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BIOMD0000000632 - Kollarovic2016 - Cell fate decision at G1-S transition

 

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Reference Publication
Publication ID: 26830321
Kollarovic G, Studencka M, Ivanova L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS, Schaber J.
To senesce or not to senesce: how primary human fibroblasts decide their cell fate after DNA damage.
Aging (Albany NY) 2016 Jan;
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.  [more]
Model
Original Model: BIOMD0000000632.origin
Submitter: Joerg Schaber
Submission ID: MODEL1505080000
Submission Date: 08 May 2015 09:45:05 UTC
Last Modification Date: 11 Apr 2017 11:30:08 UTC
Creation Date: 30 Mar 2017 15:27:28 UTC
Encoders:  Joerg Schaber
   Ryan Gutenkunst
   Varun Kothamachu
   Alyssa Fortier
   Jordan Knapp-Wilson
   Laura Haferkamp
   Cody Stepanski
   Prager Amy Beth
   Shriver Lauren
   Slavkova Kalina
   Gray William
   Bhaskar Dhananjay
set #1
bqbiol:occursIn Brenda Tissue Ontology fibroblast
bqbiol:isPartOf Gene Ontology regulation of cellular senescence
bqbiol:hasPart Gene Ontology cell cycle arrest
Gene Ontology DNA repair
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
Notes
Kollarovic2016 - Cell fate decision at G1-S transition

This model is described in the article:

Kollarovic G, Studencka M, Ivanova L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS, Schaber J.
Aging (Albany NY) 2016 Jan;

Abstract:

Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair and senesce. Model and data imply that the G1-S transition is regulated by a bistable hysteresis switch with respect to Cdk2 activity, which in turn is controlled by the Cdk2/p21 ratio rather than cyclin abundance. We experimentally confirm the resulting predictions that to induce senescence i) in healthy cells both high initial and elevated background DNA damage are necessary and sufficient, and ii) in already damaged cells much lower additional DNA damage is sufficient. Our study provides a mechanistic explanation of a) how noise in protein abundances allows cells to overcome the G1-S arrest even with substantial DNA damage, potentially leading to neoplasia, and b) how accumulating DNA damage with age increasingly sensitizes cells for senescence.

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: 26830321 Submission Date: 08 May 2015 09:45:05 UTC Last Modification Date: 11 Apr 2017 11:30:08 UTC Creation Date: 30 Mar 2017 15:27:28 UTC
Mathematical expressions
Reactions
vb5 vb6 vb3 vb4
vb7 vb8 vb1 vb2
va3 va2 va1 va5
va6 va4    
Rules
Assignment Rule (variable: Cdk2_T) Assignment Rule (variable: DNAdamagefoci_0) Assignment Rule (variable: Cdk2_Thr160) Assignment Rule (variable: Fit_Cdk2_Thr160)
Assignment Rule (variable: Fit_Cdk2_T) Assignment Rule (variable: Fit_CycE_T) Assignment Rule (variable: CycE_T) Assignment Rule (variable: Fit_Cdk2a)
Assignment Rule (variable: DDR)      
Events
DNADamage      
Physical entities
Compartments Species
MRC-5 cell CycE Cdk2 CycECdk2
CycECdk2a p21 DNADamageC
DNADamageS DDR p53
Global parameters
CycECdk2a_0 CycECdk2_0 Cdk2_0 CycE_0
Cdk2_T Gy prop_C FociPerGy
k_TAF TAF DNAdamagefoci_0 BaseDNAdamage
Cdk2_Thr160 Fit_Cdk2_Thr160 Fit_Cdk2_T Fit_CycE_T
k4b k6b k8b k2b
CycE_T k6a k4a Fit_Cdk2a
vb3_v vb5_v vb7_k1 vb1_k0
vb1_k1 vb1_ka vb1_Kmb vb1_kb
vb1_Kma vb1_Ki vb1_h va5_k
va3_k Initial for Cdk2 Initial for CycECdk2 Initial for CycECdk2a
Initial for CycE Initial for TAF    
Reactions (14)
 
 vb5  → [CycE];  
 
 vb6 [CycE] → ;   {CycE}
 
 vb3  → [Cdk2];  
 
 vb4 [Cdk2] → ;   {Cdk2}
 
 vb7 [CycE] + [Cdk2] → [CycECdk2];   {CycE} , {Cdk2}
 
 vb8 [CycECdk2] → [CycE] + [Cdk2];   {CycECdk2}
 
 vb1 [CycECdk2] → [CycECdk2a];   {p21} , {CycECdk2} , {p21} , {CycECdk2a}
 
 vb2 [CycECdk2a] → [CycECdk2];   {CycECdk2a}
 
 va3  → [p53];   {DDR} , {DDR}
 
 va2 [DNADamageC] → ;   {DNADamageC}
 
 va1 [DNADamageS] → ;   {DNADamageS}
 
 va5  → [p21];   {p53} , {p53}
 
 va6 [p21] → ;   {p21}
 
 va4 [p53] → ;   {p53}
 
Rules (9)
 
 Assignment Rule (name: Cdk2_T) Cdk2_T = Cdk2+CycECdk2+CycECdk2a
 
 Assignment Rule (name: DNAdamagefoci_0) DNAdamagefoci_0 = Gy*FociPerGy
 
 Assignment Rule (name: Cdk2_Thr160) Cdk2_Thr160 = CycECdk2+CycECdk2a
 
 Assignment Rule (name: Fit_Cdk2_Thr160) Fit_Cdk2_Thr160 = (CycECdk2+CycECdk2a)/(Metabolite_5_0+Metabolite_7_0)
 
 Assignment Rule (name: Fit_Cdk2_T) Fit_Cdk2_T = (Cdk2+CycECdk2+CycECdk2a)/(Metabolite_3_0+Metabolite_5_0+Metabolite_7_0)
 
 Assignment Rule (name: Fit_CycE_T) Fit_CycE_T = (CycECdk2+CycECdk2a+CycE)/(Metabolite_5_0+Metabolite_7_0+Metabolite_1_0)
 
 Assignment Rule (name: CycE_T) CycE_T = CycECdk2+CycECdk2a+CycE
 
 Assignment Rule (name: Fit_Cdk2a) Fit_Cdk2a = CycECdk2a/Metabolite_7_0
 
 Assignment Rule (name: DDR) DDR = BaseDNAdamage+DNADamageC+DNADamageS+TAF
 
Events (1)
 
 DNADamage
TAF = ModelValue_9_0+k_TAF*Gy^(1/2)
DNADamageC = prop_C*DNAdamagefoci_0
DNADamageS = (1-prop_C)*DNAdamagefoci_0
 
Functions (4)
 
 Constant flux (irreversible) lambda(v, v)
 
 mod(1) CF_1 lambda(DDR, va3_k_0, va3_k_0*DDR)
 
 pos. FB inh MA_1 lambda(CycECdk2, CycECdk2a, p21, vb1_Ki_0, vb1_Kma_0, vb1_Kmb_0, vb1_h_0, vb1_k0_0, vb1_k1_0, vb1_ka_0, vb1_kb_0, CycECdk2*(vb1_k0_0+vb1_k1_0*2*vb1_ka_0*CycECdk2a*vb1_Kmb_0/((vb1_kb_0-vb1_ka_0*CycECdk2a)+vb1_kb_0*vb1_Kma_0+vb1_ka_0*CycECdk2a*vb1_Kmb_0+(((vb1_kb_0-vb1_ka_0*CycECdk2a)+vb1_kb_0*vb1_Kma_0+vb1_ka_0*CycECdk2a*vb1_Kmb_0)^2-4*(vb1_kb_0-vb1_ka_0*CycECdk2a)*vb1_ka_0*CycECdk2a*vb1_Kmb_0)^(1/2)))/(1+(vb1_Ki_0*p21)^vb1_h_0))
 
 mod(1) CF_2 lambda(p53, va5_k_0, va5_k_0*p53)
 
 MRC-5 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 CycE
Compartment: MRC-5 cell
Initial concentration: 9.2179813538304
 
 Cdk2
Compartment: MRC-5 cell
Initial concentration: 0.0166736
 
 CycECdk2
Compartment: MRC-5 cell
Initial concentration: 1.36697471606784
 
 CycECdk2a
Compartment: MRC-5 cell
Initial concentration: 2.28154
 
 p21
Compartment: MRC-5 cell
Initial concentration: 1.0
 
 DNADamageC
Compartment: MRC-5 cell
Initial concentration: 0.0
 
 DNADamageS
Compartment: MRC-5 cell
Initial concentration: 0.0
 
  DDR
Compartment: MRC-5 cell
Initial concentration: 2.666908
 
 p53
Compartment: MRC-5 cell
Initial concentration: 1.0
 
Global Parameters (42)
 
 CycECdk2a_0
Value: 2.28154
Constant
 
 CycECdk2_0
Value: 1.36697471606784
Constant
 
 Cdk2_0
Value: 0.0166736
Constant
 
 CycE_0
Value: 9.2179813538304
Constant
 
  Cdk2_T
Value: 3.66518831606784
 
 Gy
Constant
 
 prop_C
Value: 0.0905648
Constant
 
 FociPerGy
Value: 28.9678
Constant
 
 k_TAF
Value: 0.973822
Constant
 
 TAF
Value: 0.506228
 
  DNAdamagefoci_0  
 
 BaseDNAdamage
Value: 2.16068
Constant
 
  Cdk2_Thr160
Value: 3.64851471606784
 
  Fit_Cdk2_Thr160
Value: 1.0
 
  Fit_Cdk2_T
Value: 1.0
 
  Fit_CycE_T
Value: 1.0
 
 k4b
Value: 5987.90902984358
Constant
 
 k6b
Value: 1.08476678528373
Constant
 
 k8b
Value: 1.12435827886665
Constant
 
 k2b
Value: 2.43594662809282
Constant
 
  CycE_T
Value: 12.8664960698982
 
 k6a
Value: 193.258
Constant
 
 k4a
Value: 0.01460046788944
Constant
 
  Fit_Cdk2a
Value: 1.0
 
   vb3_v
Value: 99.84
Constant
 
   vb5_v
Value: 9.99936
Constant
 
   vb7_k1
Value: 10.0
Constant
 
   vb1_k0
Value: 0.10249
Constant
 
   vb1_k1
Value: 4.00486
Constant
 
   vb1_ka
Value: 3.40431
Constant
 
   vb1_Kmb
Value: 0.00842472
Constant
 
   vb1_kb
Value: 0.324616
Constant
 
   vb1_Kma
Value: 0.001143917344
Constant
 
   vb1_Ki
Value: 0.394586
Constant
 
   vb1_h
Value: 4.93142
Constant
 
   va5_k
Value: 193.258
Constant
 
   va3_k
Value: 0.00547468
Constant
 
 Initial for Cdk2
Value: 0.0166736
Constant
 
 Initial for CycECdk2
Value: 1.36697471606784
Constant
 
 Initial for CycECdk2a
Value: 2.28154
Constant
 
 Initial for CycE
Value: 9.2179813538304
Constant
 
 Initial for TAF
Value: 0.506228
Constant
 
va2 (1)
 
   k1
Value: 0.0164994
Constant
 
va1 (1)
 
   k1
Value: 0.234805
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000632

Curator's comment: (updated: 30 Mar 2017 16:16:41 BST)

Panels B-D from figure 3 were reproduced using SloppyCell.

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