Model Identifier
BIOMD0000000318
Short description

This is the model described in the article:
A bistable Rb-E2F switch underlies the restriction point
Guang Yao, Tae Jun Lee, Seiichi Mori, Joseph R. Nevins, Lingchong You, Nat Cell Biol 2008 10:476-482; PMID: 18364697 ; DOI: 10.1038/ncb1711 .

Abstract:
The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that the Rb-E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses. Once turned ON by sufficient serum stimulation, E2F can memorize and maintain this ON state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point.

This model reproduces the serum-pulse stimulation-protocol in Figure 3(b).


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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novere N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Format
SBML (L2V4)
Related Publication
  • A bistable Rb-E2F switch underlies the restriction point.
  • Yao G, Lee TJ, Mori S, Nevins JR, You L
  • Nature cell biology , 4/ 2008 , Volume 10 , pages: 476-482 , PubMed ID: 18364697
  • Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA.
  • The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that the Rb-E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses. Once turned ON by sufficient serum stimulation, E2F can memorize and maintain this ON state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point.
Contributors
Submitter of the first revision: Kieran Smallbone
Submitter of this revision: Kieran Smallbone
Modellers: Kieran Smallbone

Metadata information

is (2 statements)
BioModels Database MODEL1102090000
BioModels Database BIOMD0000000318

isDescribedBy (1 statement)
PubMed 18364697

hasTaxon (1 statement)
Taxonomy Mammalia

hasVersion (1 statement)
hasProperty (1 statement)
Mathematical Modelling Ontology Ordinary differential equation model

isPartOf (2 statements)

Curation status
Curated


Connected external resources

Name Description Size Actions

Model files

BIOMD0000000318_url.xml SBML L2V4 representation of Yao2008_Rb_E2F_Switch 42.69 KB Preview | Download

Additional files

BIOMD0000000318-biopax2.owl Auto-generated BioPAX (Level 2) 22.65 KB Preview | Download
BIOMD0000000318-biopax3.owl Auto-generated BioPAX (Level 3) 32.36 KB Preview | Download
BIOMD0000000318.m Auto-generated Octave file 7.18 KB Preview | Download
BIOMD0000000318.pdf Auto-generated PDF file 217.42 KB Preview | Download
BIOMD0000000318.png Auto-generated Reaction graph (PNG) 92.63 KB Preview | Download
BIOMD0000000318.sci Auto-generated Scilab file 67.00 Bytes Preview | Download
BIOMD0000000318.svg Auto-generated Reaction graph (SVG) 32.96 KB Preview | Download
BIOMD0000000318.vcml Auto-generated VCML file 51.35 KB Preview | Download
BIOMD0000000318.xpp Auto-generated XPP file 4.24 KB Preview | Download
BIOMD0000000318_urn.xml Auto-generated SBML file with URNs 41.87 KB Preview | Download

  • Model originally submitted by : Kieran Smallbone
  • Submitted: Feb 9, 2011 2:40:44 PM
  • Last Modified: Mar 31, 2014 1:24:34 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Mar 31, 2014 1:24:34 PM
    • Submitted by: Kieran Smallbone
    • With comment: Current version of Yao2008_Rb_E2F_Switch
  • Version: 1 public model Download this version
    • Submitted on: Feb 9, 2011 2:40:44 PM
    • Submitted by: Kieran Smallbone
    • With comment: Original import of yao08

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
CE => cell*dCE*CE dCE=1.5 per hr
RE => EF + RP; CD, CE cell*(kkRBPP*CD*RE/(KD+RE)+kkRBPP*CE*RE/(KE+RE)) KD=0.92 uM; kkRBPP=18.0 per hr; KE=0.92 uM
RE => cell*dRE*RE dRE=0.03 per hr
=> EF; MC cell*(kkEF*MC*EF/((KMC+MC)*(KEF+EF))+kkb*MC/(KMC+MC)) kkEF=0.4 uM per hr; KMC=0.15 uM; KEF=0.15 uM; kkb=0.003 uM per hr
EF => cell*dEF*EF dEF=0.25 per hr
CD => cell*dCD*CD dCD=1.5 per hr
RP => cell*dRP*RP dRP=0.06 per hr
=> MC cell*kM*S/(KS+S) kM=1.0 uM per hr; S = 1.0 dimensionless; KS=0.5 dimensionless
EF + RB => RE cell*kkRE*RB*EF kkRE=180.0 per_uM per hr
=> CD cell*kkCDS*S/(KS+S) S = 1.0 dimensionless; kkCDS=0.45 uM per hr; KS=0.5 dimensionless
=> RB cell*kkRB kkRB=0.18 uM per hr
RB => RP; CD, CE cell*(kkRBP*CD*RB/(KD+RB)+kkRBP2*CE*RB/(KE+RB)) KD=0.92 uM; kkRBP2=18.0 per hr; KE=0.92 uM; kkRBP=18.0 per hr
=> CE; EF cell*kkCE*EF/(KEF+EF) kkCE=0.35 uM per hr; KEF=0.15 uM
Curator's comment:
(added: 03 May 2011, 12:10:18, updated: 03 May 2011, 12:10:18)
Bifurcation diagram as in fig. 1B of the original publication. The diagram was computed using SBW and its Auto2000 frontend (http://sys-bio.org/fbergman/files/latest/SetupAutoWrapper.exe) and gnuplot.