Two-dimensional polynomial type canonical relaxation oscillator model for p53 dynamics

Abstract

p53 network which is responsible for DNA damage response of cells exhibits three distinct qualitative behaviours, low state oscillation and high state which are associated with normal cell cycle progression cell cycle arrest and apoptosis respectively. The experimental studies demonstrate that these dynamics of p53 are due to the ATM and Wip1 interaction. This paper proposes a simple two-dimensional canonical relaxation oscillator model based on the identified topological structure of ATM and Wip1 interaction underlying these qualitative behaviours of p53 network. The model includes only polynomial terms that have the interpretability of known ATM and Wip1 interaction. The introduced model is useful for understanding relaxation oscillations in gene regulatory networks. Through mathematical analysis we investigate the roles of ATM and Wip1 in forming of these three essential behaviours and show that ATM and Wip1 constitute the core mechanism of p53 dynamics. In agreement with biological findings we show that Wip1 degradation term is a highly sensitive parameter possibly related to mutations. By perturbing the corresponding parameters our model characterizes some mutations such as ATM deficiency and Wip1 overexpression. Finally we provide intervention strategies considering our observation that Wip1 seems to be an important target to conduct therapies for these mutations. © 2018 Elsevier B.V. All rights reserved.