Abstract
p53 regulates the cellular response to genotoxic damage and prevents carcinogenic events. Theoretical and experimental studies state that the p53-Mdm2 network constitutes the core module of regulatory interactions activated by cellular stress induced by a variety of signaling pathways. In this paper, a strategy to control the p53-Mdm2 network regulated by p14ARF is developed, based on the pinning control technique, which consists into applying local feedback controllers to a small number of nodes (pinned ones) in the network. Pinned nodes are selected on the basis of their importance level in a topological hierarchy, their degree of connectivity within the network, and the biological role they perform. In this paper, two cases are considered. For the first case, the oscillatory pattern under gamma-radiation is recovered; afterward, as the second case, increased expression of p53 level is taken into account. For both cases, the control law is applied to p14ARF (pinned node based on a virtual leader methodology), and overexpressed Mdm2-mediated p53 degradation condition is considered as carcinogenic initial behavior. The approach in this paper uses a computational algorithm, which opens an alternative path to understand the cellular responses to stress, doing it possible to model and control the gene regulatory network dynamics in two different biological contexts. As the main result of the proposed control technique, the two mentioned desired behaviors are obtained.
Highlights
Gene regulatory networks play key roles in every process of life, including cell cycle, metabolism, signal transduction, cell communication, and cellular differentiation
To illustrate the applicability of complex network control, we present two cases for a deterministic network model corresponding to tumor suppressor p53, Mdm2, and p14ARF
4.1.1. p53-Mdm2nuclear Oscillatory Pattern Levels of p53 and Mdm2nuclear proteins present oscillatory behavior, caused by pulses resulting from p53 activation, p53-dependent transactivation, Mdm2 production, Mdm2nuclear sequestration by p14ARF, and Mdm2-mediated ubiquitination
Summary
Gene regulatory networks play key roles in every process of life, including cell cycle, metabolism, signal transduction, cell communication, and cellular differentiation. These complex biological networks use large amounts of data, necessary for modeling, analyzing, and controlling. The continuous-time approach consists in connecting a group of dependent variables to biochemical reaction kinetics In this case, it is essential to assume that molecules have constant concentrations with respect to cellular compartments, in which their variations are continuous functions of time (Chen et al, 1999; Szallasi et al, 2006; Cao et al, 2012).
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