Iwamoto Kazunari, Hamada Hiroyuki, Eguchi Yukihiro, Okamoto Masahiro
Graduate school of Systems Life Sciences, Kyushu University, Fukuoka, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
Department of Systems Life Sciences, Kyushu University, Fukuoka, Japan; Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; Synthetic Systems Biology Research Center, Kyushu University, Fukuoka, Japan.
PLoS One. 2014 Jul 8;9(7):e101333. doi: 10.1371/journal.pone.0101333. eCollection 2014.
A massive integrative mathematical model of DNA double-strand break (DSB) generation, DSB repair system, p53 signaling network, and apoptosis induction pathway was constructed to explore the dominant factors of unknown criteria of cell fate decision. In the proposed model, intranuclear reactions were modeled as stochastic processes and cytoplasmic reactions as deterministic processes, and both reaction sets were simulated simultaneously. The simulated results at the single-cell level showed that the model generated several sustained oscillations (pulses) of p53, Mdm2, ATM, and Wip1, and cell-to-cell variability in the number of p53 pulses depended on IR intensity. In cell populations, the model generated damped p53 oscillations, and IR intensity affected the amplitude of the first p53 oscillation. Cells were then subjected to the same IR dose exhibiting apoptosis induction variability. These simulated results are in quantitative agreement with major biological findings observed in human breast cancer epithelial MCF7, NIH3T3, and fibrosarcoma cells, demonstrating that the proposed model was concededly biologically appropriate. Statistical analysis of the simulated results shows that the generation of multiple p53 pulses is a prerequisite for apoptosis induction. Furthermore, cells exhibited considerable individual variability in p53 dynamics, which correlated with intrinsic apoptosis induction. The simulated results based on the proposed model demonstrated that the stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. Applying stochastic simulation to an exploration of intranuclear biochemical reaction processes is indispensable in enhancing the understanding of the dynamic characteristics of biological multi-layered systems of higher organisms.
构建了一个大规模的整合数学模型，该模型涵盖DNA双链断裂（DSB）生成、DSB修复系统、p53信号网络和凋亡诱导途径，以探究细胞命运决定未知标准的主导因素。在所提出的模型中，核内反应被建模为随机过程，细胞质反应被建模为确定性过程，并且同时模拟这两组反应。单细胞水平的模拟结果表明，该模型产生了p53、Mdm2、ATM和Wip1的多个持续振荡（脉冲），并且p53脉冲数量的细胞间变异性取决于辐射强度。在细胞群体中，该模型产生了衰减的p53振荡，并且辐射强度影响第一个p53振荡的幅度。然后使细胞接受相同的辐射剂量，结果显示出凋亡诱导的变异性。这些模拟结果与在人乳腺癌上皮MCF7、NIH3T3和纤维肉瘤细胞中观察到的主要生物学发现定量一致，表明所提出的模型在生物学上无疑是合适的。对模拟结果的统计分析表明，多个p53脉冲的产生是凋亡诱导的先决条件。此外，细胞在p53动态变化方面表现出相当大的个体变异性，这与内在凋亡诱导相关。基于所提出模型的模拟结果表明，核内生化反应过程的随机性控制着与DNA损伤相关的细胞命运的最终决定。将随机模拟应用于核内生化反应过程的探索对于增强对高等生物生物多层系统动态特征的理解是必不可少的。
