On the role of intrinsic noise on the response of the p53-Mdm2 module

TL;DR

This paper investigates how intrinsic cellular noise influences the sustained oscillations of the p53-Mdm2 feedback loop, challenging previous models and aligning with recent single-cell experimental observations.

Contribution

It proposes that intrinsic noise from finite molecule numbers, rather than external or ad-hoc noise, stabilizes p53-Mdm2 oscillations in single cells.

Findings

Intrinsic noise can sustain oscillations in p53-Mdm2 dynamics.

Single-cell data aligns with models incorporating intrinsic noise.

Challenges previous models relying on external noise for oscillation stability.

Abstract

The protein p53 has a well established role in protecting genomic integrity in human cells. When DNA is damaged p53 induces the cell cycle arrest to prevent the transmission of the damage to cell progeny, triggers the production of proteins for DNA repair and ultimately calls for apoptosis. In particular, the p53-Mdm2 feedback loop seems to be the key circuit in this response of cells to damage. For many years, based on measurements over populations of cells it was believed that the p53-Mdm2 feedback loop was the responsible for the existence of damped oscillations in the levels of p53 and Mdm2 after DNA damage. However, recent measurements in individual human cells have shown that p53 and its regulator Mdm2 develop sustained oscillations over long periods of time even in the absence of stress. These results have attracted a lot of interest, first because they open a new experimental framework to study the p53 and its interactions and second because they challenge years of mathematical models with new and accurate data on single cells. Inspired by these experiments standard models of the p53-Mdm2 circuit were modified introducing ad-hoc some biologically motivated noise that becomes responsible for the stability of the oscillations. Here, we follow an alternative approach proposing that the noise that stabilizes the fluctuations is the intrinsic noise due to the finite nature of the populations of p53 and Mdm2 in a single cell.