Negative feedback and time delay regulate p53 oscillation in response to DNA damage

In this paper, a novel dynamical model of p53 network is formulated to study the contribution of both negative feedback loops and time delays to the generation of p53 oscillation when cells respond to ionizing radiation. The results showed that the ATM-p53-Wip1 negative feedback loop plays a major role in inducing p53 oscillation, while the p53-Mdm2 loop cannot induce oscillation under the premise of ATM-p53-Wip11oop presence. In addition, sufficient Wip1 inhibition is also necessary for p53 oscillation, while excessive Mdm2 inhibition stops p53 oscillation. Furthermore, by analyzing the effect of time delay on p53 oscillation network, it is observed that time delay induces a supercritical Hopf bifurcation to drive p53 oscillation, and both the amplitude and period will increase with time delay. As expected, the results are in consistence with some biological experiments and observations.