Mdm2生成速率调控的p53-Mdm2振子的全局动力学和稳定性

肿瘤抑制蛋白p53的动力学在一定程度上可以决定DNA损伤后的细胞命运.p53的动力学行为与p53信号通路中p53-Mdm2振子模块密切相关.然而,p53的负调控子Mdm2的生成速率的增加使其在一些癌细胞中过表达.因此探讨Mdm2生成速率对p53动力学的影响有重要意义.同时,PDCD5作为p53的激活子也调控p53的表达.因此,本文针对PDCD5调控的p53-Mdm2振子模型,通过分岔分析获得了Mdm2生成速率所调控的p53的单稳态、振荡以及单稳态与振荡共存的动力学行为,且稳定性通过能量面进行了分析.此外,噪声强度对p53动力学的稳定性有重要的影响.因此,针对p53的振荡行为,探讨了噪声强度对势垒高度和周期的影响.本文所获得的结果对理解DNA损伤后的p53信号通路调控起到一定的指导作用.

Global dynamics and stability of p53-Mdm2 oscillator mediated by Mdm2 production rate

Studying global dynamics and stability of biological network is of importance in order to understand its function and behavior. In this paper, we consider the p53-Mdm2 oscillator module with PDCD5 as a core part of p53 signaling pathway after the DNA damage, and explore the dynamics and stability of the tumor suppressor p53. The dynamics of p53 may decide the cell fate after the DNA damage, while the oscillation of p53 may induce cell cycle arrest and so promote the repair of DNA, and the high levels of p53 can trigger apoptosis. However, p53 activity may be inhibited by its negative regulator Mdm2 in some cancer cells, as Mdm2 is of overexpression due to the increase in Mdm2 production rate. So we first investigate the effect of Mdm2 production rate on the kinetics of p53 through bifurcation analysis. after the DNA damage. With the increase in Mdm2 production rate, p53 can display a steady state, a stable-limit cycle and the coexistence of a stable-limit cycle and a stable steady state. Furthermore, the potential landscapes for oscillation show that the lower concentration of p53 means a stronger stability, whereas those for bistability of the higher steady state and the oscillatory state illustrate that stability of the higher steady state increases with the increasing Mdm2 production rate. In addition, noise strength can greatly affect the stability of p53 oscillations, so we explore the effect of noise strength on potential landscapes, barrier heights and periods. A smaller noise strength leads to a higher barrier height associated with more stable-limit cycle, and the harmonic oscillation with more uniform period and smaller variance is helpful to have more stable maintainance. Our results may be useful for understanding regulation of p53 signaling pathway after DNA damage.