Yan2012 - Rb-E2F pathway dynamics with miR449
Model Identifier
BIOMD0000000720
Short description
MiRNAs, which are a family of small non-coding RNAs, regulate a broad array of physiological and developmental processes. However, their regulatory roles have remained largely mysterious. E2F is a positive regulator of cell cycle progression and also a potent inducer of apoptosis. Positive feedback loops in the regulation of Rb-E2F pathway are predicted and shown experimentally. Recently, it has been discovered that E2F induce a cluster of miRNAs called miR449. In turn, E2F is inhibited by miR449 through regulating different transcripts, thus forming negative feedback loops in the interaction network. Here, based on the integration of experimental evidence and quantitative data, we studied Rb-E2F pathway coupling the positive feedback loops and negative feedback loops mediated by miR449. Therefore, a mathematical model is constructed based in part on the model proposed in Yao-Lee et al. (2008) and nonlinear dynamical behaviors including the stability and bifurcations of the model are discussed.
Format
SBML
(L2V4)
Related Publication
-
Dynamical behaviors of Rb-E2F pathway including negative feedback loops involving miR449.
- Yan F, Liu H, Hao J, Liu Z
- PloS one , 1/ 2012 , Volume 7 , Issue 9 , pages: e43908 , PubMed ID: 23028477
- Department of Mathematics, Shanghai University, Shanghai, PR China.
- MiRNAs, which are a family of small non-coding RNAs, regulate a broad array of physiological and developmental processes. However, their regulatory roles have remained largely mysterious. E2F is a positive regulator of cell cycle progression and also a potent inducer of apoptosis. Positive feedback loops in the regulation of Rb-E2F pathway are predicted and shown experimentally. Recently, it has been discovered that E2F induce a cluster of miRNAs called miR449. In turn, E2F is inhibited by miR449 through regulating different transcripts, thus forming negative feedback loops in the interaction network. Here, based on the integration of experimental evidence and quantitative data, we studied Rb-E2F pathway coupling the positive feedback loops and negative feedback loops mediated by miR449. Therefore, a mathematical model is constructed based in part on the model proposed in Yao-Lee et al. (2008) and nonlinear dynamical behaviors including the stability and bifurcations of the model are discussed. A comparison is given to reveal the implication of the fundamental differences of Rb-E2F pathway between regulation and deregulation of miR449. Coherent with the experiments it predicts that miR449 plays a critical role in regulating the cell cycle progression and provides a twofold safety mechanism to avoid excessive E2F-induced proliferation by cell cycle arrest and apoptosis. Moreover, numerical simulation and bifurcation analysis shows that the mechanisms of the negative regulation of miR449 to three different transcripts are quite distinctive which needs to be verified experimentally. This study may help us to analyze the whole cell cycle process mediated by other miRNAs more easily. A better knowledge of the dynamical behaviors of miRNAs mediated networks is also of interest for bio-engineering and artificial control.
Contributors
Submitter of the first revision: Ashley Xavier
Submitter of this revision: Ashley Xavier
Modellers: Ashley Xavier
Submitter of this revision: Ashley Xavier
Modellers: Ashley Xavier
Metadata information
isDescribedBy (3 statements)
is (2 statements)
isDerivedFrom (5 statements)
hasTaxon (1 statement)
hasPart (1 statement)
hasProperty (1 statement)
isPartOf (1 statement)
is (2 statements)
isDerivedFrom (5 statements)
Taxonomy
Mammalia
Gene Ontology cell cycle
Reactome G1/S Transition
BioModels Database BIOMD0000000318
Mathematical Modelling Ontology Ordinary differential equation model
Gene Ontology cell cycle
Reactome G1/S Transition
BioModels Database BIOMD0000000318
Mathematical Modelling Ontology Ordinary differential equation model
hasTaxon (1 statement)
hasPart (1 statement)
hasProperty (1 statement)
isPartOf (1 statement)
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
|||
| Yan2012.xml | SBML lvl2 file containing the model | 60.18 KB | Preview | Download |
Additional files |
|||
| Yan2012.cps | copasi file to generate figure 7 (i) | 118.32 KB | Preview | Download |
- Model originally submitted by : Ashley Xavier
- Submitted: Nov 8, 2018 10:10:08 AM
- Last Modified: Nov 8, 2018 11:34:52 AM
Revisions
-
Version: 6
- Submitted on: Nov 8, 2018 11:34:52 AM
- Submitted by: Ashley Xavier
- With comment: Automatically added model identifier BIOMD0000000720
-
Version: 3
- Submitted on: Nov 8, 2018 10:10:08 AM
- Submitted by: Ashley Xavier
- With comment: Automatically added model identifier BIOMD0000000720
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Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| Myc Myc proto-oncogene protein |
0.0 mmol |
| CycD Cyclin-dependent kinase 6 ; Cyclin-dependent kinase 4 ; G1/S-specific cyclin-D2 ; G1/S-specific cyclin-D3 ; G1/S-specific cyclin-D1 |
0.0 mmol |
| RE Transcription factor E2F1 ; Retinoblastoma-associated protein |
0.0 mmol |
| RB Retinoblastoma-associated protein |
0.55 mmol |
| PRB Retinoblastoma-associated protein ; Phosphorylated Peptide |
0.0 mmol |
| miR449 MIMAT0001541 |
0.0 mmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| miR449 + Myc => ; miR449 | compartment*kdM2*miR449*Myc/(JM+Myc) | kdM2 = 0.6; JM = 0.15 |
| => Myc; S | compartment*ksM*S/(JS+S) | ksM = 1.0; JS = 0.5 |
| => CycD; Myc | compartment*ksCD2*Myc/(JM+Myc) | JM = 0.15; ksCD2 = 0.03 |
| RE => | compartment*kdRE*RE | kdRE = 0.03 |
| E2F + RB => RE | compartment*kRE*E2F*RB | kRE = 180.0 |
| PRB => | compartment*kdP*PRB | kdP = 0.06 |
| RE => E2F + PRB; CycE | compartment*kP2*CycE*RE/(JCE+RE) | JCE = 0.92; kP2 = 18.0 |
| miR449 + CycE => ; miR449 | compartment*kdCE2*miR449*CycE/(JCE+CycE) | kdCE2 = 0.7; JCE = 0.92 |
| miR449 + CycD => ; miR449 | compartment*kdCD2*miR449*CycD/(JCD+CycD) | JCD = 0.92; kdCD2 = 1.0 |
| RE => E2F + PRB; CycD | compartment*kP1*CycD*RE/(JCD+RE) | JCD = 0.92; kP1 = 18.0 |
Curator's comment:
(added: 08 Nov 2018, 10:09:43, updated: 08 Nov 2018, 10:09:43)
(added: 08 Nov 2018, 10:09:43, updated: 08 Nov 2018, 10:09:43)
The model was encoded and simulated using COPASI 4.24 and the figure was plotted using R 3.5.1.