Adaptor Proteins
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Diphosphonates
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Imidazoles
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Pidd1 protein, mouse
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bcl-2-Associated X Protein
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Zoledronic Acid
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Cytochromes c
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Caspase 2