Hat Beata, Kochańczyk Marek, Bogdał Marta N, Lipniacki Tomasz
Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
Department of Statistics, Rice University, Houston, Texas, United States of America.
PLoS Comput Biol. 2016 Feb 29;12(2):e1004787. doi: 10.1371/journal.pcbi.1004787. eCollection 2016 Feb.
The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the "apoptotic" steady state is enabled by the existence of a subcritical Neimark-Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line).
p53转录因子是包括DNA修复、细胞周期阻滞和细胞凋亡在内的关键细胞过程的调节因子。在这项理论研究中，我们探究p53网络的复杂电路如何实现随机但明确的细胞命运决策。所提出的马尔可夫链模型由调节核心和两个负责细胞周期阻滞和细胞凋亡的从属双稳模块组成。调节核心由负责振荡的两个负反馈回路（由Mdm2和Wip1调节）和负责双稳性的两个拮抗正反馈回路（由磷酸酶Wip1和PTEN调节）控制。通过确定性近似的分岔分析，我们捕捉到了描绘随机系统时间响应的递归解（即稳态和极限环）。极限环振荡到“凋亡”稳态的直接转换是由亚临界奈马克-萨克分岔的存在实现的，在该分岔中，极限环通过与不稳定不变环面合并而失去稳定性。我们的分析解释了为什么已知Wip1和PTEN表达水平差异很大的癌细胞系对DNA损伤表现出广泛的反应：从具有高PTEN和低Wip1水平的细胞中快速转变为高水平的p53杀手（一种促进凋亡的p53磷酸化形式），到具有PTEN启动子甲基化的细胞（如MCF-7细胞系）中p53水平的持久振荡。
