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Stress-specific response of the p53-Mdm2 feedback loop.

Hunziker A, Jensen MH, Krishna S - BMC Syst Biol (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark.

ABSTRACT

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.

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Related in: MedlinePlus

Sensitivity analysis. Fold change in average p53 level for fold changes, ranging from 1/5 to 5, in various parameters. For each curve, the corresponding parameter is varied from its default value while keeping all other parameter values fixed. The slope of each curve is a measure of the sensitivity of the p53 level to changes in that parameter.
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Figure 3: Sensitivity analysis. Fold change in average p53 level for fold changes, ranging from 1/5 to 5, in various parameters. For each curve, the corresponding parameter is varied from its default value while keeping all other parameter values fixed. The slope of each curve is a measure of the sensitivity of the p53 level to changes in that parameter.

Mentions: Figure 3 shows the relative effect on the average free p53 level when each parameter of the model is varied from its default value, keeping the values of all other parameters fixed. The slope of each curve is a measure of how sensitive the p53 level is to changes in the corresponding parameter. There was no necessity to examine variations with respect to β and ktl because one can always choose units of time and mRNA concentration such that β = 1 and ktl = 1, i.e., changes in β or ktl can be mimicked by changes in other parameters.


Stress-specific response of the p53-Mdm2 feedback loop.

Hunziker A, Jensen MH, Krishna S - BMC Syst Biol (2010)

Sensitivity analysis. Fold change in average p53 level for fold changes, ranging from 1/5 to 5, in various parameters. For each curve, the corresponding parameter is varied from its default value while keeping all other parameter values fixed. The slope of each curve is a measure of the sensitivity of the p53 level to changes in that parameter.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913930&req=5

Figure 3: Sensitivity analysis. Fold change in average p53 level for fold changes, ranging from 1/5 to 5, in various parameters. For each curve, the corresponding parameter is varied from its default value while keeping all other parameter values fixed. The slope of each curve is a measure of the sensitivity of the p53 level to changes in that parameter.
Mentions: Figure 3 shows the relative effect on the average free p53 level when each parameter of the model is varied from its default value, keeping the values of all other parameters fixed. The slope of each curve is a measure of how sensitive the p53 level is to changes in the corresponding parameter. There was no necessity to examine variations with respect to β and ktl because one can always choose units of time and mRNA concentration such that β = 1 and ktl = 1, i.e., changes in β or ktl can be mimicked by changes in other parameters.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus