National Laboratory of Solid State Microstructures, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, China.
School of Physics and Electronic Engineering, Jiangsu Normal University, Xuzhou, 221116, China.
Sci Rep. 2019 Apr 10;9(1):5883. doi: 10.1038/s41598-019-41904-9.
The p53 protein is a key mediator of the cellular response to various stress signals. In response to DNA damage, the concentration of p53 can temporally oscillate with fluctuations in both the amplitude and period. The underlying mechanism for p53 variability is not fully understood. Here, we construct a core regulatory network of p53 dynamics comprising the ATM-p53-Wip1 and p53-Mdm2 negative feedback loops. We dissect the contributions of cellular heterogeneity, intrinsic noise, and multiple forms of extrinsic noise to p53 variability in terms of the coefficients of variation of four quantities. Cellular heterogeneity greatly determines the fraction of oscillating cells among a population of isogenic cells. Intrinsic noise-fluctuation in biochemical reactions-has little impact on p53 variability given large amounts of molecules, whereas extrinsic colored noise with proper strength and correlation time contributes much to oscillatory variability in individual cells. With the three sources of noise combined, our results reproduce the experimental observations, suggesting that the long correlation time of colored noise is essential to p53 variability. Compared with previous studies, the current work reveals both the individual and integrated effects of distinct noise sources on p53 variability. This study provides a framework for exploring the variability in oscillations in cellular signaling pathways.
p53 蛋白是细胞对各种应激信号反应的关键介质。在响应 DNA 损伤时，p53 的浓度可以随幅度和周期的波动而暂时波动。p53 变异性的潜在机制尚未完全理解。在这里，我们构建了一个包含 ATM-p53-Wip1 和 p53-Mdm2 负反馈回路的 p53 动力学核心调控网络。我们根据四个量的变异系数，从细胞异质性、固有噪声和多种形式的外在噪声的角度来剖析它们对 p53 变异性的贡献。细胞异质性极大地决定了同基因细胞群体中振荡细胞的比例。内在噪声-生化反应中的波动-在分子数量较大的情况下对 p53 变异性几乎没有影响，而具有适当强度和相关时间的外在有色噪声对单个细胞的振荡变异性贡献很大。结合三种噪声源，我们的结果再现了实验观察结果，表明有色噪声的长相关时间对 p53 变异性至关重要。与以前的研究相比，目前的工作揭示了不同噪声源对 p53 变异性的个体和综合影响。这项研究为探索细胞信号通路中的振荡变异性提供了一个框架。
