IEEE Trans Nanobioscience. 2019 Oct;18(4):611-621. doi: 10.1109/TNB.2019.2924079. Epub 2019 Jun 20.
DNA damage caused by γ -irradiation initiates oscillatory expression of the p53 genetic network. Although many studies revealed the effects of the p53-Mdm2 circuit on p53 dynamics, a few studies explored the contribution of upstream kinases to p53 oscillation. In this paper, an integrated mathematical model of the p53 network in response to γ -irradiation is studied, which consists of five basic components, two ubiquitous time delays, and two negative feedback loops. It is found that recurrent p53 pulses are externally initiated by ataxia telangiectasia mutated (ATM), and the negative feedback loop formed between ATM and p53, via Wip1, plays a dominant role in generating p53 oscillation. In addition, p53 oscillation requires not only an appropriate Mdm2 negative strength but also a threshold level of Wip1 negative strength. Furthermore, the time delays required for transcription and translation of Mdm2 and Wip1 proteins are essential for p53 oscillation. In particular, the critical value of time delay for inducing oscillation and the properties of delay-driven Hopf bifurcation are theoretically analyzed. As expected, the results are clearly in consistence with biological experiments and observations.
γ 射线辐射引起的 DNA 损伤会引发 p53 基因网络的振荡表达。虽然许多研究揭示了 p53-Mdm2 回路对 p53 动力学的影响，但很少有研究探讨上游激酶对 p53 振荡的贡献。本文研究了一种对 γ 射线辐射做出响应的 p53 网络综合数学模型，它由五个基本组件、两个普遍存在的时滞和两个负反馈回路组成。研究发现，共济失调毛细血管扩张突变蛋白（ATM）会外部引发周期性的 p53 脉冲，并且 ATM 和 p53 之间形成的负反馈环通过 Wip1 发挥主要作用，从而产生 p53 振荡。此外，p53 振荡不仅需要适当的 Mdm2 负强度，还需要 Wip1 负强度的阈值水平。此外，Mdm2 和 Wip1 蛋白转录和翻译所需的时滞对于 p53 振荡至关重要。特别是，诱导振荡的时滞临界值和时滞驱动的 Hopf 分岔的特性在理论上进行了分析。不出所料，结果与生物实验和观察结果完全一致。
