Stochastic Simulation of the p53-MDM2/MDMX Loop

Abstract

The p53 tumor suppressor is regulated through a negative feedback loop involving its transcriptional target MDM2. MDMX is also an essential negative regulator of p53. Several computational models have been proposed to simulate the dynamics of the p53-MDM2 loop, but they do not include MDMX and cannot capture the intrinsic noise in the loop. We present a model for the p53-MDM2/MDMX loop that is characterized by a set of molecular reactions, which enables us to employ stochastic simulation to investigate the dynamics of the loop. In agreement with experiments, our results show that p53 and MDM2 undergo oscillations after DNA damage even in the presence of noise, and the variation in oscillation amplitudes is much higher than that in oscillation periods. However, the intrinsic noise only contributes to about one-third of total variation in oscillation amplitudes and periods. Our results also show that p53 levels increase dramatically when MDM2 is knocked out, but increase with amuch less amount when MDMX is knocked out. This may explain why MDM2-null and MDMX-null mouse embryos die in different developmental stages.