Dynamics of p53 regulatory network in DNA damage response

Abstract

The tumor suppressor p53 plays a central role in the DNA damage response by inducing cell cycle arrest or apoptosis and several recent experiments have shown interesting dynamics in p53 protein expression during the repair cycle. In this paper, based on the three-module model proposed by Chickermane et al., a general model of delayed p53 regulatory network in the DNA damage response is formulated by introducing ubiquitous transcription and translation delays in the p53-Mdm2 oscillator module proposed by Zhang et al.. The dynamics of p53 regulatory network in DNA damage response are investigated through analytic analysis and numerical methods. It turns out that the pulsatile behavior can be generated due to initial DNA damage signals and ATM shows a switch-like behavior and relays the DNA damage signal. Moreover, the delays required for transcription and translation in Mdm2 gene expression can drive p53 to be oscillatory and an optimal rate of model parameters is also essential to these oscillations. Furthermore, the length of these delays can determine the amplitude and period of the oscillations. These results may provide a perspective for the development of anti-cancer therapy.