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

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

  • PLoS Comput Biol. 2020 Jun 26;16(6):e1007901. doi: 10.1371/journal.pcbi.1007901.
Fabian Konrath 1 Anna Mittermeier 2 Elena Cristiano 3 Jana Wolf 1 Alexander Loewer 2 3
Affiliations

Affiliations

  • 1 Mathematical Modelling of Cellular Processes, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
  • 2 Systems Biology of the Stress Response, Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany.
  • 3 Signaling Dynamics in Single Cells, Berlin Institute for Medical Systems Biology, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10519
    99.86%, IKK-1/IKK-2抑制剂
    IKK