Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1. Academic Article uri icon

Overview

abstract

  • Cells escape the need for mitogens at a restriction point several hours before entering S phase. The restriction point has been proposed to result from CDK4/6 initiating partial Rb phosphorylation to trigger a bistable switch whereby cyclin E-CDK2 and Rb mutually reinforce each other to induce Rb hyperphosphorylation. Here, using single-cell analysis, we unexpectedly found that cyclin E/A-CDK activity can only maintain Rb hyperphosphorylation starting at the onset of S phase and that CDK4/6 activity, but not cyclin E/A-CDK activity, is required to hyperphosphorylate Rb throughout G1 phase. Mitogen removal in G1 results in a gradual loss of CDK4/6 activity with a high likelihood of cells sustaining Rb hyperphosphorylation until S phase, at which point cyclin E/A-CDK activity takes over. Thus, it is short-term memory, or transient hysteresis, in CDK4/6 activity following mitogen removal that sustains Rb hyperphosphorylation, demonstrating a probabilistic rather than an irreversible molecular mechanism underlying the restriction point.

publication date

  • September 19, 2019

Research

keywords

  • Cell Proliferation
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Epithelial Cells
  • G1 Phase Cell Cycle Checkpoints
  • Mitogens

Identity

PubMed Central ID

  • PMC7189330

Scopus Document Identifier

  • 85074997069

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2019.08.020

PubMed ID

  • 31543423

Additional Document Info

volume

  • 76

issue

  • 4