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Wassim Abou-Jaoudé - Oscillations et variabilité dans le réseau p53-Mdm2

INRIA Grenoble-Rhône-Alpes, Montbonnot, Friday July 13, 2012, 11AM, F107


We investigate the dynamical properties of a simple four-variable model describing the interactions between the tumour suppressor protein p53, its main negative regulator Mdm2 and DNA damage, a model inspired by the work of Ciliberto et al. [2005. Steady states and oscillations in the p53/Mdm2 network. Cell Cycle 4(3), 488-493]. Its core consists of an antagonist circuit between p53 and nuclear Mdm2 embedded in a three-element negative circuit involving p53, cytoplasmic and nuclear Mdm2. A major concern has been to develop an integrated approach in which various types of descriptions complement each other : a logical approach, a differential method and a stochastic approach. We show that the essential qualitative dynamical properties of the network can be summarized by a small number of bifurcation scenarios, which can be understood in terms of the balance between the positive and negative circuits composing the network. The analysis of the differential model allows to interpret the two frequencies of oscillations experimentally observed, as a function of irradiation dose, in terms of two oscillatory regimes separated by a region of birhythmicity. The presence of these two oscillatory regimes allows to explain the frequency change of p53 oscillations observed in a fraction of cells during the response to irradiation exposure. The stochastic analysis allows to reproduce : oscillations of regular periodicity and highly variable amplitude, the increase of the fraction of cells oscillating with high frequency for increasing irradiation doses. Finally, the mechanisms at the origin of the emergence of the birhythmic behaviour has been analyzed through a theoretical study of the differential model. To do so, we have approximated this continuous non-linear model, difficult to analyze, into a piece-wise linear model. A first return map can be computed to extract the mechanisms at the origin of birhythmicity. The analysis of this map shows a discontinuity which facilitates the emergence of the birhythmic behaviour observed in the continuous differential model

Venue : INRIA Grenoble - Rhône-Alpes