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Positive effect of Mdm2 on p53 expression explains excitability of p53 in response to DNA damage

Ján Eliaš1

  • 1Laboratoire de Mathématiques d'Orsay, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 91405 Orsay, France; Sorbonne Universités, Inria, UPMC Univ Paris 06, Lab. J.L. Lions UMR CNRS 7598, Paris, France.

Journal of Theoretical Biology
|January 28, 2017
PubMed

Insights

Mdm2 and MdmX cooperate to regulate p53 synthesis and degradation, leading to p53 oscillations. This dual regulation mechanism explains the p53 network's excitability and dynamic variability following DNA damage.

Area of Science:

  • Molecular Biology
  • Systems Biology
  • Cellular Dynamics

Background:

  • Traditional models view Mdm2 solely as a negative regulator of p53.
  • Mdm2 and MdmX's role in p53 regulation is more complex than previously understood.

Purpose of the Study:

  • To elucidate the dual regulatory role of Mdm2 in p53 dynamics.
  • To investigate the mechanism behind p53 oscillations in response to DNA damage.
  • To understand the contribution of Mdm2-MdmX-p53 interactions to network excitability.

Main Methods:

  • In silico modeling of molecular mechanisms.
  • Analysis of p53 synthesis and degradation pathways.
  • Investigating the role of ATM-dependent phosphorylation in Mdm2, MdmX, and p53 regulation.

Main Results:

  • Mdm2, in conjunction with MdmX, enhances p53 synthesis, not just degradation.
  • ATM-dependent phosphorylation of Mdm2 and MdmX is crucial for this dual role.
  • This mechanism drives widely oscillating p53 levels, indicating network excitability.

Conclusions:

  • A novel molecular mechanism for Mdm2's dual regulation of p53 is proposed.
  • This mechanism explains the observed oscillations and variability in p53 dynamics.
  • Findings provide insights into the p53 network's response to DNA damage.
Keywords:
ExcitabilityMdm2OscillationsP53Reaction-diffusion model

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