Involvement of caspase-dependent activation of cytosolic phospholipase A2 in tumor necrosis factor-induced apoptosis

Wissing, D., Mouritzen, H., Egeblad, M., Poirier, G. G., Jaattela, M. (May 1997) Involvement of caspase-dependent activation of cytosolic phospholipase A2 in tumor necrosis factor-induced apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 94 (10). pp. 5073-7. ISSN 0027-8424 (Print)0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/9144192

Abstract

Tumor necrosis factor (TNF)-induced apoptosis is mediated by caspases, which are cysteine proteases related to interleukin 1beta-converting enzyme. We report here that TNF-induced activation of caspases results in the cleavage and activation of cytosolic phospholipase A2 (cPLA2) and that activated cPLA2 contributes to apoptosis. Inhibition of caspases by expression of a cowpox virus-derived inhibitor, CrmA, or by a specific tetrapeptide inhibitor of CPP32/caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), inhibited TNF-induced activation of cPLA2 and apoptosis. TNF-induced activation of cPLA2 was accompanied by a cleavage of the 100-kDa cPLA2 to a 70-kDa proteolytic fragment. This cleavage was inhibited by Ac-DEVD-CHO in a similar manner as that of poly(ADP)ribose polymerase, a known substrate of CPP32/caspase-3. Interestingly, specific inhibition of cPLA2 enzyme activity by arachidonyl trifluoromethylketone (AACOCF3) partially inhibited TNF-induced apoptosis without inhibition of caspase activity. Thus, our results suggest a novel caspase-dependent activation pathway for cPLA2 during apoptosis and identify cPLA2 as a mediator of TNF-induced cell death acting downstream of caspases.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Sequence Animals Antibodies Breast Neoplasms Caspase 1 Cell Line Cell Survival/drug effects Cysteine Endopeptidases/*metabolism Cytosol/enzymology Enzyme Activation Female Fibrosarcoma Humans Kinetics Mice Molecular Sequence Data Peptide Fragments/chemistry/immunology Phospholipases A/chemistry/*metabolism Phospholipases A2 Recombinant Proteins/pharmacology Tumor Cells, Cultured Tumor Necrosis Factor-alpha/*pharmacology
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Protease > caspases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > cytosolic phospholipase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > tumor necrosis factor
CSHL Authors:
Communities: CSHL labs > Egeblad lab
Depositing User: Matt Covey
Date: 13 May 1997
Date Deposited: 05 Dec 2014 19:46
Last Modified: 05 Dec 2014 19:46
PMCID: PMC24633
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30956

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