A Precise Cdk Activity Threshold Determines Passage through the Restriction Point

Clayton Schwarz, Amy Johnson, Mardo Kõivomägi, Evgeny Zatulovskiy, Carolyn J. Kravitz, Andreas Doncic, Jan M. Skotheim

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

At the restriction point (R), mammalian cells irreversibly commit to divide. R has been viewed as a point in G1 that is passed when growth factor signaling initiates a positive feedback loop of Cdk activity. However, recent studies have cast doubt on this model by claiming R occurs prior to positive feedback activation in G1 or even before completion of the previous cell cycle. Here we reconcile these results and show that whereas many commonly used cell lines do not exhibit a G1 R, primary fibroblasts have a G1 R that is defined by a precise Cdk activity threshold and the activation of cell-cycle-dependent transcription. A simple threshold model, based solely on Cdk activity, predicted with more than 95% accuracy whether individual cells had passed R. That a single measurement accurately predicted cell fate shows that the state of complex regulatory networks can be assessed using a few critical protein activities. Schwarz et al. examine the responses of primary cells expressing a live-cell Cdk activity sensor to growth factor removal. They find that Cdk activity at the time of growth factor removal is an accurate predictor of whether a cell subsequently divides.

Original languageEnglish (US)
Pages (from-to)253-264.e5
JournalMolecular Cell
Volume69
Issue number2
DOIs
StatePublished - Jan 18 2018

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Keywords

  • Cdk2
  • G1/S
  • HDHB
  • restriction point

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Schwarz, C., Johnson, A., Kõivomägi, M., Zatulovskiy, E., Kravitz, C. J., Doncic, A., & Skotheim, J. M. (2018). A Precise Cdk Activity Threshold Determines Passage through the Restriction Point. Molecular Cell, 69(2), 253-264.e5. https://doi.org/10.1016/j.molcel.2017.12.017