Bistability analyses of a caspase activation model for receptor-induced apoptosis.
Apoptosis is an important physiological process crucially involved in development and homeostasis of multicellular organisms. Although the major signaling pathways have been unraveled, a detailed mechanistic understanding of the complex underlying network remains elusive. We have translated here the current knowledge of the molecular mechanisms of the death-receptor-activated caspase cascade into a mathematical model. A reduction down to the apoptotic core machinery enables the application of analytical mathematical methods to evaluate the system behavior within a wide range of parameters. Using parameter values from the literature, the model reveals an unstable status of survival indicating the need for further control. Based on recent publications we tested one additional regulatory mechanism at the level of initiator caspase activation and demonstrated that the resulting system displays desired characteristics such as bistability. In addition, the results from our model studies allowed us to reconcile the fast kinetics of caspase 3 activation observed at the single cell level with the much slower kinetics found at the level of a cell population.
Eissing
Thomas
T
Institute for Systems Theory in Engineering, University of Stuttgart, Pfaffenwaldring 9, 70550 Stuttgart, Germany.
Conzelmann
Holger
H
Gilles
Ernst D
ED
Allgöwer
Frank
F
Bullinger
Eric
E
Scheurich
Peter
P
D017209:Apoptosis; D001669:Biochemical Phenomena; D001671:Biochemistry; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000737:chemistry* / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008962:Models, Theoretical; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors
C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases