Pandey2018-reversible transition between quiescence and proliferation

  public model
Model Identifier
BIOMD0000000954
Short description
Cells switch between quiescence and proliferation states for maintaining tissue homeostasis and regeneration. At the restriction point (R-point), cells become irreversibly committed to the completion of the cell cycle independent of mitogen. The mechanism involving hyper-phosphorylation of retinoblastoma (Rb) and activation of transcription factor E2F is linked to the R-point passage. However, stress stimuli trigger exit from the cell cycle back to the mitogen-sensitive quiescent state after Rb hyper-phosphorylation but only until APC/CCdh1 inactivation. In this study, we developed a mathematical model to investigate the reversible transition between quiescence and proliferation in mammalian cells with respect to mitogen and stress signals. The model integrates the current mechanistic knowledge and accounts for the recent experimental observations with cells exiting quiescence and proliferating cells. We show that Cyclin E:Cdk2 couples Rb-E2F and APC/CCdh1 bistable switches and temporally segregates the R-point and the G1/S transition. A redox-dependent mutual antagonism between APC/CCdh1 and its inhibitor Emi1 makes the inactivation of APC/CCdh1 bistable. We show that the levels of Cdk inhibitor (CKI) and mitogen control the reversible transition between quiescence and proliferation. Further, we propose that shifting of the mitogen-induced transcriptional program to G2-phase in proliferating cells might result in an intermediate Cdk2 activity at the mitotic exit and in the immediate inactivation of APC/CCdh1. Our study builds a coherent framework and generates hypotheses that can be further explored by experiments.
Format
SBML (L3V1)
Related Publication
  • Mathematical modelling of reversible transition between quiescence and proliferation.
  • Pandey N, Vinod PK
  • PloS one , 1/ 2018 , Volume 13 , Issue 6 , pages: e0198420 , PubMed ID: 29856829
  • Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India.
  • Cells switch between quiescence and proliferation states for maintaining tissue homeostasis and regeneration. At the restriction point (R-point), cells become irreversibly committed to the completion of the cell cycle independent of mitogen. The mechanism involving hyper-phosphorylation of retinoblastoma (Rb) and activation of transcription factor E2F is linked to the R-point passage. However, stress stimuli trigger exit from the cell cycle back to the mitogen-sensitive quiescent state after Rb hyper-phosphorylation but only until APC/CCdh1 inactivation. In this study, we developed a mathematical model to investigate the reversible transition between quiescence and proliferation in mammalian cells with respect to mitogen and stress signals. The model integrates the current mechanistic knowledge and accounts for the recent experimental observations with cells exiting quiescence and proliferating cells. We show that Cyclin E:Cdk2 couples Rb-E2F and APC/CCdh1 bistable switches and temporally segregates the R-point and the G1/S transition. A redox-dependent mutual antagonism between APC/CCdh1 and its inhibitor Emi1 makes the inactivation of APC/CCdh1 bistable. We show that the levels of Cdk inhibitor (CKI) and mitogen control the reversible transition between quiescence and proliferation. Further, we propose that shifting of the mitogen-induced transcriptional program to G2-phase in proliferating cells might result in an intermediate Cdk2 activity at the mitotic exit and in the immediate inactivation of APC/CCdh1. Our study builds a coherent framework and generates hypotheses that can be further explored by experiments.
Contributors
Ahmad Zyoud

Metadata information

hasTaxon
Taxonomy Homo sapiens
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Gene Ontology cell cycle
GO:0044838
isDescribedBy

Curation status
Curated


Tags
Name Description Size Actions

Model files

Pandey2018_wildtype.xml SBML L2V4 Pandey2018-reversible transition between quiescence and proliferation 232.06 KB Preview | Download

Additional files

Pandey2018_Figure2A.sedml sed-ml L1V2 Pandey2018-reversible transition between quiescence and proliferation_Figure2A 14.46 KB Preview | Download
Pandey2018_Figure2B.sedml sed-ml L1V2 Pandey2018-reversible transition between quiescence and proliferation_Figure2B 14.46 KB Preview | Download
Pandey2018_wildtype.cps COPASI version 4.27 (Build 217) Pandey2018-reversible transition between quiescence and proliferation_Curated 314.70 KB Preview | Download
Pandey2018_Figure2C.sedml sed-ml L1V2 Pandey2018-reversible transition between quiescence and proliferation_Figure2C 14.46 KB Preview | Download
Pandey2018_Figure2D.sedml sed-ml L1V2 Pandey2018-reversible transition between quiescence and proliferation_Figure2D 14.46 KB Preview | Download

  • Model originally submitted by : Ahmad Zyoud
  • Submitted: 22-Jun-2020 16:41:17
  • Last Modified: 22-Jun-2020 16:41:17
Revisions
  • Version: 3 public model Download this version
    • Submitted on: 22-Jun-2020 16:41:17
    • Submitted by: Ahmad Zyoud
    • With comment: Automatically added model identifier BIOMD0000000954
Legends
: Variable used inside SBML models


Species
No records to display
Reactions
No records to display
Curator's comment:
(added: 22 Jun 2020, 16:40:56, updated: 22 Jun 2020, 16:40:56)
Figure 2 has been reproduced using Copasi 4.27 (Build 217).