A mathematical model of caspase function in apoptosis.
Caspases (cysteine-containing aspartate-specific proteases) are at the core of the cell's suicide machinery. These enzymes, once activated, dismantle the cell by selectively cleaving key proteins after aspartate residues. The events culminating in caspase activation are the subject of intense study because of their role in cancer, and neurodegenerative and autoimmune disorders. Here we present a mechanistic mathematical model, formulated on the basis of newly emerging information, describing key elements of receptor-mediated and stress-induced caspase activation. We have used mass-conservation principles in conjunction with kinetic rate laws to formulate ordinary differential equations that describe the temporal evolution of caspase activation. Qualitative strategies for the prevention of caspase activation are simulated and compared with experimental data. We show that model predictions are consistent with available information. Thus, the model could aid in better understanding caspase activation and identifying therapeutic approaches promoting or retarding apoptotic cell death.
Fussenegger
M
M
Institute of Biotechnology, ETH-Zurich, CH-8093 Zurich, Switzerland.
Bailey
J E
JE
Varner
J
J
D017209:Apoptosis; D029681:Arabidopsis Proteins; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D003198:Computer Simulation; D004789:Enzyme Activation; D044943:Fatty Acid Desaturases / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008962:Models, Theoretical; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051020:bcl-X Protein; D019014:fas Receptor / Q000378:metabolism
D029681:Arabidopsis Proteins; C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases