Jaattela, M., Wissing, D., Kokholm, K., Kallunki, T., Egeblad, M. (November 1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO Journal, 17 (21). pp. 6124-34. ISSN 0261-4189 (Print)0261-4189
Abstract
The major heat shock protein, Hsp70, is an effective inhibitor of apoptosis. To study its mechanism of action, we created tumor cell lines with altered Hsp70 levels. The expression levels of Hsp70 in the cells obtained correlated well with their survival following treatments with tumor necrosis factor, staurosporine and doxorubicin. Surprisingly, the surviving Hsp70-expressing cells responded to the apoptotic stimuli by activation of stress-activated protein kinases, generation of free radicals, early disruption of mitochondrial transmembrane potential, release of cytochrome c from mitochondria and activation of caspase-3-like proteases in a manner essentially similar to that of the dying cells with low Hsp70 levels. However, Hsp70 inhibited late caspase-dependent events such as activation of cytosolic phospholipase A2 and changes in nuclear morphology. Furthermore, Hsp70 conferred significant protection against cell death induced by enforced expression of caspase-3. Thus, Hsp70 rescues cells from apoptosis later in the death signaling pathway than any known anti-apoptotic protein, making it a tempting target for therapeutic interventions.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Apoptosis/genetics/*physiology Calcium-Calmodulin-Dependent Protein Kinases/genetics Caspase 3 Caspases/*genetics Cell Survival/genetics Cytochrome c Group/metabolism Doxorubicin/pharmacology Endopeptidases/genetics Free Radicals/metabolism Gene Expression Regulation/genetics HSP70 Heat-Shock Proteins/*genetics/metabolism Humans JNK Mitogen-Activated Protein Kinases Mitochondria/metabolism *Mitogen-Activated Protein Kinases Oligonucleotides, Antisense/genetics Oligopeptides/pharmacology Phospholipases A/metabolism Phospholipases A2 Signal Transduction/genetics Staurosporine/pharmacology Transfection/genetics Tumor Cells, Cultured Tumor Necrosis Factor-alpha/genetics |
| 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 > Protease |
| CSHL Authors: | |
| Communities: | CSHL labs > Egeblad lab |
| Depositing User: | Matt Covey |
| Date: | 2 November 1998 |
| Date Deposited: | 05 Dec 2014 14:37 |
| Last Modified: | 05 Dec 2014 14:37 |
| PMCID: | PMC1170939 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30949 |
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