Effects of Wip1 and MiR-192 on the Dynamics of p53 Oscillation
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 simula-tions and bifurcation analyses,results for individual cells were obtained,indicating that the genera-tion of p53 oscillations requires the joint participation of Wip1 and miR-192;Wip1-mediated nega-tive feedback loop is essential for the generation of p53 oscillations.In addition,results in cell popu-lations 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 essen-tial 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.
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