| Caspase-dependent activation of calpain during drug-induced apoptosis. | |
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MedLine Citation:
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PMID: 10075737 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have previously demonstrated that calpain is responsible for the cleavage of Bax, a proapoptotic protein, during drug-induced apoptosis of HL-60 cells (Wood, D. E., Thomas, A., Devi, L. A., Berman, Y., Beavis, R. C., Reed, J. C., and Newcomb, E. W. (1998) Oncogene 17, 1069-1078). Here we show the sequential activation of caspases and calpain during drug-induced apoptosis of HL-60 cells. Time course experiments using the topoisomerase I inhibitor 9-amino-20(S)-camptothecin revealed that cleavage of caspase-3 substrates poly(ADP-ribose) polymerase (PARP) and the retinoblastoma protein as well as DNA fragmentation occurred several hours before calpain activation and Bax cleavage. Pretreatment with the calpain inhibitor calpeptin blocked calpain activation and Bax cleavage but did not inhibit PARP cleavage, DNA fragmentation, or 9-amino-20(S)-camptothecin-induced morphological changes and cell death. Pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk) inhibited PARP cleavage, DNA fragmentation, calpain activation, and Bax cleavage and increased cell survival by 40%. Interestingly, Z-VAD-fmk-treated cells died in a caspase- and calpain-independent manner that appeared morphologically distinct from apoptosis. Our results suggest that excessive or uncontrolled calpain activity may play a role downstream of and distinct from caspases in the degradation phase of apoptosis. |
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Authors:
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D E Wood; E W Newcomb |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 274 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 1999 Mar |
Date Detail:
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Created Date: 1999-04-15 Completed Date: 1999-04-15 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 8309-15 Citation Subset: IM |
Affiliation:
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Department of Pathology, New York University Medical Center, New York, New York 10016, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Chloromethyl Ketones
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pharmacology Apoptosis* / drug effects Calpain / metabolism* Caspase 3 Caspases / metabolism* Coumarins / pharmacology Cysteine Proteinase Inhibitors / pharmacology DNA Fragmentation Dipeptides / pharmacology Enzyme Activation HL-60 Cells Humans Oligopeptides / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin; 0/Amino Acid Chloromethyl Ketones; 0/Coumarins; 0/Cysteine Proteinase Inhibitors; 0/Dipeptides; 0/Oligopeptides; 0/acetyl-aspartyl-glutamyl-valyl-aspartal; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 117591-20-5/calpeptin; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Calpain; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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