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

Konrath, Fabian and Mittermeier, Anna and Cristiano, Elena and Wolf, Jana and Loewer, Alexander (2020):
A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics.
In: PLoS computational biology, 16 (6), pp. e1007901. ISSN 1553-7358,
DOI: 10.1371/journal.pcbi.1007901,
[Article]

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.

Item Type: Article
Erschienen: 2020
Creators: Konrath, Fabian and Mittermeier, Anna and Cristiano, Elena and Wolf, Jana and Loewer, Alexander
Title: A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics.
Language: English
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.

Journal or Publication Title: PLoS computational biology
Journal volume: 16
Number: 6
Divisions: 10 Department of Biology
10 Department of Biology > Systems Biology of the Stress Response
Date Deposited: 29 Jun 2020 11:25
DOI: 10.1371/journal.pcbi.1007901
Identification Number: pmid:32589666
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