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

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...

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Bibliographic Details
Published in:Scientific reports 2017-04, Vol.7 (1), p.46571-46571, Article 46571
Main Authors: Mönke, Gregor, Cristiano, Elena, Finzel, Ana, Friedrich, Dhana, Herzel, Hanspeter, Falcke, Martin, Loewer, Alexander
Format: Article
Language:English
Subjects:
14/35
631/553/1806
631/553/1833
631/553/2699
631/553/2706
631/67/1244
96/95
A549 Cells
DNA Damage
Excitability
Feedback
Heterogeneity
Humanities and Social Sciences
Humans
Information systems
MCF-7 Cells
Models, Biological
multidisciplinary
Oscillations
p53 Protein
Protein Phosphatase 2C - metabolism
Science
Signal Transduction
System theory
Tumor suppressor genes
Tumor Suppressor Protein p53 - metabolism
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep46571