Aug 9, 2016

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

BioRxiv : the Preprint Server for Biology
Gregor MoenkeAlexander Loewer

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 dataN driven model reproduced all features of measured signaling responses and explained their heterogeneity in individual cells. We predicted and validated that heterogeneity in the levels of the feedback regulator Wip1 sets cellNspecific thresholds for p53 activation, providing means to modulate its response through interacting signaling pathways. Our results demonstrate how excitable signaling networks provide high specificity, sensitivity and robustness while retaining unique possibilities to adjust their function to the physiology of individual cells.

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Mentioned in this Paper

TP53 gene
Biochemical Pathway
Physiologic Pulse
PPM1D gene
TP53
PPM1D
PPM1D protein, human
PPM1D wt Allele
Protein p53
Signal Pathways

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