Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases.
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.
Jäättelä
M
M
Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Wissing
D
D
Kokholm
K
K
Kallunki
T
T
Egeblad
M
M
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D003574:Cytochrome c Group / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics; D005609:Free Radicals / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D015398:Signal Transduction / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D003574:Cytochrome c Group; D005609:Free Radicals; D018840:HSP70 Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D004317:Doxorubicin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D010450:Endopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine