Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c.
Journal Article (Journal Article)
Apoptosis often involves the release of cytochrome c from mitochondria, leading to caspase activation. However, in apoptosis mediated by CD95 (Fas/APO-1), caspase-8 (FLICE/MACH/Mch5) is immediately activated and, in principle, could process other caspases directly. To investigate whether caspase-8 could also act through mitochondria, we added active caspase-8 to a Xenopus cell-free system requiring these organelles. Caspase-8 rapidly promoted the apoptotic program, culminating in fragmentation of chromatin and the nuclear membrane. In extracts devoid of mitochondria, caspase-8 produced DNA degradation, but left nuclear membranes intact. Thus, mitochondria were required for complete engagement of the apoptotic machinery. In the absence of mitochondria, high concentrations of caspase-8 were required to activate downstream caspases. However, when mitochondria were present, the effects of low concentrations of caspase-8 were vastly amplified through cytochrome c-dependent caspase activation. Caspase-8 promoted cytochrome c release indirectly, by cleaving at least one cytosolic substrate. Bcl-2 blocked apoptosis only at the lowest caspase-8 concentrations, potentially explaining why CD95-induced apoptosis can often evade inhibition by Bcl-2.
Full Text
Duke Authors
Cited Authors
- Kuwana, T; Smith, JJ; Muzio, M; Dixit, V; Newmeyer, DD; Kornbluth, S
Published Date
- June 1998
Published In
Volume / Issue
- 273 / 26
Start / End Page
- 16589 - 16594
PubMed ID
- 9632731
Electronic International Standard Serial Number (EISSN)
- 1083-351X
International Standard Serial Number (ISSN)
- 0021-9258
Digital Object Identifier (DOI)
- 10.1074/jbc.273.26.16589
Language
- eng