Gerard2013 - Model 3 - Embryonic-type eukaryotic Cell Cycle regulation based on negative feedback between Cdk/cyclin and APC and competitive inhibition between Cdk/cyclin and securin for polyubiquitylation_1
Model Identifier
BIOMD0000000938
Short description
The eukaryotic cell cycle is characterized by alternating oscillations in the activities of cyclin-dependent kinase (Cdk) and the anaphase-promoting complex (APC). Successful completion of the cell cycle is dependent on the precise, temporally ordered appearance of these activities. A modest level of Cdk activity is sufficient to initiate DNA replication, but mitosis and APC activation require an elevated Cdk activity. In present-day eukaryotes, this temporal order is provided by a complex network of regulatory proteins that control both Cdk and APC activities via sharp thresholds, bistability, and time delays. Using simple computational models, we show here that these dynamical features of cell-cycle organization could emerge in a control system driven by a single Cdk/cyclin complex and APC wired in a negative-feedback loop. We show that ordered phosphorylation of cellular proteins could be explained by multisite phosphorylation/dephosphorylation and competition of substrates for interconverting kinase (Cdk) and phosphatase. In addition, the competition of APC substrates for ubiquitylation can create and maintain sustained oscillations in cyclin levels. We propose a sequence of models that gets closer and closer to a realistic model of cell-cycle control in yeast. Since these models lack the elaborate control mechanisms characteristic of modern eukaryotes, they suggest that bistability and time delay
Format
SBML
(L2V4)
Related Publication
-
Minimal models for cell-cycle control based on competitive inhibition and multisite phosphorylations of Cdk substrates.
- Gérard C, Novák B
- Biophysical journal , 3/ 2013 , Volume 104 , Issue 6 , pages: 1367-1379 , PubMed ID: 23528096
- Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
- The eukaryotic cell cycle is characterized by alternating oscillations in the activities of cyclin-dependent kinase (Cdk) and the anaphase-promoting complex (APC). Successful completion of the cell cycle is dependent on the precise, temporally ordered appearance of these activities. A modest level of Cdk activity is sufficient to initiate DNA replication, but mitosis and APC activation require an elevated Cdk activity. In present-day eukaryotes, this temporal order is provided by a complex network of regulatory proteins that control both Cdk and APC activities via sharp thresholds, bistability, and time delays. Using simple computational models, we show here that these dynamical features of cell-cycle organization could emerge in a control system driven by a single Cdk/cyclin complex and APC wired in a negative-feedback loop. We show that ordered phosphorylation of cellular proteins could be explained by multisite phosphorylation/dephosphorylation and competition of substrates for interconverting kinase (Cdk) and phosphatase. In addition, the competition of APC substrates for ubiquitylation can create and maintain sustained oscillations in cyclin levels. We propose a sequence of models that gets closer and closer to a realistic model of cell-cycle control in yeast. Since these models lack the elaborate control mechanisms characteristic of modern eukaryotes, they suggest that bistability and time delay may have characterized eukaryotic cell divisions before the current cell-cycle control network evolved in all its complexity.
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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Curation status
Curated
Modelling approach(es)
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| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Gerard2013.xml | SBML L2V4 representation of Gerard2013 - Model 3 - Embryonic-type eukaryotic Cell Cycle regulation based on negative feedback between Cdk/cyclin and APC and competitive inhibition between Cdk/cyclin and securin for polyubiquitylation | 48.12 KB | Preview | Download |
Additional files |
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| Gerard2013.cps | COPASI version 4.27 (Build 217) for reproducing figure 4B in the reference publication. | 90.16 KB | Preview | Download |
| Gerard2013.sedml | sed-ml L1V2 for reproducing figure 4B in the reference publication. | 3.72 KB | Preview | Download |
- Model originally submitted by : Matthieu MAIRE
- Submitted: Sep 5, 2018 10:40:39 AM
- Last Modified: Apr 27, 2020 5:33:30 PM
Revisions
-
Version: 4
- Submitted on: Apr 27, 2020 5:33:30 PM
- Submitted by: Ahmad Zyoud
- With comment: Automatically added model identifier BIOMD0000000938
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Version: 2
- Submitted on: Sep 5, 2018 10:40:39 AM
- 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 |
|---|---|
| Cdk Cyclin-dependent kinase 1 |
0.3 mmol |
| Anaphase promoting complex Phosphorylated anaphase-promoting complex ; phosphorylated |
0.0 mmol |
| Securin Securin |
0.35 mmol |
| Anaphase promoting complex anaphase-promoting complex |
1.0 mmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| Cdk => ; Anaphase_promoting_complex_Phosphorylated, Securin | nuclear*k_dcdk*Anaphase_promoting_complex_Phosphorylated*Cdk/(K_dcdk*(1+Securin/K_dsec)+Cdk) | K_dsec = 0.001; K_dcdk = 0.01; k_dcdk = 0.35 |
| Anaphase_promoting_complex_Phosphorylated => | nuclear*V_1APC*Anaphase_promoting_complex_Phosphorylated/(K_1APC+Anaphase_promoting_complex_Phosphorylated) | K_1APC = 0.01; V_1APC = 0.15 |
| Securin => | nuclear*k_d1sec*Securin | k_d1sec = 0.01 |
| => Cdk | nuclear*V_scdk | V_scdk = 0.06 |
| Cdk => | nuclear*k_d1cdk*Cdk | k_d1cdk = 0.01 |
| => Anaphase_promoting_complex_Phosphorylated; Cdk, Anaphase_promoting_complex | nuclear*k_2APC*Cdk*Anaphase_promoting_complex/(K_2APC+Anaphase_promoting_complex) | k_2APC = 0.3; K_2APC = 0.01 |
| => Securin | nuclear*V_ssec | V_ssec = 0.1 |
| Anaphase_promoting_complex = Anaphase_promoting_complex_total-Anaphase_promoting_complex_Phosphorylated | [] | [] |
| Securin => ; Anaphase_promoting_complex_Phosphorylated, Cdk | nuclear*k_dsec*Anaphase_promoting_complex_Phosphorylated*Securin/(K_dsec*(1+Cdk/K_dcdk)+Securin) | K_dsec = 0.001; K_dcdk = 0.01; k_dsec = 0.4 |
Curator's comment:
(added: 05 Sep 2018, 10:41:20, updated: 27 Apr 2020, 17:33:11)
(added: 05 Sep 2018, 10:41:20, updated: 27 Apr 2020, 17:33:11)
Figure 4B of the referenced publication has been reproduced using Copasi 4.27 Build 217