Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by ATM
View the 2009-02 Model of the Month entry for this model
This model is described in the article:
Abstract:
BACKGROUND: In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing. RESULTS: The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells. CONCLUSION: The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.
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Explaining oscillations and variability in the p53-Mdm2 system.
- Proctor CJ, Gray DA
- BMC systems biology , 8/ 2008 , Volume 2 , pages: 75 , PubMed ID: 18706112
- Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. c.j.proctor@ncl.ac.uk
- In individual living cells p53 has been found to be expressed in a series of discrete pulses after DNA damage. Its negative regulator Mdm2 also demonstrates oscillatory behaviour. Attempts have been made recently to explain this behaviour by mathematical models but these have not addressed explicit molecular mechanisms. We describe two stochastic mechanistic models of the p53/Mdm2 circuit and show that sustained oscillations result directly from the key biological features, without assuming complicated mathematical functions or requiring more than one feedback loop. Each model examines a different mechanism for providing a negative feedback loop which results in p53 activation after DNA damage. The first model (ARF model) looks at the mechanism of p14ARF which sequesters Mdm2 and leads to stabilisation of p53. The second model (ATM model) examines the mechanism of ATM activation which leads to phosphorylation of both p53 and Mdm2 and increased degradation of Mdm2, which again results in p53 stabilisation. The models can readily be modified as further information becomes available, and linked to other models of cellular ageing.The ARF model is robust to changes in its parameters and predicts undamped oscillations after DNA damage so long as the signal persists. It also predicts that if there is a gradual accumulation of DNA damage, such as may occur in ageing, oscillations break out once a threshold level of damage is acquired. The ATM model requires an additional step for p53 synthesis for sustained oscillations to develop. The ATM model shows much more variability in the oscillatory behaviour and this variability is observed over a wide range of parameter values. This may account for the large variability seen in the experimental data which so far has examined ARF negative cells.The models predict more regular oscillations if ARF is present and suggest the need for further experiments in ARF positive cells to test these predictions. Our work illustrates the importance of systems biology approaches to understanding the complex role of p53 in both ageing and cancer.
Submitter of this revision: Carole Proctor
Modellers: Carole Proctor
Metadata information
KEGG Pathway p53 signaling pathway - Homo sapiens (human)
Gene Ontology regulation of DNA damage response, signal transduction by p53 class mediator
Connected external resources
Name | Description | Size | Actions |
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Model files |
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BIOMD0000000188_url.xml | SBML L2V4 representation of Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by ATM | 43.83 KB | Preview | Download |
Additional files |
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BIOMD0000000188-biopax2.owl | Auto-generated BioPAX (Level 2) | 39.82 KB | Preview | Download |
BIOMD0000000188-biopax3.owl | Auto-generated BioPAX (Level 3) | 65.47 KB | Preview | Download |
BIOMD0000000188.m | Auto-generated Octave file | 9.48 KB | Preview | Download |
BIOMD0000000188.pdf | Auto-generated PDF file | 229.59 KB | Preview | Download |
BIOMD0000000188.png | Auto-generated Reaction graph (PNG) | 181.07 KB | Preview | Download |
BIOMD0000000188.sci | Auto-generated Scilab file | 67.00 Bytes | Preview | Download |
BIOMD0000000188.svg | Auto-generated Reaction graph (SVG) | 50.89 KB | Preview | Download |
BIOMD0000000188.vcml | Auto-generated VCML file | 69.63 KB | Preview | Download |
BIOMD0000000188.xpp | Auto-generated XPP file | 6.66 KB | Preview | Download |
BIOMD0000000188_urn.xml | Auto-generated SBML file with URNs | 42.77 KB | Preview | Download |
- Model originally submitted by : Carole Proctor
- Submitted: Sep 5, 2008 3:13:40 PM
- Last Modified: Apr 8, 2016 4:43:18 PM
Revisions
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Version: 2
- Submitted on: Apr 8, 2016 4:43:18 PM
- Submitted by: Carole Proctor
- With comment: Current version of Proctor2008 - p53/Mdm2 circuit - p53 stabilisation by ATM
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Version: 1
- Submitted on: Sep 5, 2008 3:13:40 PM
- Submitted by: Carole Proctor
- With comment: Original import of BIOMD0000000188.xml.origin
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: Variable used inside SBML models
Species | Initial Concentration/Amount |
---|---|
Mdm2 E3 ubiquitin-protein ligase Mdm2 ; MDM2 |
5.0 mol |
p53 mRNA messenger RNA ; RNA |
10.0 mol |
damDNA deoxyribonucleic acid ; cellular response to DNA damage stimulus |
0.0 mol |
Mdm2mRNAsyn transcription factor activity, sequence-specific DNA binding |
0.0 mol |
Sink | 1.0 mol |
Mdm2mRNAdeg mRNA catabolic process |
0.0 mol |
p53 Cellular tumor antigen p53 ; TP53 |
5.0 mol |
Mdm2 p53 Cellular tumor antigen p53 ; E3 ubiquitin-protein ligase Mdm2 |
95.0 mol |
ATMA Serine-protein kinase ATM |
0.0 mol |
Reactions | Rate | Parameters |
---|---|---|
p53 + Mdm2 => Mdm2_p53 | kbinMdm2p53*p53*Mdm2 | kbinMdm2p53 = 0.001155 pmolpsec |
p53_mRNA => p53 + p53_mRNA + p53syn | ksynp53*p53_mRNA | ksynp53 = 0.006 psec |
=> damDNA | kdam*IR | IR = 0.0 dGy; kdam = 0.08 molepsecpdGy |
p53_P => p53_P + Mdm2_mRNA + Mdm2mRNAsyn | ksynMdm2mRNA*p53_P | ksynMdm2mRNA = 1.0E-4 psec |
Mdm2_p53 => Mdm2 + p53deg | kdegp53*Mdm2_p53*kproteff | kproteff = 1.0 dimensionless; kdegp53 = 8.25E-4 psec |
Mdm2_P => Sink + mdm2deg | kdegATMMdm2*Mdm2_P | kdegATMMdm2 = 4.0E-4 psec |
Mdm2_mRNA => Sink + Mdm2mRNAdeg | kdegMdm2mRNA*Mdm2_mRNA | kdegMdm2mRNA = 1.0E-4 psec |
Mdm2 => Sink + mdm2deg | kdegMdm2*Mdm2*kproteff | kproteff = 1.0 dimensionless; kdegMdm2 = 4.33E-4 psec |
p53_P => p53 | kdephosp53*p53_P | kdephosp53 = 0.5 psec |
p53 => p53 + Mdm2_mRNA + Mdm2mRNAsyn | ksynMdm2mRNA*p53 | ksynMdm2mRNA = 1.0E-4 psec |
p53 + ATMA => p53_P + ATMA | kphosp53*p53*ATMA | kphosp53 = 5.0E-4 pmolpsec |
damDNA + ATMI => damDNA + ATMA | kactATM*damDNA*ATMI | kactATM = 1.0E-4 pmolpsec |
(added: 05 Sep 2008, 15:08:16, updated: 05 Sep 2008, 15:08:16)