Tumor necrosis factor induces distinct patterns of caspase activation in WEHI-164 cells associated with apoptosis or necrosis depending on cell cycle stage.
TNF is unusual among the death receptor ligands in being able to induce either apoptotic or necrotic cell death. We have observed that in WEHI 164 fibrosarcoma, cells the mode of TNF-induced cell death is dependent on the stage of the cell cycle. Cells arrested in G(0)/G(1) undergo necrosis, while those progressing through the cell cycle undergo apoptosis. TNF induces caspase activity in both settings, and the broad spectrum caspase inhibitor zVAD-fmk inhibits this activity and blocks both TNF-induced apoptosis and necrosis. Inhibition of oxygen radical accumulation does not block cytotoxicity. The presence and activation of specific caspases were examined by Western blotting. The procaspase-8a isoform was down-regulated in proliferating cells. Procaspases-8b and -7 were cleaved during TNF-induced apoptosis but not necrosis. Thus, a different pattern of caspase expression and activation occurs dependent on the cell cycle and which may determine the mode of cell death.
Faraco
P R
PR
Department of Clinical Biochemistry, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd., Cambridge, CB2 2QQ, United Kingdom.
Ledgerwood
E C
EC
Vandenabeele
P
P
Prins
J B
JB
Bradley
J R
JR
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D051379:Mice; D008854:Microscopy, Electron; D009842:Oligopeptides / Q000737:chemistry; D011994:Recombinant Proteins / Q000494:pharmacology; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D016166:Free Radical Scavengers; D009842:Oligopeptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002083:Butylated Hydroxyanisole; C505524:Casp7 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases