Exploring mechanisms of oscillations in p53 and NF-κB systems

From Q-Bio Seminar Series

Tomasz Lipniacki, Institute of Fundamental Technological Research, Polish Academy of Sciences.

Join work with Beata Hat and Krzysztof Puszynski

A number of regulatory networks have the potential to generate sustained oscillations of irregular amplitude, but well conserved period. We propose a computational method of validation of molecular pathways models, based on the analysis of sensitivity of the oscillation period to the particular gene(s) copy number and the level of stimulation. Using this method we demonstrate that existing p53 models, in which oscillations arise at a saddle-node-on-invariant-circle or subcritical Hopf bifurcations (characteristic for systems with interlinked positive and negative feedbacks), are highly sensitive to gene copy number. Hence, these models cannot explain existing experiments. Analyzing NF-κB system, we demonstrate the necessity of saturation in transcription of the NF-κB inhibitor IkappaBalpha. Our study supports the hypothesis that oscillations of robust period are based on supercritical Hopf bifurcation, characteristic for dynamical systems involving negative feedback and time delay. We hypothesize that in the p53 system the role of positive feedback is not sustaining oscillations, but terminating them in severely damaged cells in which the apoptotic program should be initiated.