Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System.
Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System.
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DOI：
10.1371/journal.pcbi.1004787
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发表时间：
2016-02
影响因子：
4.3
通讯作者：
Lipniacki T
中科院分区：
文献类型：
--
作者：
Hat B;Kochańczyk M;Bogdał MN;Lipniacki T
p53转录因子是包括DNA修复、细胞周期停滞和细胞凋亡的关键细胞过程的调节因子。在这项理论研究中，我们研究了p53网络的复杂电路如何允许随机但明确的细胞命运决策。建议的马尔可夫链模型由调节核心和两个从属的控制模块负责细胞周期停滞和凋亡。调节核心由负责振荡的两个负反馈回路（由Mdm 2和Wip1调节）和负责双稳态的两个拮抗性正反馈回路（由磷酸酶Wip1和PTEN调节）控制。通过确定性近似的分支分析，我们捕获了递归解（即，稳态和极限环），其描绘随机系统的时间响应。从极限环振荡到"凋亡"稳态的直接切换是通过亚临界Neimark-Sacker分叉的存在而实现的，其中极限环通过与不稳定的不变环面合并而失去其稳定性。我们的分析提供了一个解释，为什么已知具有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：从快速转变为高水平的p53杀手（一种促进细胞凋亡的p53磷酸形式）在以高PTEN和低Wip1水平为特征的细胞中的表达，到具有PTEN启动子甲基化的细胞中的持久p53水平振荡（例如，MCF-7细胞系）。癌症是信号网络的疾病。转录因子p53是整合各种应激信号并控制DNA修复、细胞周期停滞和凋亡的关键过程的网络的关键节点。有些矛盾的是，尽管事实上癌的发生是由p53网络功能障碍引起的，但我们对p53信号传导的大部分知识都是基于癌症或永生化细胞系。在本文中，我们构建了一个完整的p53网络的数学模型，以了解非癌细胞的动力学，然后通过引入扰动的调节系统的癌细胞的动力学。细胞命运的决定是由相互联系的反馈回路的存在，从而产生了丰富的行为剧目。我们通过数值模拟解释和分析了调控系统的动态结构如何允许产生明确的单细胞命运决定，也是在细胞群分裂成凋亡和存活亚群的情况下。扰动分析提供了一种解释，为什么已知具有非常不同的p53调节剂表达水平的癌细胞系可以表现出对DNA损伤的广谱反应。
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). Cancers are diseases of signaling networks. Transcription factor p53 is a pivotal node of a network that integrates a variety of stress signals and governs critical processes of DNA repair, cell cycle arrest, and apoptosis. Somewhat paradoxically, despite the fact that carcinogenesis is prevalently caused by p53 network malfunction, most of our knowledge about p53 signaling is based on cancer or immortalized cell lines. In this paper, we construct a mathematical model of intact p53 network to understand dynamics of non-cancerous cells and then dynamics of cancerous cells by introducing perturbations to the regulatory system. Cell fate decisions are enabled by the presence of interlinked feedback loops which give rise to a rich repertoire of behaviors. We explain and analyze by means of numerical simulations how the dynamical structure of the regulatory system allows for generating unambiguous single-cell fate decisions, also in the case when the cell population splits into an apoptotic and a surviving subpopulation. Perturbation analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of p53 regulators can exhibit a broad spectrum of responses to DNA damage.