Cell-Fate Decisions Mediated by Bistability and Oscillations in the p53-AKT-Mdm2 Network.

Abstract

The tumor suppressor p53 plays a central role in stress-response signaling and exhibits crosstalk with the AKT pathway through the AKT-Mdm2 axis. Although this coupling has been linked to cell-fate choices between survival and death, the dynamical basis of these transitions remains unclear. In this paper, we develop a delay-differential equation model of the p53-AKT-Mdm2 network to study how interlocked feedback loops, together with transcriptional-translational delay, shape p53 dynamics. Bifurcation analysis reveals three dynamical regimes that can be linked to distinct cellular outcomes: a stable low-p53 equilibrium (pro-survival), sustained p53 oscillations (repair-associated dynamics), and a stable high-p53 equilibrium (pro-death). We show that the positive feedback generated by p53-dependent inhibition of AKT and AKT-enhanced Mdm2 activity produces bistability within a certain range of total AKT levels. We further find that increasing the delay destabilizes the low-p53 equilibrium and induces oscillations through a Hopf bifurcation. For the baseline parameter setting, a further increase in delay suppresses the oscillatory state and drives the system toward the high-p53 attractor. These results indicate how AKT-dependent bistability and delay-controlled instability jointly organize state transitions in the p53-AKT-Mdm2 circuit.