Gerard2009 - An Integrated Mammalian Cell Cycle Model
We propose an integrated computational model for the network of cyclin-dependent kinases (Cdks) that controls the dynamics of the mammalian cell cycle. The model contains four Cdk modules regulated by reversible phosphorylation, Cdk inhibitors, and protein synthesis or degradation. Growth factors (GFs) trigger the transition from a quiescent, stable steady state to self-sustained oscillations in the Cdk network. These oscillations correspond to the repetitive, transient activation of cyclin D/Cdk4-6 in G(1), cyclin E/Cdk2 at the G(1)/S transition, cyclin A/Cdk2 in S and at the S/G(2) transition, and cyclin B/Cdk1 at the G(2)/M transition. The model accounts for the following major properties of the mammalian cell cycle: (i) repetitive cell cycling in the presence of suprathreshold amounts of GF; (ii) control of cell-cycle progression by the balance between antagonistic effects of the tumor suppressor retinoblastoma protein (pRB) and the transcription factor E2F; and (iii) existence of a restriction point in G(1), beyond which completion of the cell cycle becomes independent of GF. The model also accounts for endoreplication. Incorporating the DNA replication checkpoint mediated by kinases ATR and Chk1 slows down the dynamics of the cell cycle without altering its oscillatory nature and leads to better separation of the S and M phases. The model for the mammalian cell cycle shows how the regulatory structure of the Cdk network results in its temporal self-organization, leading to the repetitive, sequential activation of the four Cdk modules that brings about the orderly progression along cell-cycle phases.
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Temporal self-organization of the cyclin/Cdk network driving the mammalian cell cycle.
- Gérard C, Goldbeter A
- Proceedings of the National Academy of Sciences of the United States of America , 12/ 2009 , Volume 106 , Issue 51 , pages: 21643-21648 , PubMed ID: 20007375
- Unité de Chronobiologie Théorique, Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
- We propose an integrated computational model for the network of cyclin-dependent kinases (Cdks) that controls the dynamics of the mammalian cell cycle. The model contains four Cdk modules regulated by reversible phosphorylation, Cdk inhibitors, and protein synthesis or degradation. Growth factors (GFs) trigger the transition from a quiescent, stable steady state to self-sustained oscillations in the Cdk network. These oscillations correspond to the repetitive, transient activation of cyclin D/Cdk4-6 in G(1), cyclin E/Cdk2 at the G(1)/S transition, cyclin A/Cdk2 in S and at the S/G(2) transition, and cyclin B/Cdk1 at the G(2)/M transition. The model accounts for the following major properties of the mammalian cell cycle: (i) repetitive cell cycling in the presence of suprathreshold amounts of GF; (ii) control of cell-cycle progression by the balance between antagonistic effects of the tumor suppressor retinoblastoma protein (pRB) and the transcription factor E2F; and (iii) existence of a restriction point in G(1), beyond which completion of the cell cycle becomes independent of GF. The model also accounts for endoreplication. Incorporating the DNA replication checkpoint mediated by kinases ATR and Chk1 slows down the dynamics of the cell cycle without altering its oscillatory nature and leads to better separation of the S and M phases. The model for the mammalian cell cycle shows how the regulatory structure of the Cdk network results in its temporal self-organization, leading to the repetitive, sequential activation of the four Cdk modules that brings about the orderly progression along cell-cycle phases.
Submitter of this revision: Krishna Kumar Tiwari
Modellers: Ashley Xavier, Krishna Kumar Tiwari
Metadata information
isDescribedBy (2 statements)
hasTaxon (1 statement)
hasProperty (2 statements)
Gene Ontology mitotic cell cycle
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Gerard2009.xml | SBML lvl2 file containing the model | 578.48 KB | Preview | Download |
Additional files |
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| Gerard2009.cps | Copasi file to generate the plot data | 650.62 KB | Preview | Download |
- Model originally submitted by : Ashley Xavier
- Submitted: Dec 21, 2018 10:39:36 AM
- Last Modified: Jun 28, 2019 11:47:48 AM
Revisions
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Version: 5
- Submitted on: Jun 28, 2019 11:47:48 AM
- Submitted by: Krishna Kumar Tiwari
- With comment: updated xml file after correcting issues with biol calling
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Version: 4
- Submitted on: Dec 21, 2018 10:39:36 AM
- Submitted by: Ashley Xavier
- With comment: Automatically added model identifier BIOMD0000000730
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| pRBp Retinoblastoma-associated protein ; Phosphorylated Peptide |
0.25 μmol |
| E2F Transcription factor E2F1 |
0.1 μmol |
| Mdi G1/S-specific cyclin-D2 ; G1/S-specific cyclin-D3 ; Cyclin-dependent kinase 6 ; G1/S-specific cyclin-D1 ; Cyclin-dependent kinase 4 |
0.01 μmol |
| Mai Cyclin-dependent kinase 2 ; Cyclin-A2 |
0.01 μmol |
| pRBc1 Retinoblastoma-associated protein ; Transcription factor E2F1 |
0.1 μmol |
| Cd G1/S-specific cyclin-D2 ; G1/S-specific cyclin-D3 ; G1/S-specific cyclin-D1 |
0.01 μmol |
| Ca Cyclin-A2 |
0.01 μmol |
| Cdh1i Cadherin-1 |
0.01 μmol |
| Reactions | Rate | Parameters |
|---|---|---|
| pRBpp => pRBp; pRBpp | cell*V4*pRBpp/(K4+pRBpp)*eps | V4 = 2.0; eps = 17.0; K4 = 0.1 |
| pRBc1 => pRB + E2F; pRBc1 | cell*kpc2*pRBc1*eps | eps = 17.0; kpc2 = 0.5 |
| Mdi => Cd; Mdi | cell*kdecom1*Mdi*eps | kdecom1 = 0.1; eps = 17.0 |
| Ma => Mai; Wee1, Ma | cell*Vm2a*(Wee1+ib2)*Ma/(K2a+Ma)*eps | K2a = 0.1; Vm2a = 1.85; eps = 17.0; ib2 = 0.5 |
| pRB + E2F => pRBc1; pRB, E2F | cell*kpc1*pRB*E2F*eps | kpc1 = 0.05; eps = 17.0 |
| => Cd; AP1 | cell*kcd1*AP1*eps | eps = 17.0; kcd1 = 0.4 |
| Ca => Mai; Mei, Me, Mep27, Mai, Ma, Map27 | cell*kcom3*Ca*(Cdk2_tot-(Mei+Me+Mep27+Mai+Ma+Map27))*eps | Cdk2_tot = 2.0; kcom3 = 0.2; eps = 17.0 |
| Ca => ; Ca | cell*kdda*Ca*eps | kdda = 0.005; eps = 17.0 |
| Cdh1a => Cdh1i; Cdh1a, Ma, Mb | cell*V2cdh1*Cdh1a/(K2cdh1+Cdh1a)*(Ma+Mb)*eps | V2cdh1 = 8.0; K2cdh1 = 0.01; eps = 17.0 |
(added: 21 Dec 2018, 10:38:04, updated: 21 Dec 2018, 10:38:04)