Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest.

Authors:
Jose Reyes
Jose Reyes
Fox Chase Cancer Center
Jia-Yun Chen
Jia-Yun Chen
Stanford University
United States
Jacob Stewart-Ornstein
Jacob Stewart-Ornstein
University of California
United States
Caroline S Mock
Caroline S Mock
Harvard Medical School
Boston | United States
Galit Lahav
Galit Lahav
Harvard Medical School
United States

Mol Cell 2018 Aug 26;71(4):581-591.e5. Epub 2018 Jul 26.

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Biological signals need to be robust and filter small fluctuations yet maintain sensitivity to signals across a wide range of magnitudes. Here, we studied how fluctuations in DNA damage signaling relate to maintenance of long-term cell-cycle arrest. Using live-cell imaging, we quantified division profiles of individual human cells in the course of 1 week after irradiation. We found a subset of cells that initially establish cell-cycle arrest and then sporadically escape and divide. Using fluorescent reporters and mathematical modeling, we determined that fluctuations in the oscillatory pattern of the tumor suppressor p53 trigger a sharp switch between p21 and CDK2, leading to escape from arrest. Transient perturbation of p53 stability mimicked the noise in individual cells and was sufficient to trigger escape from arrest. Our results show that the self-reinforcing circuitry that mediates cell-cycle transitions can translate small fluctuations in p53 signaling into large phenotypic changes.

Abstract Video

Pulsating p53 levels in single damaged cells


Source: Cell Press

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Source
http://dx.doi.org/10.1016/j.molcel.2018.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282757PMC

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August 2018
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