Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System

The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the “apoptotic” steady state is enabled by the existence of a subcriti...

• Type: Journal
• Year: 2016
• Where: PLOSCB
• Authors: Beata Hat, Marek Kochanczyk, Marta N. Bogdal, Tomasz Lipniacki
• Keywords: PLOSCB 2016