Hunziker2010_p53_StressSpecificResponse

This a model from the article:

Stress-specific response of the p53-Mdm2 feedback loop

Alexander Hunziker, Mogens H Jensen and Sandeep Krishna
BMC Systems Biology 2010, Jul 12;4(1):94
20624280,

Abstract:

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.

The parameters of the model corresponds to the resting state, with delta = 11hr-1, gamma = 0.2hr-1, kt = 0.03nM-1hr-1 and kf = 5000nM-1hr-1.
To simulate different stress conditions as in figure 2A (also look at the curation figure of this model) of the reference publication, the above parameter should be changed. The parameter values corresponding to different stress conditions are shown in the following table.

Stress Condition/Parameter
delta
gamma

kt

kf

Nutlin
11hr-1

0.2hr-1

0.03nM-1hr-1

500nM-1hr-1

Oncogene
2hr-1
0.2hr-1
0.03nM-1hr-1
5000nM-1hr-1

DNA damage
2hr-1
0.5hr-1
0.03nM-1hr-1
2500nM-1hr-1

Hypoxia
2hr-1
0.2hr-1
0.01nM-1hr-1
5000nM-1hr-1

This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2011 The BioModels.net Team.For more information see the terms of use.To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.