Ubiquitous Calpains Promote Both Apoptosis and Survival Signals in Response to Different Cell Death Stimuli.
From: Division of Cancer Biology and Genetics, Queen’s University Cancer Research Institute, Botterall Hall Rm. A309, Kingston, Ontario K7L-3N6, Canada.
The Journal of biological chemistry
- Publish Date: Jun 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 26
- Pages: 17689-98
- Medium: Print
- Language: English
- Citation (JAMA): Tan Yinfei, Wu Chao, De Veyra Teresa, et al. Ubiquitous Calpains Promote Both Apoptosis and Survival Signals in Response to Different Cell Death Stimuli.. J. Biol. Chem. Jun 2006;281:17689-98
Abstract
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.
Mesh Headings (Keywords): 1-Phosphatidylinositol 3-Kinase, Animals, Apoptosis, Calpain, Cell Survival, Cells, Cultured, Cytochromes c, Enzyme Inhibitors, Fibroblasts, Lysosomes, Mice, Mice, Mutant Strains, Mitochondria, Phosphatidylserines, Poly(ADP-ribose) Polymerases, Proto-Oncogene Proteins c-akt, Signal Transduction, Staurosporine, Tumor Suppressor Protein p53
Check for Full Text / PubMed Unique Identifier (PMID): 16632474
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