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
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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: | 11 Sep 2019 16:31 |
| PMCID: | PMC24633 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30956 |
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