Gerard2009 - An Integrated Mammalian Cell Cycle Model

  public model
Short description

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.

Format
SBML (L2V4)
Related Publication
  • 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
  • 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.
Contributors
Ashley Xavier

Metadata information

hasTaxon
Taxonomy Homo sapiens
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Gene Ontology mitotic cell cycle
isDescribedBy
Curation status
Curated
Name Description Size Actions

Model files

Gerard2009.xml SBML lvl2 file containing the model 578.48 KB Preview | Download

Additional files

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: Dec 21, 2018 10:39:36 AM
Revisions
  • Version: 4 public model Download this version
    • Submitted on: Dec 21, 2018 10:39:36 AM
    • Submitted by: Ashley Xavier
    • With comment: Automatically added model identifier BIOMD0000000730
Curator's comment:
(added: 21 Dec 2018, 10:38:04, updated: 21 Dec 2018, 10:38:04)
Figure 2C of the publication. The parameter k_ce was assigned 0.25 unlike 0.24 mentioned in the figure description. The maximum concentration of Cyclin E/Cdk2 is higher than the publication figure.