Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation

  1. Hee Won Yang  Is a corresponding author
  2. Steven D Cappell
  3. Ariel Jaimovich
  4. Chad Liu
  5. Mingyu Chung
  6. Leighton H Daigh
  7. Lindsey R Pack
  8. Yilin Fan
  9. Sergi Regot
  10. Markus Covert
  11. Tobias Meyer  Is a corresponding author
  1. Columbia University, United States
  2. NIH, United States
  3. Stanford University, United States
  4. Johns Hopkins University School of Medicine, United States

Abstract

Mammalian cells typically start the cell-cycle entry program by activating cyclin-dependent protein kinase 4/6 (CDK4/6). CDK4/6 activity is clinically relevant as mutations, deletions, and amplifications that increase CDK4/6 activity contribute to the progression of many cancers. However, when CDK4/6 is activated relative to CDK2 remained incompletely understood. Here we developed a reporter system to simultaneously monitor CDK4/6 and CDK2 activities in single cells and found that CDK4/6 activity increases rapidly before CDK2 activity gradually increases, and that CDK4/6 activity can be active after mitosis or inactive for variable time periods. Markedly, stress signals in G1 can rapidly inactivate CDK4/6 to return cells to quiescence but with reduced probability as cells approach S phase. Together, our study reveals a regulation of G1 length by temporary inactivation of CDK4/6 activity after mitosis, and a progressively increasing persistence in CDK4/6 activity that restricts cells from returning to quiescence as cells approach S phase.

Data availability

Source data files have been provided for Figures 1, 2, 3, 4, Figure 1-figure supplement 2 and 4. Source data for Figure 2-figure supplement 2 and Figure 3-figure supplement 1 will be made available online with the final version of record.

Article and author information

Author details

  1. Hee Won Yang

    Department of Pathology and Cell Biology, Columbia University, New York, United States
    For correspondence
    hy2602@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Steven D Cappell

    NCI, NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ariel Jaimovich

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chad Liu

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mingyu Chung

    Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Leighton H Daigh

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lindsey R Pack

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yilin Fan

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sergi Regot

    Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9786-3897
  10. Markus Covert

    Bioengineering, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5993-8912
  11. Tobias Meyer

    Department of Chemical and Systems Biology, Stanford University, Stanford, United States
    For correspondence
    tobias1@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4339-3804

Funding

National Institute of General Medical Sciences (GM127026)

  • Tobias Meyer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sander Van den Heuvel, Utrecht University, Netherlands

Version history

  1. Received: December 20, 2018
  2. Accepted: April 2, 2020
  3. Accepted Manuscript published: April 7, 2020 (version 1)
  4. Version of Record published: May 11, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Hee Won Yang
  2. Steven D Cappell
  3. Ariel Jaimovich
  4. Chad Liu
  5. Mingyu Chung
  6. Leighton H Daigh
  7. Lindsey R Pack
  8. Yilin Fan
  9. Sergi Regot
  10. Markus Covert
  11. Tobias Meyer
(2020)
Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation
eLife 9:e44571.
https://doi.org/10.7554/eLife.44571

Share this article

https://doi.org/10.7554/eLife.44571

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