1998 | Carsten Scaffidi, Simone Fulda, Anu Srinivasan, Claudia Friesen, Feng Li, Kevin J.Tomaselli, Klaus-Michael Debatin, Peter H.Krammer and Marcus E.Peter
The study identifies two distinct cell types, type I and type II, that use different CD95 (APO-1/Fas) signaling pathways. Type I cells activate caspase-8 within seconds and caspase-3 within 30 minutes, while type II cells delay the activation of both caspases by about 60 minutes. Both types show similar kinetics of CD95-mediated apoptosis and loss of mitochondrial transmembrane potential (ΔΨm). Overexpression of Bcl-2 or Bcl-xL blocks mitochondrial functions but not caspase activation in type I cells, whereas in type II cells, it blocks caspase activation and apoptosis. In type I cells, caspase-8 activation occurs through the death-inducing signaling complex (DISC), leading to caspase-3 activation, while in type II cells, caspase-8 and caspase-3 activation occurs downstream of mitochondria. Overexpression of caspase-3 in MCF7-Fas cells, which normally lack caspase-3, converts them into type I cells, indicating that the amount of active caspase-8 generated at the DISC determines whether a cell uses a mitochondria-independent apoptosis pathway (type I) or not (type II). The study also discusses the evolutionary and physiological roles of these two CD95 signaling pathways.The study identifies two distinct cell types, type I and type II, that use different CD95 (APO-1/Fas) signaling pathways. Type I cells activate caspase-8 within seconds and caspase-3 within 30 minutes, while type II cells delay the activation of both caspases by about 60 minutes. Both types show similar kinetics of CD95-mediated apoptosis and loss of mitochondrial transmembrane potential (ΔΨm). Overexpression of Bcl-2 or Bcl-xL blocks mitochondrial functions but not caspase activation in type I cells, whereas in type II cells, it blocks caspase activation and apoptosis. In type I cells, caspase-8 activation occurs through the death-inducing signaling complex (DISC), leading to caspase-3 activation, while in type II cells, caspase-8 and caspase-3 activation occurs downstream of mitochondria. Overexpression of caspase-3 in MCF7-Fas cells, which normally lack caspase-3, converts them into type I cells, indicating that the amount of active caspase-8 generated at the DISC determines whether a cell uses a mitochondria-independent apoptosis pathway (type I) or not (type II). The study also discusses the evolutionary and physiological roles of these two CD95 signaling pathways.