Ubiquitous calpains promote both apoptosis and survival signals in response to different cell death stimuli

J Biol Chem. 2006 Jun 30;281(26):17689-98. doi: 10.1074/jbc.M601978200. Epub 2006 Apr 21.


The mu- and m-calpain proteases have been implicated in both pro- or anti-apoptotic functions. Here we compared cell death responses and apoptotic or survival signaling pathways in primary mouse embryonic fibroblasts (MEFs) derived from wild type or capn4 knock-out mice which lack both mu- and m-calpain activities. Capn4(-/-) MEFs displayed resistance to puromycin, camptothecin, etoposide, hydrogen peroxide, ultraviolet light, and serum starvation, which was consistent with pro-apoptotic roles for calpain. In contrast, capn4(-/-) MEFs were more susceptible to staurosporine (STS) and tumor necrosis factor alpha-induced cell death, which provided evidence for anti-apoptotic signaling roles for calpain. Bax activation, release of cytochrome c, and activation of caspase-9 and caspase-3 all correlated with the observed cell death responses of wild type or capn4(-/-) MEFs to the various challenges, suggesting that calpain might play distinct roles in transducing different death signals to the mitochondria. There was no evidence that calpain cleaved Bcl-2 family member proteins that regulate mitochondrial membrane permeability including Bcl-2, Bcl-xl, Bad, Bak, Bid, or Bim. However, activation of the phosphatidylinositol 3 (PI3)-kinase/Akt survival signaling pathway was compromised in capn4(-/-) MEFs under all challenges regardless of the cell death outcome, and blocking Akt activation using the PI3-kinase inhibitor LY294002 abolished the protective effect of calpain to STS challenge. We conclude that the anti-apoptotic function of calpain in tumor necrosis factor alpha- and STS-challenged cells relates to a novel role in activating the PI3-kinase/Akt survival pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Calpain / genetics
  • Calpain / metabolism*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / enzymology*
  • Lysosomes / metabolism
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylserines / pharmacology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Staurosporine / pharmacology
  • Tumor Suppressor Protein p53 / metabolism


  • Enzyme Inhibitors
  • Phosphatidylserines
  • Tumor Suppressor Protein p53
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Calpain
  • m-calpain
  • mu-calpain
  • Staurosporine