TY - JOUR T1 - Excitability in the p53 network mediates robust signaling with tunable activation thresholds in single cells JF - bioRxiv DO - 10.1101/068668 SP - 068668 AU - Gregor Moenke AU - Elena Cristiano AU - Ana Finzel AU - Dhana Friedrich AU - Hanspeter Herzel AU - Martin Falcke AU - Alexander Löwer Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/08/09/068668.abstract N2 - Background Cellular signaling pathways transmit information in the presence of molecular noise while retaining flexibility to accommodate the needs of individual cells. A commonly observed strategy to enable such versatile signal transmission is pulsed activation in a digital-like response. For the tumor suppressor p53, single cell analysis has shown such pulsatile activation upon induction of DNA double strand breaks. While in general, the number of uniform pulses in a given time period correlated to the amount of damage, a high degree of heterogeneity was observed even in genetically identical cells treated with equal doses of damaging agents. We now aimed to understand the molecular mechanism underlying the heterogeneous p53 response and explore how it is adjusted to the needs of individual cells.Results To understand design principles underlying p53 signaling, we analyzed its dose-dependent response to radiomimetic drug application in individual cells and observed a switch between signaling modes characterized by isolated pulses and sustained oscillations. Guided by dynamical systems theory we show that this requires an excitable network comprising positive feedback and provide experimental evidence for its molecular identity. Our data-driven model reproduced all features of measured responses and explained 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 pathways.Conclusions Our results demonstrate how excitability enables high specificity, sensitivity and robustness while retaining unique possibilities to adjust signaling functions to the physiology of individual cells. ER -