Oscillatory Dynamics of p53-Mdm2 Circuit in Response to DNA Damage Caused by Ionizing Radiation

AbstractAlthough the dynamical behavior of the p53-Mdm2 loop has been extensively studied, the understanding of the mechanism underlying the regulation of this pathway still remains limited. Herein, we developed an integrated model with five basic components and three ubiquitous time delays for the p53-Mdm2 interaction in response to DNA damage following ionizing radiation (IR). We showed that a sufficient amount of activated ATM level can initiate the p53 oscillations with nearly the same amplitude over a wide range of the ATM level; a proper range of p53 level is also required for generating the oscillations, for too high or too low levels it would fail to generate the oscillations; and increased Mdm2 level leads to decreased amplitude of the p53 oscillation and reduced expression of the p53 activity. Moreover, we found that the negative feedback loop formed between p53 and nuclear Mdm2 plays a dominant role in determining the p53 dynamics, whereas when interaction strength of the negative feedback loop becomes weaker, the positive feedback loop formed between p53 and cytoplasmatic Mdm2 can induce different types of dynamics. Furthermore, we demonstrated that the total time delay required for protein production and nuclear translocation of Mdm2 can induce p53 oscillations even when the p53 level is at a certain stable high steady state or at a certain stable low steady state. In addition, the two important features of the oscillatory dynamics-amplitude and period-can be controlled by such time delay. These results are in agreement with multiple experimental observations and may enrich our understanding of the dynamics of the p53 network.