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BIOMD0000000189 - Proctor2008 - p53/Mdm2 circuit - p53 stablisation by p14ARF

 

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Reference Publication
Publication ID: 18706112
Proctor CJ, Gray DA.
Explaining oscillations and variability in the p53-Mdm2 system.
BMC Syst Biol 2008; 2: 75
Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. c.j.proctor@ncl.ac.uk  [more]
Model
Original Model: BIOMD0000000189.xml.origin
Submitter: Carole Proctor
Submission ID: MODEL8142536273
Submission Date: 05 Sep 2008 15:30:23 UTC
Last Modification Date: 11 Aug 2014 16:42:13 UTC
Creation Date: 05 Sep 2008 13:47:15 UTC
Encoders:  Carole Proctor
   Vijayalakshmi Chelliah
   Douglas A Gray
set #1
bqbiol:isPartOf KEGG Pathway hsa04115
Reactome REACT_85.1
set #2
bqbiol:hasTaxon Taxonomy Homo sapiens
set #3
bqbiol:isVersionOf Gene Ontology DNA damage response, signal transduction by p53 class mediator
Notes
Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by p14ARF

This model is described in the article:

Proctor CJ, Gray DA.
BMC Syst Biol 2008; 2: 75

Abstract:

BACKGROUND: In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing. RESULTS: The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells. CONCLUSION: The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 18706112 Submission Date: 05 Sep 2008 15:30:23 UTC Last Modification Date: 11 Aug 2014 16:42:13 UTC Creation Date: 05 Sep 2008 13:47:15 UTC
Mathematical expressions
Reactions
Mdm2Synthesis Mdm2mRNASynthesis Mdm2mRNADegradation Mdm2Degradation
p53Synthesis p53Degradation P53_Mdm2Binding P53_Mdm2Release
DNAdamage DNArepair ARFactivation ARF_Mdm2Binding
ARF_Mdm2Degradation ARFDegradation    
Rules
Assignment Rule (variable: totp53) Assignment Rule (variable: totMdm2)    
Events
stressCell stopStress    
Physical entities
Compartments Species
cell Mdm2 p53 Mdm2_p53
Mdm2_mRNA ARF ARF_Mdm2
damDNA Sink Source
p53deg p53syn mdm2deg
mdm2syn Mdm2mRNAdeg Mdm2mRNAsyn
totdamDNA totp53 totMdm2
Global parameters
IR ksynMdm2 kdegMdm2 ksynp53
kdegp53 kbinMdm2p53 krelMdm2p53 ksynMdm2mRNA
kdegMdm2mRNA kbinARFMdm2 kdegARFMdm2 kdegARF
kactARF kdam krepair kproteff
Reactions (14)
 
 Mdm2Synthesis [Mdm2_mRNA] → [Mdm2_mRNA] + [Mdm2] + [mdm2syn];  
 
 Mdm2mRNASynthesis [p53] → [p53] + [Mdm2_mRNA] + [Mdm2mRNAsyn];  
 
 Mdm2mRNADegradation [Mdm2_mRNA] → [Sink] + [Mdm2mRNAdeg];  
 
 Mdm2Degradation [Mdm2] → [Sink] + [mdm2deg];  
 
 p53Synthesis [Source] → [p53] + [p53syn];  
 
 p53Degradation [Mdm2_p53] → [Mdm2] + [p53deg];  
 
 P53_Mdm2Binding [p53] + [Mdm2] → [Mdm2_p53];  
 
 P53_Mdm2Release [Mdm2_p53] → [p53] + [Mdm2];  
 
 DNAdamage  → [damDNA] + [totdamDNA];  
 
 DNArepair [damDNA] → [Sink];  
 
 ARFactivation [damDNA] → [damDNA] + [ARF];  
 
 ARF_Mdm2Binding [ARF] + [Mdm2] → [ARF_Mdm2];  
 
 ARF_Mdm2Degradation [ARF_Mdm2] → [ARF] + [mdm2deg];  
 
 ARFDegradation [ARF] → [Sink];  
 
Rules (2)
 
 Assignment Rule (name: totp53) totp53 = p53+Mdm2_p53
 
 Assignment Rule (name: totMdm2) totMdm2 = Mdm2+Mdm2_p53+ARF_Mdm2
 
Events (2)
 
 stressCell
IR = 25
 
 stopStress
IR = 0
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 Mdm2
Compartment: cell
Initial amount: 5.0
 
 p53
Compartment: cell
Initial amount: 5.0
 
 Mdm2_p53
Compartment: cell
Initial amount: 95.0
 
 Mdm2_mRNA
Compartment: cell
Initial amount: 0.0
 
 ARF
Compartment: cell
Initial amount: 0.0
 
 ARF_Mdm2
Compartment: cell
Initial amount: 0.0
 
 damDNA
Compartment: cell
Initial amount: 0.0
 
   Sink
Compartment: cell
Initial amount: 1.0
Constant
 
   Source
Compartment: cell
Initial amount: 1.0
Constant
 
 p53deg
Compartment: cell
Initial amount: 0.0
 
 p53syn
Compartment: cell
Initial amount: 0.0
 
 mdm2deg
Compartment: cell
Initial amount: 0.0
 
 mdm2syn
Compartment: cell
Initial amount: 0.0
 
 Mdm2mRNAdeg
Compartment: cell
Initial amount: 0.0
 
 Mdm2mRNAsyn
Compartment: cell
Initial amount: 0.0
 
   totdamDNA
Compartment: cell
Initial amount: 0.0
 
   totp53
Compartment: cell
Initial amount: 0.0
 
   totMdm2
Compartment: cell
Initial amount: 0.0
 
Global Parameters (16)
 
   IR  
 
   ksynMdm2
Value: 4.95E-4   (Units: psec)
Constant
 
   kdegMdm2
Value: 4.33E-4   (Units: psec)
Constant
 
   ksynp53
Value: 0.078   (Units: psec)
Constant
 
   kdegp53
Value: 8.25E-4   (Units: psec)
Constant
 
   kbinMdm2p53
Value: 0.001155   (Units: pmolepsec)
Constant
 
   krelMdm2p53
Value: 1.155E-5   (Units: psec)
Constant
 
   ksynMdm2mRNA
Value: 1.0E-4   (Units: psec)
Constant
 
   kdegMdm2mRNA
Value: 1.0E-4   (Units: psec)
Constant
 
   kbinARFMdm2
Value: 0.01   (Units: pmolepsec)
Constant
 
   kdegARFMdm2
Value: 0.0010   (Units: psec)
Constant
 
   kdegARF
Value: 1.0E-4   (Units: psec)
Constant
 
   kactARF
Value: 3.3E-5   (Units: psec)
Constant
 
   kdam
Value: 0.08   (Units: molepsecpdGy)
Constant
 
   krepair
Value: 2.0E-5   (Units: psec)
Constant
 
   kproteff
Value: 1.0   (Units: dimensionless)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000189

Curator's comment: (updated: 05 Sep 2008 16:20:29 BST)

Comment: Comment: The model is simulated and integrated using SBML OdeSolver with options (-n --printstep 1e4 --error 1e-14 -z). Figure 12 (for ARF model) of the original paper (Procter CJ, 2008) is reproduced in here.

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