Schwarz2018-Cdk Activity Threshold Determines Passage through the Restriction Point
View the 2020-07 Model of the Month entry for this model
Model Identifier
BIOMD0000000918
Short description
At the restriction point (R), mammalian cells irreversibly commit to divide. R has been viewed as a point in G1 that is passed when growth factor signaling initiates a positive feedback loop of Cdk activity. However, recent studies have cast doubt on this model by claiming R occurs prior to positive feedback activation in G1 or even before completion of the previous cell cycle. Here we reconcile these results and show that whereas many commonly used cell lines do not exhibit a G1 R, primary fibroblasts have a G1 R that is defined by a precise Cdk activity threshold and the activation of cell-cycle-dependent transcription. A simple threshold model, based solely on Cdk activity, predicted with more than 95% accuracy whether individual cells had passed R. That a single measurement accurately predicted cell fate shows that the state of complex regulatory networks can be assessed using a few critical protein activities.
Format
SBML
(L2V4)
Related Publication
-
A Precise Cdk Activity Threshold Determines Passage through the Restriction Point.
- Schwarz C, Johnson A, Kõivomägi M, Zatulovskiy E, Kravitz CJ, Doncic A, Skotheim JM
- Molecular cell , 1/ 2018 , Volume 69 , Issue 2 , pages: 253-264.e5 , PubMed ID: 29351845
- Department of Biology, Stanford University, Stanford, CA 94305, USA.
- At the restriction point (R), mammalian cells irreversibly commit to divide. R has been viewed as a point in G1 that is passed when growth factor signaling initiates a positive feedback loop of Cdk activity. However, recent studies have cast doubt on this model by claiming R occurs prior to positive feedback activation in G1 or even before completion of the previous cell cycle. Here we reconcile these results and show that whereas many commonly used cell lines do not exhibit a G1 R, primary fibroblasts have a G1 R that is defined by a precise Cdk activity threshold and the activation of cell-cycle-dependent transcription. A simple threshold model, based solely on Cdk activity, predicted with more than 95% accuracy whether individual cells had passed R. That a single measurement accurately predicted cell fate shows that the state of complex regulatory networks can be assessed using a few critical protein activities.
Contributors
Submitter of the first revision: Ahmad Zyoud
Submitter of this revision: Ahmad Zyoud
Modellers: Ahmad Zyoud
Submitter of this revision: Ahmad Zyoud
Modellers: Ahmad Zyoud
Metadata information
is (3 statements)
isDescribedBy (1 statement)
hasProperty (2 statements)
occursIn (1 statement)
hasTaxon (1 statement)
BioModels Database
MODEL2003030001
BioModels Database BIOMD0000000918
BioModels Database MODEL2003030001
BioModels Database BIOMD0000000918
BioModels Database MODEL2003030001
isDescribedBy (1 statement)
hasProperty (2 statements)
occursIn (1 statement)
hasTaxon (1 statement)
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Schwarz2018.xml | SBML L2V4 file Schwarz2018-Cdk Activity Threshold Determines Passage through the Restriction Point_ Curated | 74.22 KB | Preview | Download |
Additional files |
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| Schwarz2018.cps | COPASI version 4.27 (Build 217) Schwarz2018-Cdk Activity Threshold Determines Passage through the Restriction Point_ Curated | 119.54 KB | Preview | Download |
| Schwarz2018.sedml | sed-ml L1V2_Schwarz2018-Cdk Activity Threshold Determines Passage through the Restriction Point_Curated | 2.17 KB | Preview | Download |
| Schwarz2018_orignal.xml | SBML L2V4 file Schwarz2018-Cdk Activity Threshold Determines Passage through the Restriction Point_Original File | 93.57 KB | Preview | Download |
- Model originally submitted by : Ahmad Zyoud
- Submitted: Mar 5, 2020 12:23:05 PM
- Last Modified: Mar 5, 2020 12:23:05 PM
Revisions
-
Version: 3
- Submitted on: Mar 5, 2020 12:23:05 PM
- Submitted by: Ahmad Zyoud
- With comment: Automatically added model identifier BIOMD0000000918
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| Rb 0016708 |
55.0 μmol |
| Phosphorylated Rb 0016708 ; phosphorylated |
0.0 μmol |
| CycD C104194 |
0.0 μmol |
| Myc C18538 |
0.0 μmol |
| E2F C129647 |
0.0 μmol |
| CycE C104197 |
0.0 μmol |
| Rb E2F complex Rb-E2F complex |
0.0 μmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| => Rb; Phosphorylated_Rb, E2F, CycD, CycE | Cell*(((((kR+kDP*Phosphorylated_Rb/(KRP+Phosphorylated_Rb))-kRE*Rb*E2F)-kP1*CycD*Rb/(KCD+Rb))-kP2*CycE*Rb/(KCE+Rb))-dR*Rb) | kR = 0.18; kP1 = 18.0; kP2 = 18.0; KCD = 0.92; KCE = 0.92; kDP = 3.6; dR = 0.06; kRE = 180.0; KRP = 0.01 |
| => Phosphorylated_Rb; CycD, Rb, CycE, Rb_E2F_complex | Cell*((kP1*CycD*Rb/(KCD+Rb)+kP2*CycE*Rb/(KCE+Rb_E2F_complex)+kP1*CycD*Rb_E2F_complex/(KCD+Rb_E2F_complex)+kP2*CycE*Rb_E2F_complex/(KCE+Rb_E2F_complex))-dRP*Phosphorylated_Rb) | kP1 = 18.0; kP2 = 18.0; dRP = 0.06; KCD = 0.92; KCE = 0.92 |
| => CycD; Myc, serum | Cell*((kCD*Myc/(KM+Myc)+kCDS*serum/(KS+serum))-dCD*CycD) | kCD = 0.03; KM = 0.15; kCDS = 0.45; dCD = 1.5; KS = 0.5 |
| => Myc; serum | Cell*(kM*Myc/(KS+serum)-dM*Myc) | kM = 1.0; dM = 0.7; KS = 0.5 |
| => E2F; Myc, CycD, Rb_E2F_complex, CycE, Rb | Cell*(((kE*(kpfb+Myc/(KM+Myc))*E2F/(KE+E2F)+kb*Myc/(KM+Myc)+kP1*CycD*Rb_E2F_complex/(KCD+Rb_E2F_complex)+kP2*CycE*Rb_E2F_complex/(KCE+Rb_E2F_complex))-dE*E2F)-kRE*Rb*E2F) | kP1 = 18.0; dE = 0.25; kb = 0.003; kpfb = 4.0; kP2 = 18.0; KCD = 0.92; KCE = 0.92; kE = 0.4; KM = 0.15; KE = 0.15; kRE = 180.0 |
| => CycE; E2F | Cell*(kCE*E2F/(KE+E2F)-dCE*CycE) | kCE = 0.35; dCE = 1.5; KE = 0.15 |
| => Rb_E2F_complex; CycD, CycE | Cell*(((kRE-kP1*CycD*Rb_E2F_complex/(KCD+Rb_E2F_complex))+kP2*CycE*Rb_E2F_complex/(KCE+Rb_E2F_complex))-dRE*Rb_E2F_complex) | kP1 = 18.0; kP2 = 18.0; dRE = 0.03; KCD = 0.92; KCE = 0.92; kRE = 180.0 |
Curator's comment:
(added: 05 Mar 2020, 12:22:26, updated: 05 Mar 2020, 12:22:26)
(added: 05 Mar 2020, 12:22:26, updated: 05 Mar 2020, 12:22:26)
To be able to reproduce a similar simulation for figure 7B, The initial value of the Rb was changed into 55uM rather than 0.55uM, Also the base serum pulse was changed into 0
However, the reproduced figure is not an exact replica of the 7B figure mentioned in the paper, the value of the y-axis doesn't fit ( much lower in the model)- as its been explained by the authors- because the model puts out cyclin E concentration which it has re-scaled to Cdk activity.