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Two feedback loop stochastic model of p53 regulation
Krzysztof Puszyński Beata Hat Tomasz Lipniacki
Outline
- Introduction
- p53|Mdm2 regulatory module
- Existing models
- p53|Mdm2 model with feedback loop
- Model’s equations
- Results
Two feedback loop stochastic model of p53 regulation Krzysztof Puszy - - PowerPoint PPT Presentation
Two feedback loop stochastic model of p53 regulation Krzysztof Puszy - - PowerPoint PPT Presentation
Two feedback loop stochastic model of p53 regulation Krzysztof Puszy ski Beata Hat Tomasz Lipniacki Outline Introduction p53|Mdm2 regulatory module Existing models p53|Mdm2 model with feedback loop Models equations
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Why p53|Mdm2 ?
- p53 regulates activity of hundreds of genes responsible among
- thers for :
- cell cycle arrest
- DNA repair processes
- apoptosis
- In 50% cancer cases p53 is mutated or not present. In remaining
cases genes which are in it’s regulatory module are mutated
- There is over 50 000 experimental citations and only about 100
theoretical work.
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Apoptosis
- Programmed cell death
- Characteristic cell
morphology
- Safely cell’s fragments
removal
- About 50 - 70 billions of
cells die every day due to apoptosis in average adult human
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Apoptosis
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Kohn and Pommier 2005 p53|Mdm2 module
10 or more feedbacks, Over 100 components, Stochastic noises
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Inputs and outputs of the p53|Mdm2 regulatory unit
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Cilliberto 2005
- Three forms of p53
- Positive feedback loop to
simplified (PTEN, PIP3 i Akt proteins are absent)
- One stable state and limit
cycle
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Ma 2005
- Two forms of p53
- The lack of the
positive feedback
- One stable state and
limit cycle
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Wee 2006
- One form of p53
- Limit cycle
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Zhang 2007
- One form of p53
- Neglected delays
- One stable state and
limit cycle
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p53|Mdm2 model
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Negative feedback loop
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Positive feedback loop
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Modeling
- Deterministic models based on
ODE – fast but can be used on population not the single cell level
- Stochastic models based on
Gillespie algorithm – can work
- n the single cell level but are very
slow
- Haseltine and Rawlings
approach – fast (modeled by using ODE) and slow (modeled stochastically) reaction channels – fast and can work on the single cell level
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Stochasticity in the p53|Mdm2 model
- IR dose increases
the probability of DNA damage
- ccurs
- Level of the p53pn
protein increases the probability of the DNA repair and Mdm2 and PTEN gene activation
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Equations
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Equations
Proapoptotic factors
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Stochasticity in model
probability of gene copy activation: probability of gene copy deactivation: transcriptional efficiency of p53 (probability that the gene copy is active if p53np(t)=const): probability that new DSB appears: propability that the number of DSB decreases by one:
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PTEN off, DNA repair off, dose 5Gy (oscillations)
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PTEN off, DNA repair off, dose 5Gy
(a1 – p53 activation, d1 – Mdm2 degradation)
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PTEN on, DNA repair off, dose 5Gy (apoptosis)
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PTEN on, DNA repair off, doses 5Gy
(a1 – p53 activation, d1 – Mdm2 degradation)
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PTEN on, DNA repair on (competition)
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PTEN on, DNA on + proapoptotic factors (competition)
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Cell fate
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Cell fate - PTEN on
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Cell fate – PTEN off
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Thank you
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Parameters
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