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Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells

Mönke, Gregor and Cristiano, Elena and Finzel, Ana and Friedrich, Dhana and Herzel, Hanspeter and Falcke, Martin and Loewer, Alexander (2017):
Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells.
In: Scientific Reports, 7, ISSN 2045-2322,
DOI: 10.1038/srep46571,
[Article]

Abstract

Cellular signaling systems precisely transmit information in the presence of molecular noise while retaining flexibility to accommodate the needs of individual cells. To understand design principles underlying such versatile signaling, we analyzed the response of the tumor suppressor p53 to varying levels of DNA damage in hundreds of individual cells and observed a switch between distinct signaling modes characterized by isolated pulses and sustained oscillations of p53 accumulation. Guided by dynamic systems theory we show that this requires an excitable network structure comprising positive feedback and provide experimental evidence for its molecular identity. The resulting data-driven model reproduced all features of measured signaling responses and is sufficient to explain their heterogeneity in individual cells. We present evidence that heterogeneity in the levels of the feedback regulator Wip1 sets cell-specific thresholds for p53 activation, providing means to modulate its response through interacting signaling pathways. Our results demonstrate how excitable signaling networks can provide high specificity, sensitivity and robustness while retaining unique possibilities to adjust their function to the physiology of individual cells.

Item Type: Article
Erschienen: 2017
Creators: Mönke, Gregor and Cristiano, Elena and Finzel, Ana and Friedrich, Dhana and Herzel, Hanspeter and Falcke, Martin and Loewer, Alexander
Title: Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells
Language: German
Abstract:

Cellular signaling systems precisely transmit information in the presence of molecular noise while retaining flexibility to accommodate the needs of individual cells. To understand design principles underlying such versatile signaling, we analyzed the response of the tumor suppressor p53 to varying levels of DNA damage in hundreds of individual cells and observed a switch between distinct signaling modes characterized by isolated pulses and sustained oscillations of p53 accumulation. Guided by dynamic systems theory we show that this requires an excitable network structure comprising positive feedback and provide experimental evidence for its molecular identity. The resulting data-driven model reproduced all features of measured signaling responses and is sufficient to explain their heterogeneity in individual cells. We present evidence that heterogeneity in the levels of the feedback regulator Wip1 sets cell-specific thresholds for p53 activation, providing means to modulate its response through interacting signaling pathways. Our results demonstrate how excitable signaling networks can provide high specificity, sensitivity and robustness while retaining unique possibilities to adjust their function to the physiology of individual cells.

Journal or Publication Title: Scientific Reports
Journal volume: 7
Divisions: 10 Department of Biology > Systems Biology of the Stress Response
10 Department of Biology
Date Deposited: 22 Oct 2017 19:55
DOI: 10.1038/srep46571
Official URL: https://doi.org/10.1038/srep46571
URN: urn:nbn:de:tuda-tuprints-68921
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