Barr2017 - Dynamics of p21 in hTert-RPE1 cells

  public model
Short description
Barr2017 - Dynamics of p21 in hTert-RPE1 cells
This deteministic model reveals that a bistable switch created by Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, prevents premature S-phase exit upon DNA damage

This model is described in the article:

Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C.
Nat Commun 2017 Mar; 8: 14728

Abstract:

Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability.

This model is hosted on BioModels Database and identified by: BIOMD0000000660.

To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression.
  • Barr AR, Cooper S, Frank Stefan Heldt, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C
  • Nature communications , 3/ 2017 , Volume 8 , pages: 14728
  • Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
  • Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability.
Contributors
Frank Stefan Heldt, Rahuman Sheriff

Metadata information

is
BioModels Database MODEL1607210001
BIOMD0000000660
hasTaxon
Taxonomy Homo sapiens
isDescribedBy
hasProperty
Curation status
Curated
Name Description Size Actions

Model file

BIOMD0000000660_url.xml SBML L2V4 representation of Barr2017 - Dynamics of p21 in hTert-RPE1 cells 156.95 KB Preview | Download

Additional files

MODEL1607210001.cps Simulations shown in supplementary Figure 7a of the reference publication can be reproduced using this COPASI file. 195.36 KB Preview | Download
BIOMD0000000660.sci Auto-generated Scilab file 0.00 bytes Preview | Download
BIOMD0000000660_urn.xml Auto-generated SBML file with URNs 156.03 KB Preview | Download
BIOMD0000000660.svg Auto-generated Reaction graph (SVG) 94.84 KB Preview | Download
BIOMD0000000660.pdf Auto-generated PDF file 236.47 KB Preview | Download
BIOMD0000000660-biopax2.owl Auto-generated BioPAX (Level 2) 53.18 KB Preview | Download
BIOMD0000000660.png Auto-generated Reaction graph (PNG) 308.87 KB Preview | Download
BIOMD0000000660.m Auto-generated Octave file 17.38 KB Preview | Download
BIOMD0000000660.xpp Auto-generated XPP file 12.83 KB Preview | Download
BIOMD0000000660-biopax3.owl Auto-generated BioPAX (Level 3) 87.26 KB Preview | Download
BIOMD0000000660.vcml Auto-generated VCML file 964.00 bytes Preview | Download

  • Model originally submitted by : Frank Stefan Heldt
  • Submitted: 21-Jul-2016 09:15:17
  • Last Modified: 06-Dec-2017 16:32:10
Revisions
  • Version: 3 public model Download this version
    • Submitted on: 06-Dec-2017 16:32:10
    • Submitted by: Rahuman Sheriff
    • With comment: Current version of Barr2017 - Dynamics of p21 in hTert-RPE1 cells
  • Version: 2 public model Download this version
    • Submitted on: 20-Mar-2017 13:17:56
    • Submitted by: Frank Stefan Heldt
    • With comment: Current version of Barr2017 - Dynamics of p21 in hTert-RPE1 cells
  • Version: 1 public model Download this version
    • Submitted on: 21-Jul-2016 09:15:17
    • Submitted by: Frank Stefan Heldt
    • With comment: Original import of Barr 2016 - Dynamics of p21 in hTert-RPE1 cells
Curator's comment:
(added: 28 Nov 2017, 15:19:27, updated: 28 Nov 2017, 15:19:27)
Supplementary Figure 7a of the reference publication has been reproduced. The model as such reproduces the deterministic simulation of the mathematical model. Time courses of model components (Cdk2:Cyclin (blue), PCNA (purple), p21 (red) and aRC (green)) are shown relative to the G1/s transition. The simulations where performed using Copasi 4.19 (Build 140) and the plots were obtained using Matlab R2014b.