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BIOMD0000000287 - Passos2010_DNAdamage_CellularSenescence

 

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Reference Publication
Publication ID: 20160708
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T.
Feedback between p21 and reactive oxygen production is necessary for cell senescence.
Mol. Syst. Biol. 2010; 6: 347
Ageing Research Laboratories, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.  [more]
Model
Original Model: Proctor2009_DNA_DamageResp...
Submitter: Carole Proctor
Submission ID: MODEL5989624192
Submission Date: 02 Mar 2009 10:27:04 UTC
Last Modification Date: 03 Jun 2014 21:10:42 UTC
Creation Date: 01 Mar 2010 12:01:28 UTC
Encoders:  Vijayalakshmi Chelliah
   Carole J Proctor
set #1
bqmodel:isDerivedFrom BioModels Database Proctor2008_p53_Mdm2_ARF
BioModels Database Proctor2008_p53_Mdm2_ATM
set #2
bqbiol:isVersionOf Gene Ontology cellular response to DNA damage stimulus
Gene Ontology cellular senescence
set #3
bqbiol:hasTaxon Taxonomy Homo sapiens
set #4
bqbiol:isPartOf KEGG Pathway Pathways in cancer
Notes

This is the model described in: Feedback between p21 and reactive oxygen production is necessary for cell senescence.
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. ;Mol Sys Biol2010;6:347. Epub 2010 Feb 16. PMID:20160708 doi:10.1038/msb.2010.5;
Abstract:
Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 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.

Model
Publication ID: 20160708 Submission Date: 02 Mar 2009 10:27:04 UTC Last Modification Date: 03 Jun 2014 21:10:42 UTC Creation Date: 01 Mar 2010 12:01:28 UTC
Mathematical expressions
Reactions
p53mRNASynthesis p53mRNADegradation Mdm2Synthesis Mdm2mRNASynthesis1
Mdm2mRNASynthesis2 Mdm2mRNADegradation Mdm2Degradation p53Synthesis
p53Degradation p53Mdm2IndepDegradation1 p53Mdm2IndepDegradation2 P53_Mdm2Binding
P53_Mdm2Release DNAdamage DNArepair ATMactivation
p53phoshorylation p53dephosorylation Mdm2phoshorylation Mdm2dephosorylation
Mdm2Pdegradation ATMInactivation p21mRNASynthesis1 p21mRNASynthesis2
p21mRNADegradation p21Synthesis1 p21Synthesis2 p21Synthesis3
p21degradation GADD45activation2 GADD45degradation p38activation
p38inactivation ROSgenerationP38 ROSremoval ROSDNAdamage
basalROSDNAdamage      
Events
stressCell stopStress stopp38ROS  
Physical entities
Compartments Species
cell Mdm2 p53 Mdm2_p53
Mdm2_mRNA p53_mRNA ATMA
ATMI p21 p21_mRNA
p21step1 p21step2 p53_P
Mdm2_P p21_basal p38
p38_P GADD45 IR
damDNA ROS basalROS
Sink Source  
Global parameters
ksynMdm2 kdegMdm2 ksynp53 kdegp53
kdegp53mdm2ind kbinMdm2p53 krelMdm2p53 ksynMdm2mRNA
kdegMdm2mRNA kactATM kdegATMMdm2 kinactATM
kphosp53 kdephosp53 kphosMdm2 kdephosMdm2
kphosp38 kdephosp38 kdam krepair
kGADD45 kdegGADD45 ksynp53mRNA kdegp53mRNA
ksynp21mRNAp53P ksynp21mRNAp53 kdegp21mRNA ksynp21step1
ksynp21step2 ksynp21step3 kdegp21 kremROS
kgenROSp38 kdamROS kdamBasalROS kp38ROS
Reactions (37)
 
 p53mRNASynthesis [Source] → [p53_mRNA];  
 
 p53mRNADegradation [p53_mRNA] → [Sink];  
 
 Mdm2Synthesis [Mdm2_mRNA] → [Mdm2_mRNA] + [Mdm2];  
 
 Mdm2mRNASynthesis1 [p53] → [p53] + [Mdm2_mRNA];  
 
 Mdm2mRNASynthesis2 [p53_P] → [p53_P] + [Mdm2_mRNA];  
 
 Mdm2mRNADegradation [Mdm2_mRNA] → [Sink];  
 
 Mdm2Degradation [Mdm2] → [Sink];  
 
 p53Synthesis [p53_mRNA] → [p53] + [p53_mRNA];  
 
 p53Degradation [Mdm2_p53] → [Mdm2];  
 
 p53Mdm2IndepDegradation1 [p53_P] → [Sink];  
 
 p53Mdm2IndepDegradation2 [p53] → [Sink];  
 
 P53_Mdm2Binding [p53] + [Mdm2] → [Mdm2_p53];  
 
 P53_Mdm2Release [Mdm2_p53] → [p53] + [Mdm2];  
 
 DNAdamage [IR] → [IR] + [damDNA];  
 
 DNArepair [damDNA] → [Sink];  
 
 ATMactivation [damDNA] + [ATMI] → [damDNA] + [ATMA];  
 
 p53phoshorylation [p53] + [ATMA] → [p53_P] + [ATMA];  
 
 p53dephosorylation [p53_P] → [p53];  
 
 Mdm2phoshorylation [Mdm2] + [ATMA] → [Mdm2_P] + [ATMA];  
 
 Mdm2dephosorylation [Mdm2_P] → [Mdm2];  
 
 Mdm2Pdegradation [Mdm2_P] → [Sink];  
 
 ATMInactivation [ATMA] → [ATMI];  
 
 p21mRNASynthesis1 [p53] → [p53] + [p21_mRNA];  
 
 p21mRNASynthesis2 [p53_P] → [p53_P] + [p21_mRNA];  
 
 p21mRNADegradation [p21_mRNA] → [Sink];  
 
 p21Synthesis1 [p21_mRNA] → [p21_mRNA] + [p21step1];  
 
 p21Synthesis2 [p21step1] → [p21step2];  
 
 p21Synthesis3 [p21step2] → [p21];  
 
 p21degradation [p21] → [Sink];  
 
 GADD45activation2 [p21] → [p21] + [GADD45];  
 
 GADD45degradation [GADD45] → [Sink];  
 
 p38activation [p38] + [GADD45] → [p38_P] + [GADD45];  
 
 p38inactivation [p38_P] → [p38];  
 
 ROSgenerationP38 [p38_P] → [p38_P] + [ROS];  
 
 ROSremoval [ROS] → [Sink];  
 
 ROSDNAdamage [ROS] → [ROS] + [damDNA];  
 
 basalROSDNAdamage [basalROS] → [basalROS] + [damDNA];  
 
Events (3)
 
 stressCell
IR = 200
 
 stopStress
IR = 0
 
 stopp38ROS
kp38ROS = 0.6
 
  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: 10.0
 
 p53_mRNA
Compartment: cell
Initial amount: 10.0
 
 ATMA
Compartment: cell
Initial amount: 0.0
 
 ATMI
Compartment: cell
Initial amount: 200.0
 
 p21
Compartment: cell
Initial amount: 0.0
 
 p21_mRNA
Compartment: cell
Initial amount: 1.0
 
 p21step1
Compartment: cell
Initial amount: 0.0
 
 p21step2
Compartment: cell
Initial amount: 0.0
 
 p53_P
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P
Compartment: cell
Initial amount: 0.0
 
 p21_basal
Compartment: cell
Initial amount: 7.0
 
 p38
Compartment: cell
Initial amount: 100.0
 
 p38_P
Compartment: cell
Initial amount: 0.0
 
 GADD45
Compartment: cell
Initial amount: 0.0
 
 IR
Compartment: cell
Initial amount: 0.0
 
 damDNA
Compartment: cell
Initial amount: 0.0
 
 ROS
Compartment: cell
Initial amount: 0.0
 
 basalROS
Compartment: cell
Initial amount: 10.0
 
 Sink
Compartment: cell
Initial amount: 1.0
Constant
 
 Source
Compartment: cell
Initial amount: 1.0
Constant
 
Global Parameters (36)
 
 ksynMdm2
Value: 4.95E-4
Constant
 
 kdegMdm2
Value: 4.33E-4
Constant
 
 ksynp53
Value: 0.006
Constant
 
 kdegp53
Value: 8.25E-4
Constant
 
 kdegp53mdm2ind
Value: 8.25E-7
Constant
 
 kbinMdm2p53
Value: 0.001155
Constant
 
 krelMdm2p53
Value: 1.155E-6
Constant
 
 ksynMdm2mRNA
Value: 1.0E-4
Constant
 
 kdegMdm2mRNA
Value: 1.0E-4
Constant
 
 kactATM
Value: 2.0E-5
Constant
 
 kdegATMMdm2
Value: 4.0E-4
Constant
 
 kinactATM
Value: 5.0E-4
Constant
 
 kphosp53
Value: 0.006
Constant
 
 kdephosp53
Value: 0.5
Constant
 
   kphosMdm2
Value: 2.0
Constant
 
 kdephosMdm2
Value: 0.5
Constant
 
 kphosp38
Value: 0.008
Constant
 
 kdephosp38
Value: 0.1
Constant
 
 kdam
Value: 0.007
Constant
 
 krepair
Value: 6.0E-5
Constant
 
 kGADD45
Value: 4.0E-6
Constant
 
 kdegGADD45
Value: 1.0E-5
Constant
 
 ksynp53mRNA
Value: 0.001
Constant
 
 kdegp53mRNA
Value: 1.0E-4
Constant
 
   ksynp21mRNAp53P
Value: 6.0E-6
Constant
 
 ksynp21mRNAp53
Value: 6.0E-8
Constant
 
 kdegp21mRNA
Value: 2.4E-5
Constant
 
 ksynp21step1
Value: 4.0E-4
Constant
 
 ksynp21step2
Value: 4.0E-5
Constant
 
 ksynp21step3
Value: 4.0E-5
Constant
 
 kdegp21
Value: 1.9E-4
Constant
 
 kremROS
Value: 3.83E-4
Constant
 
 kgenROSp38
Value: 4.5E-4
Constant
 
 kdamROS
Value: 1.0E-5
Constant
 
 kdamBasalROS
Value: 1.0E-9
Constant
 
 kp38ROS
Value: 1.0
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000287

Curator's comment: (updated: 13 Dec 2010 14:42:48 GMT)

a) Figure 3B (DNA damage, p53 S15 and
p21 (CDKN1A)) and b)Figure S17
are reproduced here. Figure 3B in the
paper is the mean+sd of the plot obtained
from 500 stochastic simulation runs.
Figure S17 is the stochastic simulation of 6
randomly selected cells. But, the curation
figure is obtained using deterministic simulation
run using Copasi v4.6 (Build 32). This is why the curation figure and corresponding figures in the paper do not look alike.

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