[HTML][HTML] Two CD95 (APO-1/Fas) signaling pathways

C Scaffidi, S Fulda, A Srinivasan, C Friesen, F Li… - The EMBO …, 1998 - embopress.org
C Scaffidi, S Fulda, A Srinivasan, C Friesen, F Li, KJ Tomaselli, KM Debatin, PH Krammer…
The EMBO journal, 1998embopress.org
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 …
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).
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