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A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics

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Item Type:Article
Title:A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics
Creators Name:Konrath, F. and Mittermeier, A. and Cristiano, E. and Wolf, J. and Loewer, A.
Abstract:The transcription factors NF-κB and p53 are key regulators in the genotoxic stress response and are critical for tumor development. Although there is ample evidence for interactions between both networks, a comprehensive understanding of the crosstalk is lacking. Here, we developed a systematic approach to identify potential interactions between the pathways. We perturbed NF-κB signaling by inhibiting IKK2, a critical regulator of NF-κB activity, and monitored the altered response of p53 to genotoxic stress using single cell time lapse microscopy. Fitting subpopulation-specific computational p53 models to this time-resolved single cell data allowed to reproduce in a quantitative manner signaling dynamics and cellular heterogeneity for the unperturbed and perturbed conditions. The approach enabled us to untangle the integrated effects of IKK/ NF-κB perturbation on p53 dynamics and thereby derive potential interactions between both networks. Intriguingly, we find that a simultaneous perturbation of multiple processes is necessary to explain the observed changes in the p53 response. Specifically, we show interference with the activation and degradation of p53 as well as the degradation of Mdm2. Our results highlight the importance of the crosstalk and its potential implications in p53-dependent cellular functions.
Keywords:Microscopy, NF-kappa B, Reproducibility of Results, Signal Transduction, Single-Cell Analysis, Tumor Suppressor Protein p53
Source:PLoS Computational Biology
Publisher:Public Library of Science
Page Range:e1007901
Date:26 June 2020
Official Publication:https://doi.org/10.1371/journal.pcbi.1007901
PubMed:View item in PubMed

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