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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

p53 dynamics. A: Time dependence of the p53 concentration after application of different cellular stresses at time zero. B-D: The colors show peak concentration of free p53, after the system has settled into a steady-state or stable oscillations (note that the peak level differs from the average only when there are oscillations), as a function of two model parameters. The white line marks where the spikyness (amplitude/average [25]) of p53 oscillations becomes equal to 2 (i.e., where the amplitude becomes twice the average). Thus, spiky oscillations occur to the right of the line in (B) and (D), and to the left in (C). The white dot shows the parameters corresponding to the default resting state (see Table 1). Black arrows illustrate the change in parameters we impose on the system to model the respective stresses.
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Figure 2: p53 dynamics. A: Time dependence of the p53 concentration after application of different cellular stresses at time zero. B-D: The colors show peak concentration of free p53, after the system has settled into a steady-state or stable oscillations (note that the peak level differs from the average only when there are oscillations), as a function of two model parameters. The white line marks where the spikyness (amplitude/average [25]) of p53 oscillations becomes equal to 2 (i.e., where the amplitude becomes twice the average). Thus, spiky oscillations occur to the right of the line in (B) and (D), and to the left in (C). The white dot shows the parameters corresponding to the default resting state (see Table 1). Black arrows illustrate the change in parameters we impose on the system to model the respective stresses.

Mentions: This model system of a negative feedback loop shows plenty of variety in output behaviour. Depending on the values of parameters, the system is capable of steady state solutions with any combination of high or low p53 and Mdm2, as well as oscillations with high or low average p53. Figure 2A shows four examples: a steady state response and oscillations with differing amplitudes and periods. The oscillations are typically spiky, but smooth oscillations can also be generated.


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

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

p53 dynamics. A: Time dependence of the p53 concentration after application of different cellular stresses at time zero. B-D: The colors show peak concentration of free p53, after the system has settled into a steady-state or stable oscillations (note that the peak level differs from the average only when there are oscillations), as a function of two model parameters. The white line marks where the spikyness (amplitude/average [25]) of p53 oscillations becomes equal to 2 (i.e., where the amplitude becomes twice the average). Thus, spiky oscillations occur to the right of the line in (B) and (D), and to the left in (C). The white dot shows the parameters corresponding to the default resting state (see Table 1). Black arrows illustrate the change in parameters we impose on the system to model the respective stresses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: p53 dynamics. A: Time dependence of the p53 concentration after application of different cellular stresses at time zero. B-D: The colors show peak concentration of free p53, after the system has settled into a steady-state or stable oscillations (note that the peak level differs from the average only when there are oscillations), as a function of two model parameters. The white line marks where the spikyness (amplitude/average [25]) of p53 oscillations becomes equal to 2 (i.e., where the amplitude becomes twice the average). Thus, spiky oscillations occur to the right of the line in (B) and (D), and to the left in (C). The white dot shows the parameters corresponding to the default resting state (see Table 1). Black arrows illustrate the change in parameters we impose on the system to model the respective stresses.
Mentions: This model system of a negative feedback loop shows plenty of variety in output behaviour. Depending on the values of parameters, the system is capable of steady state solutions with any combination of high or low p53 and Mdm2, as well as oscillations with high or low average p53. Figure 2A shows four examples: a steady state response and oscillations with differing amplitudes and periods. The oscillations are typically spiky, but smooth oscillations can also be generated.

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