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A serine protease is involved in the initiation of DNA damage-induced apoptosis.

de Bruin, EC; Meersma, D; de Wilde, J; den Otter, I; Schipper, EM; Medema, JP; Peltenburg, LTC; (2003) A serine protease is involved in the initiation of DNA damage-induced apoptosis. Cell Death Differ , 10 (10) pp. 1204-1212. 10.1038/sj.cdd.4401296.

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Abstract

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.

Type: Article
Title: A serine protease is involved in the initiation of DNA damage-induced apoptosis.
Location: England
DOI: 10.1038/sj.cdd.4401296
Keywords: Amino Acid Chloromethyl Ketones, Animals, Apoptosis, Blotting, Western, Caspase 2, Caspase 3, Caspase Inhibitors, Caspases, Cell Line, Cell Line, Tumor, Coumarins, Cysteine Proteinase Inhibitors, DNA Damage, Etoposide, Fibroblasts, Flow Cytometry, Humans, Microscopy, Phase-Contrast, Oligopeptides, Peptide Hydrolases, Poly(ADP-ribose) Polymerases, Rats, Serine Endopeptidases, Serine Proteinase Inhibitors, Sulfones, Tumor Necrosis Factor-alpha
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/1424491
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