Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation
- Columbia University, United States
- NIH, United States
- Stanford University, United States
- 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
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
- Sander Van den Heuvel, Utrecht University, Netherlands
Version history
- Received: December 20, 2018
- Accepted: April 2, 2020
- Accepted Manuscript published: April 7, 2020 (version 1)
- 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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Stress-mediated exit to quiescence restricted by increasing persistence in CDK4/6 activation
eLife 9:e44571.
https://doi.org/10.7554/eLife.44571
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