Caspase-2 is required for cell death induced by cytoskeletal disruption

Oncogene. 2008 May 29;27(24):3393-404. doi: 10.1038/sj.onc.1211005. Epub 2008 Jan 14.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Bone Density Conservation Agents / pharmacology
  • CRADD Signaling Adaptor Protein
  • Carrier Proteins
  • Caspase 2 / physiology*
  • Cells, Cultured
  • Colony-Forming Units Assay
  • Cytochromes c / metabolism
  • Cytoskeleton / metabolism*
  • Death Domain Receptor Signaling Adaptor Proteins
  • Diphosphonates / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Imidazoles / pharmacology
  • Immunoblotting
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Zoledronic Acid
  • bcl-2-Associated X Protein / metabolism

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Bax protein, mouse
  • Bid protein, mouse
  • Bone Density Conservation Agents
  • CRADD Signaling Adaptor Protein
  • Carrier Proteins
  • Cradd protein, mouse
  • Death Domain Receptor Signaling Adaptor Proteins
  • Diphosphonates
  • Imidazoles
  • Pidd1 protein, mouse
  • bcl-2-Associated X Protein
  • Zoledronic Acid
  • Cytochromes c
  • Caspase 2