Wip1和MiR-192对p53振荡动力学的影响

Effects of Wip1 and MiR-192 on the Dynamics of p53 Oscillation

细胞应激触发动态的p53响应,包括与细胞命运紧密相关的振荡。通过构建包括p53-Mdm2负反馈回路、耦合ATM-p53-Wip1负反馈回路和p53-miR-192-Mdm2正反馈回路的数学模型,描述了MCF-7细胞中的p53振荡产生的机制,探究了Wip1和miR-192对p53振荡的影响。利用数值模拟和分岔分析获得了单个细胞的结果,表明p53振荡的产生需要Wip1和miR-192的共同参与;Wip1介导的负反馈回路对p53振荡的产生是必不可少的。此外,通过设置随机参数集,获得了细胞群中的结果,展现了细胞之间振荡特性的显著变异性;miR-192介导的正反馈回路对于增强p53响应系统的性能稳健性至关重要。研究结果与实验结论高度吻合,对理解p53振荡动力学行为有一定意义。

Cellular stress triggers dynamic p53 responses,including oscillations that are tightly linked to cell fate.The mechanism by which p53 oscillations are generated in MCF-7 cells was described by constructing a mathematical model including a p53-Mdm2 negative feedback loop,a coupled ATM-p53-Wip1 negative feedback loop and a p53-miR-192-Mdm2 positive feedback loop.The effects of Wip1 and miR-192 on p53 oscillations were also explored.Using numerical simulations and bifurcation analyses,results for individual cells were obtained,indicating that the generation of p53 oscillations requires the joint participation of Wip1 and miR-192;Wip1-mediated negative feedback loop is essential for the generation of p53 oscillations.In addition,results in cell populations were obtained by setting random parameter sets,demonstrating that there are significant variability in oscillation properties between cells;miR-192-mediated positive feedback loop is essential for enhancing the robustness of the p53 response system.These findings are highly compatible with the experimental conclusions and have important implications for understanding the behaviour of p53 oscillatory dynamics.