A Canonical 3-D P53 Network Model that Determines Cell Fate by Counting Pulses

Abstract

From a system theory perspective p53 network dynamics is interesting since it can exhibit three dynamical modes of p53 namely low-level equilibrium oscillation and high-level equilibrium. Each of these modes are associated with different cell fate outcomes: cell survival cell cycle arrest and apoptosis.The literature reveals that a high level (apoptosis) is seen only after ending the oscillation phase so called two-phase dynamics which provides thedecision of apoptosis depending on the oscillation duration. This paper proposes that a negative feedback can keep time by counting the pulses ofoscillation to take the decision of apoptosis or cell survival. P53DINP1 which is the mediator of this feedback is added as a variable to a 2-D oscillatormodel of the p53 network. The resulting canonical 3-D model successfully replicates the two-phase dynamics. That is it possesses temporary oscillatorybehavior in which first oscillations (first phase) and then high level state (second phase) are observed. By introducing a new variable to the core oscillatorin the p53 network this study demonstrates that p53 network can be considered a modular structure which consists of an oscillator and other variablesthat control this oscillator to contribute to cell fate determination.