Abstract
We have identified two cell types, each using almost exclusively one of two different CD95 (APO-1/Fas) signaling pathways, In type I cells, caspase-8 was activated within seconds and caspase-3 within 30 min of receptor engagement, whereas in type II cells cleavage of both caspases was delayed for ~ 60 min. However, both type I and type II cells showed similar kinetics of CD95-mediated apoptosis and loss of mitochondrial transmembrane potential (ΔΨ(m)). Upon CD95 triggering, all mitochondrial apoptogenic activities were blocked by Bcl-2 or Bcl-x(L) overexpression in both cell types. However, in type II but not type I cells, overexpression of Bcl-2 or Bcl-x(L) blocked caspase-8 and caspase-3 activation as well as apoptosis. In type I cells, induction of apoptosis was accompanied by activation of large amounts of caspase-8 by the death-inducing signaling complex (DISC), whereas in type II cells DISC formation was strongly reduced and activation of caspase-8 and caspase-3 occurred following the loss of ΔΨ(m). Overexpression of caspase-3 in the caspase-3-negative cell line MCF7-Fas, normally resistant to CD95-mediated apoptosis by overexpression of Bcl-x(L), converted these cells into true type I cells in which apoptosis was no longer inhibited by Bcl-x(L). In summary, in the presence of caspase-3 the amount of active caspase-8 generated at the DISC determines whether a mitochondria-independent apoptosis pathway is used (type I cells) or not (type II cells).
Original language | English (US) |
---|---|
Pages (from-to) | 1675-1687 |
Number of pages | 13 |
Journal | EMBO Journal |
Volume | 17 |
Issue number | 6 |
DOIs | |
State | Published - Mar 16 1998 |
Keywords
- Apoptosis
- Bcl-2
- Caspases
- Cytochrome c
- Mitochondria
ASJC Scopus subject areas
- General Immunology and Microbiology
- General Biochemistry, Genetics and Molecular Biology
- Molecular Biology
- General Neuroscience