Biological mechanisms revealed by a mathematical model for p53-Mdm2 core regulation

Abstract

p53 is a paramount protein in cancer studies, and p53-Mdm2 interaction is the core regulation for most activities of p53 protein-related networks. In this study, a new mathematical model is built to characterise the p53-Mdm2 interaction based on the recent biological findings, as well as a few reasonable hypotheses and approximations. The dynamics of ATM (Ataxia Telangiectasia Mutated) is introduced to the model so as to connect DNA damage signal with the core regulation. The simulation results are in good accord with the experimental observations in the literature. More importantly, through bifurcation analysis on the model, a new threshold mechanism is predicted with respect to the dose of ionising radiation (IR). Furthermore, a novel frequency shifting phenomenon is also observed through Fourier frequency analysis on the simulation data. Finally, based on the predicted dominant frequency, an optimised experimental scheme is proposed to guide the experimental procedure. Once these two predicted mechanisms are validated through wet-lab experiments, they could provide us more insights for p53-Mdm2 core regulation and related pathways. © The Institution of Engineering and Technology 2009.