Influence of the Stochasticity in Threshold Localization on Cell Fate in the PLDE-Model of the P53 Module

摘要

Due to the heterogeneity of cells in a population, they react differently to the same stimuli. This diversification results in the population separating into subpopulations with different cell responses such as apoptosis, cell cycle blockade, or proliferation. Here we focus on the regulatory module of the protein p53, which is responsible for cell responses to DNA damage, and analyze a piece-wise linear model with switches discussed in our previous publications. The main goal of this work was to examine the influence of differences occurring between cells on the cellular response for different doses of external stress. We investigate the properties of the whole cell population in the case of three different types of cell diversity: diversity in sensitivity to stress, diversity in gene expression, and diversity in all the processes analyzed. The diversification of the cell population is acquired by stochastic localization of the switching thresholds. The results show that a population with high diversity in sensitivity to stress has a wide range of responses, so that almost all possible trajectories are present and consequently it is impossible, for example, to force all the cells to apoptosis. Differences in gene activation result in differences in the time courses. The apoptotic response can be activated much later and additional possible results appear. In the case of diversity in all processes analyzed, a variety of different responses can be observed even for a narrow range of the changes, and moreover additional stationary points appear. These results show that even minor changes in proper cell functioning can lead to abnormalities, which may lead to cancer.