a theoretical exploration of birhythmicity in the p53-mdm2 networkbirhythmicity p53-mdm2网络的理论探索.pdfVIP

A Theoretical Exploration of Birhythmicity in the p53-Mdm2 Network ´ ´ Wassim Abou-Jaoude*, Madalena Chaves, Jean-Luc Gouze COMORE Project-team, INRIA Sophia Antipolis, Sophia Antipolis, France Abstract Experimental observations performed in the p53-Mdm2 network, one of the key protein modules involved in the control of proliferation of abnormal cells in mammals, revealed the existence of two frequencies of oscillations of p53 and Mdm2 in irradiated cells depending on the irradiation dose. These observations raised the question of the existence of birhythmicity, i.e. the coexistence of two oscillatory regimes for the same external conditions, in the p53-Mdm2 network which would be ´ at the origin of these two distinct frequencies. A theoretical answer has been recently suggested by Ouattara, Abou-Jaoude and Kaufman who proposed a 3-dimensional differential model showing birhythmicity to reproduce the two frequencies experimentally observed. The aim of this work is to analyze the mechanisms at the origin of the birhythmic behavior through a theoretical analysis of this differential model. To do so, we reduced this model, in a first step, into a 3-dimensional piecewise linear differential model where the Hill functions have been approximated by step functions, and, in a second step, into a 2-dimensional piecewise linear differential model by setting one autonomous variable as a constant in each domain of the phase space. We find that two features related to the phase space structure of the system are at the origin of the birhythmic behavior: the existence of two embedded cycles in the transition graph of the