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BIOMD0000000252 - Hunziker2010_p53_StressSpecificResponse


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Reference Publication
Publication ID: 20624280
Hunziker A, Jensen MH, Krishna S.
Stress-specific response of the p53-Mdm2 feedback loop.
BMC Syst Biol 2010; 4: 94
Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark.  [more]
Original Model: BIOMD0000000252.origin
Submitter: Alexander Hunziker
Submission ID: MODEL1006280000
Submission Date: 28 Jun 2010 13:13:55 UTC
Last Modification Date: 25 Feb 2015 12:12:31 UTC
Creation Date: 16 Jul 2010 13:06:03 UTC
Encoders:  Vijayalakshmi Chelliah
   Alexander Hunziker
set #1
bqbiol:hasProperty Human Disease Ontology polycythemia due to hypoxia
set #2
bqbiol:hasTaxon Taxonomy Eukaryota
set #3
bqbiol:hasPart Gene Ontology DNA damage response, signal transduction by p53 class mediator
Gene Ontology response to hypoxia
bqbiol:isPartOf KEGG Pathway p53 signaling pathway
Reactome REACT_309

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: 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 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.

Publication ID: 20624280 Submission Date: 28 Jun 2010 13:13:55 UTC Last Modification Date: 25 Feb 2015 12:12:31 UTC Creation Date: 16 Jul 2010 13:06:03 UTC
Mathematical expressions
Rate Rule (variable: p) Rate Rule (variable: mm) Rate Rule (variable: m) Rate Rule (variable: pm)
Physical entities
Compartments Species
cell p mm m
Global parameters
S alpha k_t k_tl
k_b k_f beta gamma
Reactions (0)
Rules (4)
 Rate Rule (name: p) d [ p] / d t= ((S-k_f*p*m)-alpha*p)+(k_b+gamma)*pm
 Rate Rule (name: mm) d [ mm] / d t= k_t*p^2-beta*mm
 Rate Rule (name: m) d [ m] / d t= ((k_tl*mm-k_f*p*m)+(k_b+delta)*pm)-gamma*m
 Rate Rule (name: pm) d [ pm] / d t= (k_f*p*m-(k_b+delta)*pm)-gamma*pm
   cell Spatial dimensions: 3.0  Compartment size: 1.0
Compartment: cell
Initial concentration: 1.0
Compartment: cell
Initial concentration: 1.0
Compartment: cell
Initial concentration: 1.0
Compartment: cell
Initial concentration: 1.0
Global Parameters (9)
Value: 1000.0
Value: 0.1
Value: 0.03
Value: 1.4
Value: 7200.0
Value: 5000.0
Value: 0.6
Value: 0.2
Value: 11.0
Representative curation result(s)
Representative curation result(s) of BIOMD0000000252

Curator's comment: (updated: 16 Jul 2010 14:14:45 BST)

All the parameters of the model corresponds to the resting state. In order to generate the plot that corresponds to different stress conditions (figure 2A of the reference publication), the following parameters were changed for different stress conditions.
Nutlin: kf =500;
DNA Damage: delta=2, gamma=0.5 and kf=2500.
Oncogene: delta=2;
Hypoxia: delta=2, kt=0.01;