Stress-specific response of the p53-Mdm2 feedback loop.
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.
Hunziker
Alexander
A
Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark.
Jensen
Mogens H
MH
Krishna
Sandeep
S
D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2