Complex p53 dynamics regulated by miR-125b in cellular responses to reactive oxidative stress and DNA damage
Authors: Malik Md Zubbair , Dashti Mohammed , Jangid Amit , Channanath Arshad , Elsa John Sumi , Singh R K Brojen , Al-Mulla Fahd , Alphonse Thanaraj Thangavel 
Published: January 2025

Abstract
In response to distinct cellular stresses, the p53 exhibits distinct dynamics. These p53 dynamics subsequently control cell fate. However, different stresses can generate the same p53 dynamics with different cell fate outcomes, suggesting that the integration of dynamic information from other pathways is important for cell fate regulation. The interactions between miRNA-125b, p53, and reactive oxygen species (ROS) are significant in the context of cellular stress responses and apoptosis. However, the regulating mechanism of miR-125b with p53 is not fully studied. The dynamics of p53 and its response to the miR-125b regulation are still open questions. In the present study, we try to answer some of these fundamental questions based on basic model built from available experimental reports. The miR-125b-p53 regulatory network is modeled using a set of 11 molecular species variables. The biochemical network of miR-125b-p53, described by 22 reaction channels, is represented by coupled ordinary differential equations (ODEs) using the mass action law of chemical kinetics. These ODEs are solved numerically using the standard fourth-order Runge–Kutta method to analyze the dynamical behavior of the system. The biochemical network model we designed is based on both experimental and theoretical reported data. The p53 dynamics driven by miR-125b exhibit five distinct dynamical states: first and second stable states, first and second dynamical states, and a sustained oscillation state. These different p53 dynamical states may correspond to various cellular conditions. If the stress induced by miR-125b is weak, the system will be weakly activated, favoring a return to normal functioning. However, if the stress is significantly strong, the system will move to an active state. To sustain this active state, which is far from equilibrium with little scope for returning to normal conditions, the system may transition to an apoptotic state by crossing through other intermediate states, as it is unlikely to regain normal functioning. The p53 dynamical states show a multifractal nature, contributed by both short- and long-range correlations. The networks illustrated from these dynamical states follow hierarchical scale-free features, exhibiting an assortative nature with an absence of the centrality-lethality rule. Furthermore, the active dynamical state is generally closer to hierarchical characteristics and is self-organized. Our research study reveals that significant activity of miR-125b on the p53 regulatory network and its dynamics can only be observed when the system is slightly activated by ROS. However, this process does not necessarily require the direct study of ROS activity. These findings elucidate the mechanisms by which cells integrate signaling pathways with distinct temporal activity patterns to encode stress specificity and direct diverse cell fate decisions.