肿瘤抑制因子 p53 对细胞应激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 水平的剧烈振荡。在同步和夹带理论的指导下，我们开发了数学模型和实验系统来测试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 振荡器可以被锁定并夹带到多种夹带模式。远离 p53 自然振荡的外部周期会增加单个细胞之间的异质性，而较强的输入则会减少这种异质性。单细胞测量可以得出 p53 的相位响应曲线 (PRC) 和多个 Arnold 舌头。此外，还对多稳定性和非线性行为进行了数学预测和实验检测，包括模式跳跃、周期倍增和混沌。我们的工作揭示了 p53 振荡器的关键动力学特性，并为理解和控制它提供了见解。补充信息中包含了本文透明同行评审过程的记录。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.