人体细胞中 p53 振荡器的协调性和多重稳定性。

Cell systems Pub Date : 2024-10-16 Epub Date: 2024-10-04 DOI:10.1016/j.cels.2024.09.001
Alba Jiménez, Alessandra Lucchetti, Mathias S Heltberg, Liv Moretto, Carlos Sanchez, Ashwini Jambhekar, Mogens H Jensen, Galit Lahav
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引用次数: 0

摘要

肿瘤抑制因子 p53 会对细胞压力做出反应,并激活对调节细胞命运至关重要的转录程序。DNA 损伤会引发 p53 水平的振荡,振荡周期较长。在同步和夹带理论的指导下,我们建立了一个数学模型和实验系统,以测试 p53 振荡器夹带不同周期和强度的外部药物脉冲的能力。我们发现,p53 振荡器可以锁定和夹带多种夹带模式。远离 p53 自然振荡的外部周期增加了单个细胞之间的异质性,而较强的输入则减少了这种异质性。通过单细胞测量,可以得出 p53 的相位响应曲线(PRC)和多个阿诺舌。此外,我们还从数学上预测并从实验中检测到了多稳定性和非线性行为,包括跳模、周期倍增和混沌。我们的工作揭示了 p53 振荡器的关键动态特性,并为理解和控制它提供了见解。本文的同行评审过程透明,相关记录见补充信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Entrainment and multi-stability of the p53 oscillator in human cells.

The tumor suppressor p53 responds to cellular stress and activates transcription programs critical for regulating cell fate. DNA damage triggers oscillations in p53 levels with a robust period. Guided by the theory of synchronization and entrainment, we developed a mathematical model and experimental system to test the ability of the p53 oscillator to entrain to external drug pulses of various periods and strengths. We found that the p53 oscillator can be locked and entrained to a wide range of entrainment modes. External periods far from p53's natural oscillations increased the heterogeneity between individual cells whereas stronger inputs reduced it. Single-cell measurements allowed deriving the phase response curves (PRCs) and multiple Arnold tongues of p53. In addition, multi-stability and non-linear behaviors were mathematically predicted and experimentally detected, including mode hopping, period doubling, and chaos. Our work revealed critical dynamical properties of the p53 oscillator and provided insights into understanding and controlling it. A record of this paper's transparent peer review process is included in the supplemental information.

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