| A serine protease is involved in the initiation of DNA damage-induced apoptosis. | |
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MedLine Citation:
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PMID: 14502243 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Caspases are considered to be the key effector proteases of apoptosis. Initiator caspases cleave and activate downstream executioner caspases, which are responsible for the degradation of numerous cellular substrates. We studied the role of caspases in apoptotic cell death of a human melanoma cell line. Surprisingly, the pancaspase inhibitor zVAD-fmk was unable to block cleavage of poly(ADP-ribose) polymerase (PARP) after treatment with etoposide, while it did prevent DEVDase activity. It is highly unlikely that caspase-2, which is a relatively zVAD-fmk-resistant caspase, is mediating etoposide-induced PARP cleavage, as a preferred inhibitor of this caspase could not prevent cleavage. In contrast, caspase activation and PARP degradation were blocked by pretreatment of the cells with the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF). We therefore conclude that a serine protease regulates an alternative initiation mechanism that leads to caspase activation and PARP cleavage. More importantly, while zVAD-fmk could not rescue melanoma cells from etoposide-induced death, the combination with AEBSF resulted in substantial protection. This indicates that this novel pathway fulfills a critical role in the execution of etoposide-induced programmed cell death. |
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Authors:
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E C de Bruin; D Meersma; J de Wilde; I den Otter; E M Schipper; J P Medema; L T C Peltenburg |
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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: Cell death and differentiation Volume: 10 ISSN: 1350-9047 ISO Abbreviation: Cell Death Differ. Publication Date: 2003 Oct |
Date Detail:
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Created Date: 2003-09-22 Completed Date: 2004-06-07 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 1204-12 Citation Subset: IM |
Affiliation:
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Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Chloromethyl Ketones
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pharmacology Animals Apoptosis / drug effects, genetics* Blotting, Western Caspase 2 Caspase 3 Caspases / antagonists & inhibitors, metabolism Cell Line Cell Line, Tumor / drug effects, radiation effects Coumarins / metabolism Cysteine Proteinase Inhibitors / pharmacology DNA Damage* Etoposide / pharmacology Fibroblasts / cytology, drug effects, metabolism Flow Cytometry Humans Microscopy, Phase-Contrast Oligopeptides / metabolism, pharmacology Peptide Hydrolases / metabolism Poly(ADP-ribose) Polymerases / metabolism Rats Serine Endopeptidases / metabolism* Serine Proteinase Inhibitors / pharmacology Sulfones / pharmacology Tumor Necrosis Factor-alpha / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Amino Acid Chloromethyl Ketones; 0/Coumarins; 0/Cysteine Proteinase Inhibitors; 0/Oligopeptides; 0/Serine Proteinase Inhibitors; 0/Sulfones; 0/Tumor Necrosis Factor-alpha; 0/aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; 0/benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 33419-42-0/Etoposide; 34284-75-8/4-(2-aminoethyl)benzenesulfonylfluoride; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.-/Peptide Hydrolases; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 2; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 3.4.99.-/DEVDase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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