Stress-mediated exit to quiescence restricted by increasing persistence in cdk4/6 activation

Hee Won Yang, Steven D. Cappell, Ariel Jaimovich, Chad Liu, Mingyu Chung, Leighton H. Daigh, Lindsey R. Pack, Yilin Fan, Sergi Regot, Markus Covert, Tobias Meyer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere44571
JournaleLife
Volume9
DOIs
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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