Inhibitor of apoptosis proteins (IAPs) are best known for their roles as inhibitors of caspases and thus of apoptotic cell death. Legewie et al. develop a mathematical model of the core intrinsic apoptotic process involving Apaf-1, caspase 9, caspase 3, and X-linked IAP (XIAP). In the wild-type model, as active Apaf-1 concentration increased, the time course with which active caspase 3 was produced decreased as expected. When the activation of caspase 3 was plotted against the concentration of active Apaf-1, a bistable and irreversible state was observed both in the wild-type model and in a caspase 9 mutant model. This suggested that the positive feedback between caspase 9 and caspase 3 was not the only contributor to bistability in the system. Further analysis suggested that XIAP contributed a positive feedback to caspase 3 activation. Caspase 3 was proposed to sequester XIAP away from caspase 9 under conditions of strong stimulation, thereby allowing caspase 9 to become further activated and ultimately allowing caspase 3 to be activated. The bistability and irreversibility of the models depended on the concentrations of both caspase 3 and caspase 9, with only the wild-type model showing irreversibility in the physiological concentrations of each caspase, indicating that both caspase 3-mediated feedback and XIAP-mediated feedback contribute to irreversible bistability under physiological conditions. The models echo observed differences in cellular responses to apoptotic stimuli by showing that the all-or-none threshold of the system is influenced by the abundance of caspase 3, caspase 9, and XIAP. — NRG
PLoS Comput. Biol. 2, e120 (2006).