title: Monte Carlo simulation of cell death signaling predicts large cell-to-cell stochastic fluctuations through the type 2 pathway of apoptosis.
abstract: Apoptosis, or genetically programmed cell death, is a crucial cellular process that maintains the balance between life and death in cells. The precise molecular mechanism of apoptosis signaling and the manner in which type 1 and type 2 pathways of the apoptosis signaling network are differentially activated under distinct apoptotic stimuli is poorly understood. Based on Monte Carlo stochastic simulations, we show that the type 1 pathway becomes activated under strong apoptotic stimuli, whereas the type 2 mitochondrial pathway dominates apoptotic signaling in response to a weak death signal. Our results also show signaling in the type 2 pathway is stochastic; the population average over many cells does not capture the cell-to-cell fluctuations in the time course (approximately 1-10 h) of downstream caspase-3 activation. On the contrary, the probability distribution of caspase-3 activation for the mitochondrial pathway shows a distinct bimodal behavior that can be used to characterize the stochastic signaling in type 2 apoptosis and other similar complex signaling processes. Interestingly, such stochastic fluctuations in apoptosis signaling occur even in the presence of large numbers of signaling molecules.
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, California, USA. raychaudhuri@ucdavis.edu
authors.forename: Subhadip
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Eric
authors.initials: E
authors.lastname: Willgohs
authors.forename: Thuc-Nghi
authors.initials: TN
authors.lastname: Nguyen
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Khan
authors.forename: Tzipora
authors.initials: T
authors.lastname: Goldkorn
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D003198:Computer Simulation; D004789:Enzyme Activation; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D015398:Signal Transduction; D013269:Stochastic Processes; D013997:Time Factors
chemical_list: D053148:Caspase 3