p53 pulse modulation differentially regulates target gene promoters to regulate cell fate decisions

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Article numbere8685
JournalMolecular Systems Biology
Volume15
Issue number9
DOIs
StatePublished - Sep 1 2019

Bibliographical note

Funding Information:
We thank all members of the Batchelor laboratory and the Levens laboratory for thoughtful discussions. The pLV‐EF‐mCherry‐Geminin IRES‐Puro plasmid was kindly provided by S Cappell. We thank J Porter for assistance with data analysis. We thank M Aldred, J Wu, and C Corcoran for assistance with image analysis and plasmids. This work was supported by NIH grants 5R01GM124446 (to AS), 5R01GM126557 (to AS), and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH project ZIA BC011382 (to EB).

Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

  • gene regulation
  • microfluidics
  • p53
  • single cell
  • transcription factor dynamics

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