title: Modeling of the role of a Bax-activation switch in the mitochondrial apoptosis decision.
abstract: We performed in silico modeling of the regulatory network of mitochondrial apoptosis through which we examined the role of a Bax-activation switch in governing the mitochondrial apoptosis decision. Two distinct modeling methods were used in this article. One is continuous and deterministic, comprised of a set of ordinary differential equations. The other, carried out in a discrete manner, is based on a cellular automaton, which takes stochastic fluctuations into consideration. We focused on dynamic properties of the mitochondrial apoptosis regulatory network. The roles of Bcl-2 family proteins in cellular responses to apoptotic stimuli were examined. In our simulations, a self-amplification process of Bax-activation is indicated. Further analysis suggests that the core module of Bax-activation is bistable in both deterministic and stochastic models, and this feature is robust to noise and wide ranges of parameter variation. When coupling with Bax-polymerization, it forms a one-way-switch, which governs irreversible behaviors of Bax-activation even with attenuation of apoptotic stimulus. Together with the growing biochemical evidence, we propose a novel molecular switch mechanism embedded in the mitochondrial apoptosis regulatory network and give a plausible explanation for the all-or-none, irreversible character of mitochondrial apoptosis.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Cui
authors.forename: Haizhu
authors.initials: H
authors.lastname: Lu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.forename: Pingping
authors.initials: P
authors.lastname: Shen
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013269:Stochastic Processes; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein