Yao2008_Rb_E2F_Switch
View the 2012-06 Model of the Month entry for this model
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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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.
Submitter of this revision: Kieran Smallbone
Modellers: Kieran Smallbone
Metadata information
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasVersion (1 statement)
hasProperty (1 statement)
isPartOf (2 statements)
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000318_url.xml | SBML L2V4 representation of Yao2008_Rb_E2F_Switch | 42.69 KB | Preview | Download |
Additional files |
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| 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
- Submitted on: Mar 31, 2014 1:24:34 PM
- Submitted by: Kieran Smallbone
- With comment: Current version of Yao2008_Rb_E2F_Switch
-
Version: 1
- Submitted on: Feb 9, 2011 2:40:44 PM
- Submitted by: Kieran Smallbone
- With comment: Original import of yao08
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| CE cyclin-dependent protein kinase holoenzyme complex ; G1/S-specific cyclin-E1 ; G1/S-specific cyclin-E2 ; cyclin-dependent protein serine/threonine kinase activity |
0.0 μmol |
| EF Transcription factor E2F1 |
0.0 μmol |
| RE Retinoblastoma-associated protein ; Transcription factor E2F1 |
0.55 μmol |
| CD cyclin-dependent protein kinase holoenzyme complex ; IPR015451 ; cyclin-dependent protein serine/threonine kinase activity |
0.0 μmol |
| RP Phosphoprotein ; Retinoblastoma-associated protein ; MOD:00046 |
0.0 μmol |
| MC Myc proto-oncogene protein |
0.0 μmol |
| 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 |
(added: 03 May 2011, 12:10:18, updated: 03 May 2011, 12:10:18)