P53 pulse modulation differentially regulates target gene promoters to regulate cell fate decisions.

Marie D Harton,Eric Batchelor,Amie D Bunker,Abhyudai Singh,Woo Seuk Koh

doi:10.15252/msb.20188685

Marie D Harton, Eric Batchelor + Show 3 more

Open Access

https://doi.org/10.15252/msb.20188685

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Abstract

The p53 tumor suppressor regulates distinct responses to cellular stresses. Although different stresses generate different p53 dynamics, the mechanisms by which cells decode p53 dynamics to differentially regulate target genes are not well understood. Here, we determined in individual cells how canonical p53 target gene promoters vary in responsiveness to features of p53 dynamics. Employing a chemical perturbation approach, we independently modulated p53 pulse amplitude, duration, or frequency, and we then monitored p53 levels and target promoter activation in individual cells. We identified distinct signal processing features—thresholding in response to amplitude modulation, a refractory period in response to duration modulation, and dynamic filtering in response to frequency modulation. We then showed that the signal processing features not only affect p53 target promoter activation, they also affect p53 regulation and downstream cellular functions. Our study shows how different promoters can differentially decode features of p53 dynamics to generate distinct responses, providing insight into how perturbing p53 dynamics can be used to generate distinct cell fates.

Highlights

Pulsatile dynamics have been identified in a growing number of important cellular signal transduction pathways
Our study demonstrates that p53 target promoters respond to specific features of transcription factor dynamics differently in individual cells, suggesting that cells may leverage target promoter activation to provide an additional level of p53 decoding beyond mRNA
To determine the specific impact of p53 pulse characteristics on target promoter activation, independent of parallel DNA damage response pathways, we developed a method to control p53 dynamics in the absence of extrinsic DNA damage

Summary

Introduction

Pulsatile dynamics have been identified in a growing number of important cellular signal transduction pathways. Molecular Systems Biology important for decoding temporal dynamics into diverse target gene expression patterns, including promoter activation For the yeast transcription factor Msn, distinct modes of target promoter activation in terms of both target gene expression variability and activation threshold are encoded by the protein’s pulsatile dynamics in individual cells We quantified changes in the activation of two canonically regulated p53 target promoters in response to independent manipulation of p53 pulse amplitude, duration, and frequency in single living cells (Fig 1A). Our study demonstrates that p53 target promoters respond to specific features of transcription factor dynamics differently in individual cells, suggesting that cells may leverage target promoter activation to provide an additional level of p53 decoding beyond mRNA instability to produce distinct target gene expression patterns that impact cell fate decisions

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Discussion

Materials and Methods

Methods and Protocols

Conflict of interest