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

Mönke, Gregor ; Cristiano, Elena ; Finzel, Ana ; Friedrich, Dhana ; Herzel, Hanspeter ; Falcke, Martin ; Loewer, Alexander (2017)
Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells.
In: Scientific Reports, 2017, 7
Article, Secondary publication

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Item Type: Article
Type of entry: Secondary publication
Title: Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells
Language: German
Date: 2017
Place of Publication: Darmstadt
Year of primary publication: 2017
Journal or Publication Title: Scientific Reports
Volume of the journal: 7
Corresponding Links:
Origin: Secondary publication via sponsored Golden Open Access
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.

URN: urn:nbn:de:tuda-tuprints-68921
Classification DDC: 500 Science and mathematics > 570 Life sciences, biology
Divisions: 10 Department of Biology > Systems Biology of the Stress Response
Date Deposited: 18 Oct 2017 11:13
Last Modified: 13 Dec 2022 11:30
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/6892
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