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

Gregor Mönke,Dhana Friedrich,Elena Cristiano,Ana Finzel,Alexander Loewer,Martin Falcke,Hanspeter Herzel

doi:10.1038/srep46571

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.

Highlights

IntroductionThere were indications that the sensitivity of the p53 system was adjusted according to the state of an individual cells
To analyze p53 dynamics in response to different doses of DNA damage, we used previously generated single cell data obtained from a breast cancer cell line expressing a fluorescent reporter system (Fig. 1A)[14]
We showed that an excitable network structure comprised of both negative and positive feedbacks is capable of reproducing the p53 response in healthy and stressed cells

Summary

Introduction

There were indications that the sensitivity of the p53 system was adjusted according to the state of an individual cells These observations elicit the question how the same molecular network can generate such diverse dynamic responses and how the transition between isolated p53 pulses and oscillatory dynamics is regulated. To investigate the design principles underlying dynamic signal processing in the p53 network, we combined quantitative single cell data with an abstracted mathematical model of selected molecular interactions. It is well known that negative feedback loops can give rise to sustained oscillations[20], it is less evident how such a system would generate isolated, tunable pulses. We combined quantitative single cell data with methods from dynamical systems theory and propose a network architecture based on positive and negative feedback loops that reproduced experimentally measured p53 dynamics over a wide range of conditions. The corresponding mathematical model revealed sources of cellular heterogeneity and allowed us to predict and validate entry points to modulate the sensitivity of the p53 response

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