Explaining oscillations and variability in the p53-Mdm2 system.

BMC Systems Biology
Carole J Proctor, Douglas A Gray

Abstract

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 dama...Continue Reading

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Software Mentioned

SBML
BASIS
Biology of Ageing e - Science Integration and Simulation syste...
MathSBML
Systems Biology Markup Language ( SBML )
Mathematica
R

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