Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes.
Caspases are fundamental components of the mammalian apoptotic machinery, but the precise contribution of individual caspases is controversial. CPP32 (caspase 3) is a prototypical caspase that becomes activated during apoptosis. In this study, we took a comprehensive approach to examining the role of CPP32 in apoptosis using mice, embryonic stem (ES) cells, and mouse embryonic fibroblasts (MEFs) deficient for CPP32. CPP32(ex3-/-) mice have reduced viability and, consistent with an earlier report, display defective neuronal apoptosis and neurological defects. Inactivation of CPP32 dramatically reduces apoptosis in diverse settings, including activation-induced cell death (AICD) of peripheral T cells, as well as chemotherapy-induced apoptosis of oncogenically transformed CPP32(-/-) MEFs. As well, the requirement for CPP32 can be remarkably stimulus-dependent: In ES cells, CPP32 is necessary for efficient apoptosis following UV- but not gamma-irradiation. Conversely, the same stimulus can show a tissue-specific dependence on CPP32: Hence, TNFalpha treatment induces normal levels of apoptosis in CPP32 deficient thymocytes, but defective apoptosis in oncogenically transformed MEFs. Finally, in some settings, CPP32 is required for certain apoptotic events but not others: Select CPP32(ex3-/-) cell types undergoing cell death are incapable of chromatin condensation and DNA degradation, but display other hallmarks of apoptosis. Together, these results indicate that CPP32 is an essential component in apoptotic events that is remarkably system- and stimulus-dependent. Consequently, drugs that inhibit CPP32 may preferentially disrupt specific forms of cell death.
Woo
M
M
Amgen Institute Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G2C1, Canada.
Hakem
R
R
Soengas
M S
MS
Duncan
G S
GS
Shahinian
A
A
Kägi
D
D
Hakem
A
A
McCurrach
M
M
Khoo
W
W
Kaufman
S A
SA
Senaldi
G
G
Howard
T
T
Lowe
S W
SW
Mak
T W
TW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D017252:CD3 Complex / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D005314:Embryonic and Fetal Development; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D008136:Longevity / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D009997:Osmotic Pressure; D013234:Stem Cells / Q000528:radiation effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000494:pharmacology
D017252:CD3 Complex; D019014:fas Receptor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases