title: Involvement of caspase 3 in apoptotic death of cortical neurons evoked by DNA damage.
abstract: Previous reports have shown that DNA-damage-evoked death of embryonic cortical neurons is delayed by general caspase inhibitors and is accompanied by an increase in DEVD-AFC cleavage activity. We show here that this cleavage activity is lacking in camptothecin-treated caspase 3-deficient neurons. Moreover, we report that death of camptothecin-treated caspase 3-deficient neurons cultured from E16 embryos is delayed and that no significant increase in survival is observed with cotreatment with the general caspase inhibitor BAF. These results indicate that caspase-dependent death of camptothecin-treated cortical neurons requires caspase 3 activity. The delay in death is accompanied by impairment of DNA fragmentation. However, Bax-dependent cytochrome c release still occurs in camptothecin-treated caspase 3-deficient cortical neurons. Accordingly, we hypothesize that the delayed death which occurs in the absence of caspase 3 activity may be due to mitochondrial dysfunction. Finally, we show that the delay in death observed with E16 caspase 3-deficient neurons does not occur in neurons cultured from E19 embryos. This suggests that the requirement for caspase 3 in death of neurons evoked by DNA damage may differ depending upon the developmental state of the cell.
authors.affiliation: Neuroscience Research Institute, University of Ottawa, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Keramaris
authors.forename: L
authors.initials: L
authors.lastname: Stefanis
authors.forename: J
authors.initials: J
authors.lastname: MacLaurin
authors.forename: N
authors.initials: N
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Takaku
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: M M
authors.initials: MM
authors.lastname: Taketo
authors.forename: G S
authors.initials: GS
authors.lastname: Robertson
authors.forename: D W
authors.initials: DW
authors.lastname: Nicholson
authors.forename: R S
authors.initials: RS
authors.lastname: Slack
authors.forename: D S
authors.initials: DS
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001921:Brain / Q000166:cytology / Q000196:embryology; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D053938:DNA Fragmentation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology
chemical_list: D003374:Coumarins; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C115495:aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002166:Camptothecin