Iwamoto2010 - Cell cycle reponse to DNA damage
Model Identifier
BIOMD0000000939
Short description
After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.
Format
SBML
(L2V4)
Related Publication
-
Mathematical modeling of cell cycle regulation in response to DNA damage: exploring mechanisms of cell-fate determination.
- Iwamoto K, Hamada H, Eguchi Y, Okamoto M
- Bio Systems , 3/ 2011 , Volume 103 , Issue 3 , pages: 384-391 , PubMed ID: 21095219
- Laboratory for Bioinformatics, Graduate School of Systems Life Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.
- After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.
Contributors
Submitter of the first revision: Matthieu MAIRE
Submitter of this revision: Ahmad Zyoud
Modellers: Matthieu MAIRE, Ahmad Zyoud
Submitter of this revision: Ahmad Zyoud
Modellers: Matthieu MAIRE, Ahmad Zyoud
Metadata information
is (2 statements)
isDescribedBy (2 statements)
hasTaxon (1 statement)
hasPart (1 statement)
hasProperty (1 statement)
isDescribedBy (2 statements)
hasTaxon (1 statement)
hasPart (1 statement)
hasProperty (1 statement)
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Iwamoto2010.xml | SBML L2V4 representation of Iwamoto2010 - Cell cycle reponse to DNA damage | 472.77 KB | Preview | Download |
Additional files |
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| Iwamoto2010.cps | COPASI version 4.27 (Build 217) Iwamoto2010 - Cell cycle reponse to DNA damage_ for Fig.2,3,4 and 6 in the reference publication. | 548.24 KB | Preview | Download |
| iwamoto2010_Fig3.sedml | sed-ml L1V2 Iwamoto2010 - Cell cycle reponse to DNA damage_ for Fig.3 in the reference publication. | 6.04 KB | Preview | Download |
| iwamoto2010_Fig4.sedml | sed-ml L1V2 Iwamoto2010 - Cell cycle reponse to DNA damage_ for Fig.4 in the reference publication. | 6.03 KB | Preview | Download |
| iwamoto2010_Fig6.sedml | sed-ml L1V2 Iwamoto2010 - Cell cycle reponse to DNA damage_ for Fig.6 in the reference publication. | 6.04 KB | Preview | Download |
- Model originally submitted by : Matthieu MAIRE
- Submitted: Sep 6, 2018 1:28:55 PM
- Last Modified: Apr 27, 2020 5:45:30 PM
Revisions
-
Version: 4
- Submitted on: Apr 27, 2020 5:45:30 PM
- Submitted by: Ahmad Zyoud
- With comment: Automatically added model identifier BIOMD0000000939
-
Version: 2
- Submitted on: Sep 6, 2018 1:28:55 PM
- Submitted by: Matthieu MAIRE
- With comment: Edited model metadata online.
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Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| Cdk4 Cyclin-dependent kinase 4 |
5.0 mmol |
| Cyclin A Cyclin-A2 |
4.0E-5 mmol |
| Cyclin A Cdk2 inactive Cyclin-dependent kinase 2 ; Cyclin-A2 ; inactive ; protein-containing complex |
4.0E-4 mmol |
| Cyclin A Cdk2 active Cyclin-dependent kinase 2 ; Cyclin-A2 ; protein-containing complex ; active |
1.0E-4 mmol |
| APC Ccdh1 active anaphase-promoting complex ; Cadherin-1 ; protein-containing complex ; active |
0.9 mmol |
| p21 Cyclin-dependent kinase inhibitor 1 |
0.0 mmol |
| Rb PPP Retinoblastoma-like protein 2 ; phosphorylated |
0.01 mmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| Cyclin_D_Cdk4 => Cdk4 | nuclear*k13*Cyclin_D_Cdk4 | k13 = 5.0E-4 |
| Cyclin_A => | nuclear*k10*Cyclin_A | k10 = 5.0E-4 |
| Cyclin_A + Cdk2 => Cyclin_A_Cdk2_inactive | nuclear*k11*Cyclin_A*Cdk2 | k11 = 5.0E-4 |
| Cyclin_A => ; APC_Ccdh1_active | nuclear*k127*Cyclin_A*APC_Ccdh1_active | k127 = 0.005 |
| Cyclin_A_Cdk2_inactive => Cyclin_A_Cdk2_active; Cdc25A_active | nuclear*k28*Cdc25A_active*Cyclin_A_Cdk2_inactive | k28 = 9.0E-4 |
| Cyclin_A_Cdk2_active => Cyclin_A_Cdk2_inactive | nuclear*k29*Cyclin_A_Cdk2_active | k29 = 5.0E-5 |
| Cyclin_A_Cdk2_active + p21 => p21_CyclinA_Cdk2 | nuclear*k32*Cyclin_A_Cdk2_active*p21 | k32 = 0.0025 |
| APC_Ccdh1_inactive => APC_Ccdh1_active | nuclear*k125*APC_Ccdh1_inactive | k125 = 0.005 |
| p21_CyclinD_Cdk4 => p21 + Cyclin_D_Cdk4 | nuclear*k19*p21_CyclinD_Cdk4 | k19 = 0.005 |
| Rb_PPP => Rb | nuclear*k55*Rb_PPP | k55 = 5.0E-8 |
Curator's comment:
(added: 06 Sep 2018, 13:30:37, updated: 27 Apr 2020, 17:45:16)
(added: 06 Sep 2018, 13:30:37, updated: 27 Apr 2020, 17:45:16)
Figure 2,3,4 and 6 of the reference publication has been reproduced using Copasi 4.27 (Build 217).
Use attached SEDML file to reproduce the Figures 2,3,4 and 6.