Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria.
In L929sAhFas cells, tumor necrosis factor (TNF) leads to necrotic cell death, whereas agonistic anti-Fas antibodies elicit apoptotic cell death. Apoptosis, but not necrosis, is correlated with a rapid externalization of phosphatidylserine and the appearance of a hypoploid population. During necrosis no cytosolic and organelle-associated active caspase-3 and -7 fragments are detectable. The necrotic process does not involve proteolytic generation of truncated Bid; moreover, no mitochondrial release of cytochrome c is observed. Bcl-2 overexpression slows down the onset of necrotic cell death. In the case of apoptosis, active caspases are released to the culture supernatant, coinciding with the release of lactate dehydrogenase. Following necrosis, mainly unprocessed forms of caspases are released. Both TNF-induced necrosis and necrosis induced by anti-Fas in the presence of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone are prevented by the serine protease inhibitor N-tosyl-L-phenylalanine chloromethylketone and the oxygen radical scavenger butylated hydroxyanisole, while Fas-induced apoptosis is not affected.
Denecker
G
G
Molecular Signaling and Cell Death Unit, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and Ghent University, 9000 Gent, Belgium.
Vercammen
D
D
Steemans
M
M
Vanden Berghe
T
T
Brouckaert
G
G
Van Loo
G
G
Zhivotovsky
B
B
Fiers
W
W
Grooten
J
J
Declercq
W
W
Vandenabeele
P
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D012697:Serine Endopeptidases; D020169:Caspases