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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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Published on: August 4, 2019

Explaining oscillations and variability in the p53-Mdm2 system.

Carole J Proctor1, Douglas A Gray

  • 1Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. c.j.proctor@ncl.ac.uk

BMC Systems Biology
|August 19, 2008
PubMed
Summary
This summary is machine-generated.

Mathematical models reveal that the p53/Mdm2 circuit exhibits sustained oscillations due to core biological mechanisms. These models offer insights into cellular aging and cancer by explaining p53 pulsing after DNA damage.

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Area of Science:

  • Cellular Biology
  • Systems Biology
  • Biophysics

Background:

  • The p53 protein, a key regulator in cellular response to DNA damage, is known to be expressed in pulses.
  • Its negative regulator, Mdm2, also exhibits oscillatory behavior, suggesting a complex regulatory circuit.
  • Previous mathematical models have not fully captured the explicit molecular mechanisms driving these oscillations.

Purpose of the Study:

  • To develop and analyze two stochastic mechanistic models of the p53/Mdm2 circuit.
  • To demonstrate that sustained oscillations arise directly from fundamental biological features of the circuit.
  • To explore different negative feedback mechanisms contributing to p53 activation post-DNA damage.

Main Methods:

  • Developed two distinct stochastic mechanistic models of the p53/Mdm2 feedback loop.
  • Model 1 (ARF model) incorporates the p14ARF mechanism, sequestering Mdm2 to stabilize p53.
  • Model 2 (ATM model) includes ATM activation, leading to p53 and Mdm2 phosphorylation and Mdm2 degradation.

Main Results:

  • The ARF model predicts robust, undamped oscillations in p53 levels as long as DNA damage persists.
  • Both models show oscillations can be triggered by accumulating DNA damage, relevant to cellular aging.
  • The ATM model requires an additional p53 synthesis step for sustained oscillations and exhibits greater variability, potentially explaining experimental observations in ARF-negative cells.

Conclusions:

  • The models suggest that the presence of ARF leads to more regular p53 oscillations, highlighting the need for experimental validation in ARF-positive cells.
  • These findings underscore the utility of systems biology approaches in understanding the multifaceted roles of p53 in aging and cancer.
  • The models are adaptable for future modifications and integration with other models, such as those for cellular senescence.