Hat2016 - Reponse of p53 System to irradiation in cell fate decision making

Model Identifier
BIOMD0000000943
Short description
The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the "apoptotic" steady state is enabled by the existence of a subcritical Neimark-Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line).
Format
SBML
(L2V4)
Related Publication
-
Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System.
- Hat B, Kochańczyk M, Bogdał MN, Lipniacki T
- PLoS computational biology , 2/ 2016 , Volume 12 , Issue 2 , pages: e1004787 , PubMed ID: 26928575
- Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
- The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the "apoptotic" steady state is enabled by the existence of a subcritical Neimark-Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line).
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
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hasTaxon (1 statement)
hasPart (1 statement)
hasProperty (1 statement)
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasPart (1 statement)
hasProperty (1 statement)
isDescribedBy (1 statement)
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
Name | Description | Size | Actions |
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Model files |
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Hat2016.xml | SBML L2V4 representation of Reponse of p53 System to irradiation in cell fate decision making | 350.00 KB | Preview | Download |
Additional files |
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Hat2016.cps | COPASI version 4.27 (Build 217) file for reproducing figure 7 in the reference publication | 441.89 KB | Preview | Download |
Hat2016.sedml | sed-ml L1V2 file for reproducing figure 7 in the reference publication. | 5.63 KB | Preview | Download |
- Model originally submitted by : Matthieu MAIRE
- Submitted: Sep 6, 2018 12:17:17 PM
- Last Modified: May 4, 2020 6:06:11 PM
Revisions
-
Version: 4
- Submitted on: May 4, 2020 6:06:11 PM
- Submitted by: Ahmad Zyoud
- With comment: Automatically added model identifier BIOMD0000000943
-
Version: 2
- Submitted on: Sep 6, 2018 12:17:17 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 |
---|---|
HIPK2 Homeodomain-interacting protein kinase 2 |
0.0 mmol |
p53 0phosphorylated Cellular tumor antigen p53 ; phosphorylated |
0.0 mmol |
Mdm2 nuc S166S186p S395p E3 ubiquitin-protein ligase Mdm2 ; phosphorylated |
0.0 mmol |
PTEN mRNA Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN ; ribonucleic acid |
0.0 mmol |
p21 free p21 RAS Protein |
0.0 mmol |
Bad phosphorylated free Bcl2-associated agonist of cell death ; phosphorylated |
0.0 mmol |
proCaspase Precursor |
0.0 mmol |
Reactions
Reactions | Rate | Parameters |
---|---|---|
=> HIPK2 | nuclear*s8 | s8 = 30.0 |
p53_0phosphorylated => ; Mdm2_nuc_S166S186phosphorylated | nuclear*(g101+g11*Mdm2_nuc_S166S186phosphorylated^h)*p53_0phosphorylated | g101 = 1.0E-5; h = 2.0; g11 = 1.0E-11 |
Mdm2_nuc_S166S186p_S395p => | nuclear*g16*Mdm2_nuc_S166S186p_S395p | g16 = 1.0E-4 |
=> PTEN_mRNA; p53_killer | nuclear*s2*(q0_pten+q1_pten*p53_killer^h)/(q2+q0_pten+q1_pten*p53_killer^h) | q1_pten = 3.0E-13; s2 = 0.03; h = 2.0; q0_pten = 1.0E-5; q2 = 0.003 |
p21__free + Cyclin_E__free => Cyclin_E_p21_complex | nuclear*b5*p21__free*Cyclin_E__free | b5 = 1.0E-5 |
Bad_0__free => Bad_phosphorylated__free; AKT_phosphorylated | cytoplasm*p7*AKT_phosphorylated*Bad_0__free | p7 = 3.0E-9 |
=> Bad_phosphorylated__free; AKT_phosphorylated, BclXL_Bad_complex | cytoplasm*p7*AKT_phosphorylated*BclXL_Bad_complex | p7 = 3.0E-9 |
Bad_phosphorylated__free => ; Fourteen33_free | b3*Fourteen33_free*Bad_phosphorylated__free | b3 = 0.003 |
proCaspase => | nuclear*g17*proCaspase | g17 = 3.0E-4 |
p53_0phosphorylated => p53_S46phosphorylated; HIPK2 | nuclear*p11*HIPK2*p53_0phosphorylated | p11 = 1.0E-10 |
Curator's comment:
(added: 06 Sep 2018, 12:18:43, updated: 04 May 2020, 18:05:59)
(added: 06 Sep 2018, 12:18:43, updated: 04 May 2020, 18:05:59)
Figure 7 of the reference publication has been reproduced using Copasi 4.27 Build 217.
Use attached SEDML file to reproduce the figure 7.