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Updated: Jun 11, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Stress-specific response of the p53-Mdm2 feedback loop
Alexander Hunziker1, Mogens H Jensen, Sandeep Krishna
1Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark.
Background:
The p53 signalling pathway has hundreds of inputs and outputs. It can trigger cellular senescence, cell-cycle arrest and apoptosis in response to diverse stress conditions, including DNA damage, hypoxia and nutrient deprivation. Signals from all these inputs are channeled through a single node, the transcription factor p53. Yet, the pathway is flexible enough to produce different downstream gene expression patterns in response to different stresses.
Results:
We construct a mathematical model of the negative feedback loop involving p53 and its inhibitor, Mdm2, at the core of this pathway, and use it to examine the effect of different stresses that trigger p53. In response to DNA damage, hypoxia, etc., the model exhibits a wide variety of specific output behaviour - steady states with low or high levels of p53 and Mdm2, as well as spiky oscillations with low or high average p53 levels.
Conclusions:
We show that even a simple negative feedback loop is capable of exhibiting the kind of flexible stress-specific response observed in the p53 system. Further, our model provides a framework for predicting the differences in p53 response to different stresses and single nucleotide polymorphisms.
Insights
A mathematical model of the p53-Mdm2 feedback loop shows how this system generates diverse responses to different cellular stresses. This flexibility allows the p53 pathway to adapt to various conditions.
Area of Science:
- Cellular Biology
- Systems Biology
- Mathematical Modeling
Background:
- The p53 signaling pathway regulates critical cellular processes like senescence, cell-cycle arrest, and apoptosis in response to various stresses.
- All stress signals converge on the transcription factor p53, yet the pathway exhibits stress-specific downstream gene expression patterns.
Purpose of the Study:
- To investigate the mechanisms underlying the p53 pathway's flexible, stress-specific responses.
- To model the core negative feedback loop involving p53 and its inhibitor, Mdm2.
Main Methods:
- Construction of a mathematical model of the p53-Mdm2 negative feedback loop.
- Simulation of the model under different stress conditions (e.g., DNA damage, hypoxia).
Main Results:
- The model accurately reproduces diverse output behaviors, including steady states (low/high p53 and Mdm2) and oscillatory patterns (spiky oscillations with varying average p53 levels).
- These varied outputs correspond to different cellular stress inputs.
Conclusions:
- A simple negative feedback loop can generate the observed flexibility in the p53 system's stress response.
- The model serves as a predictive framework for understanding p53 responses to different stresses and genetic variations.
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