Controlling Depth of Cellular Quiescence by an Rb-E2F Network Switch

Jungeun Sarah Kwon, Nicholas J. Everetts, Xia Wang, Weikang Wang, Kimiko Della Croce, Jianhua Xing, Guang Yao

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Quiescence is a non-proliferative cellular state that is critical to tissue repair and regeneration. Although often described as the G0 phase, quiescence is not a single homogeneous state. As cells remain quiescent for longer durations, they move progressively deeper and display a reduced sensitivity to growth signals. Deep quiescent cells, unlike senescent cells, can still re-enter the cell cycle under physiological conditions. Mechanisms controlling quiescence depth are poorly understood, representing a currently underappreciated layer of complexity in growth control. Here, we show that the activation threshold of a Retinoblastoma (Rb)-E2F network switch controls quiescence depth. Particularly, deeper quiescent cells feature a higher E2F-switching threshold and exhibit a delayed traverse through the restriction point (R-point). We further show that different components of the Rb-E2F network can be experimentally perturbed, following computer model predictions, to coarse- or fine-tune the E2F-switching threshold and drive cells into varying quiescence depths. Cellular quiescence is not a single homogeneous state but displays different depths. Kwon et al. now show that quiescence depth is controlled by the activation threshold of a bistable Rb-E2F network switch, which can be coarse- or fine-tuned by different network components to change the growth responses of quiescent cells.

Original languageEnglish (US)
Pages (from-to)3223-3235
Number of pages13
JournalCell Reports
Volume20
Issue number13
DOIs
StatePublished - Sep 26 2017

Keywords

  • Rb-E2F pathway
  • activation threshold
  • bistable switch
  • cell cycle entry
  • cell growth
  • cell proliferation
  • cellular quiescence
  • model simulation
  • quiescence depth
  • quiescence heterogeneity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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