Simple computational models of type I/type II cells in Fas signaling-induced apoptosis.
Distinct apoptotic response of the type I/type II cells against Fas-ligand stimulation is considered to arise from the difference in dominant signaling pathways involved. In the type I cells, apoptotic signaling predominantly takes place via the direct activation of caspase-3 by activated caspase-8 (D channel) while mitochondrial pathway (M channel) plays a major role in the type II cells. To elucidate the selection mechanism of dominant pathway, we carried out systematic model analysis of the Fas signaling-induced apoptosis network. An increase in the expression level of caspase-8 induced a switch of dominant pathway from M- to D-channel (M-D transition), showing a phenotypic change from type II to type I cells. With the aid of sensitivity analysis and kinetic considerations, we succeeded in constructing a minimal network model relevant for the M-D transition, which revealed that mechanistic origin of the transition lies in the competition between the activated forms of caspase-8 and caspase-9 for their common substrate caspase-3. The pathway dominance was found to be primarily controlled by the balance between the activation rate of caspase-8 and the initial level of caspase-9. In the full network model, we showed that differential formation ability of the death-inducing signaling complex (DISC) can also induce M-D transition, in accordance with the experimental observations.
Okazaki
Noriaki
N
Institute of Health Biosciences, The University of Tokushima, Shomachi, Tokushima 7708505, Japan. okazaki@ph.tokushima-u.ac.jp
Asano
Ryoji
R
Kinoshita
Takashi
T
Chuman
Hiroshi
H
D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8 / Q000502:physiology; D053453:Caspase 9 / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D004789:Enzyme Activation / Q000502:physiology; D053222:Fas Ligand Protein / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology
D053222:Fas Ligand Protein; D053181:Caspase 8; D053453:Caspase 9