The dynamics of p53 in single cells: physiologically based ODE and reaction-diffusion PDE models

Area of Science:

• Cellular biology
• Molecular biology
• Biophysics

Background:

• The p53 protein is crucial for genome stability and cell cycle regulation.
• Observed p53 oscillations in single cells under stress warrant further investigation into their physiological significance.
• Understanding p53 dynamics is key to comprehending cellular responses to DNA damage.

Purpose of the Study:

• To model the activation and regulation of p53 in single cells after DNA damage.
• To investigate the mechanisms underlying p53 oscillatory behavior.
• To determine if known negative feedback loops are sufficient to explain these oscillations.

Main Methods:

• Development of compartmental Ordinary Differential Equation (ODE) and Partial Differential Equation (PDE) models.
• Simulation of p53 dynamics following DNA damage.
• Analysis of the role of p53-Mdm2 and ATM-p53-Wip1 negative feedback loops.

Main Results:

• The proposed models successfully reproduce p53 oscillations.
• p53 oscillations can be explained solely by the p53-Mdm2 and ATM-p53-Wip1 negative feedback loops.
• No additional delays or positive feedback mechanisms are required to generate oscillations.

Conclusions:

• The interplay of p53-Mdm2 and ATM-p53-Wip1 negative feedbacks is sufficient to drive p53 oscillations.
• These findings provide a simplified yet robust explanation for p53 dynamics in response to DNA damage.
• The study offers insights into the fundamental mechanisms of cellular stress response.