2022 , Volume 27, № 1, p.4-20

Using the basic mathematical model developed in the Part 1 of this work [8] and the experimental data [6], a new mathematical model describing the activation of the p53–Mdm2–Wip1–p21–Apaf1– Bax segment of the p53 signalling pathway under the influence of gamma radiation was obtained. The model, like the laboratory experiment, is aimed at evaluating the response of proteins controlled by p53 that represent various functional pathways to changes in the dynamics of p53 under the influence of the external stress. The model showed the same response of the p53–Mdm2–Wip1–p21– Apaf1–Bax system, which was observed in the experiment. It includes a change in the level of the p53 protein and the Mdm2 and Wip1 regulators as well as a pronounced response of the p21 protein involved in stopping the cell cycle and DNA repair. At the initial stage of activation of the system its amplitude was increased at least in 15 times, along with the minor changes in the pro-apoptotic proteins Apaf1 and Bax. Thus, the results of mathematical modelling, to a certain extent, support the conclusions on the selective ability of p53 to activate different segments of the signaling pathway that participate in reactions to DNA damage and initiate the final decision of the fate of a cell with DNA damage. Using the developed model, a numerical analysis of the effectiveness of some therapeutic effects was carried out, including a strategy for maintaining the level of a signal about DNA damage, inhibition of the regulatory function of inhibitor proteins, and others. The model demonstrates a rather complex sequence of dynamic modes that can be considered as a variant of the functioning of the p53 signaling pathway under stress conditions against the background of relatively weak deregulation of protein-protein bonds.