Irreversible APC(Cdh1) Inactivation Underlies the Point of No Return for Cell-Cycle Entry

Cell. 2016 Jun 30;166(1):167-80. doi: 10.1016/j.cell.2016.05.077.


Proliferating cells must cross a point of no return before they replicate their DNA and divide. This commitment decision plays a fundamental role in cancer and degenerative diseases and has been proposed to be mediated by phosphorylation of retinoblastoma (Rb) protein. Here, we show that inactivation of the anaphase-promoting complex/cyclosome (APC(Cdh1)) has the necessary characteristics to be the point of no return for cell-cycle entry. Our study shows that APC(Cdh1) inactivation is a rapid, bistable switch initiated shortly before the start of DNA replication by cyclin E/Cdk2 and made irreversible by Emi1. Exposure to stress between Rb phosphorylation and APC(Cdh1) inactivation, but not after APC(Cdh1) inactivation, reverted cells to a mitogen-sensitive quiescent state, from which they can later re-enter the cell cycle. Thus, APC(Cdh1) inactivation is the commitment point when cells lose the ability to return to quiescence and decide to progress through the cell cycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / metabolism*
  • Cdh1 Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle* / drug effects
  • Cell Line
  • Cell Line, Tumor
  • F-Box Proteins / metabolism
  • Humans
  • Mitogens / toxicity
  • Phosphorylation
  • Retinoblastoma Protein / metabolism


  • Cdh1 Proteins
  • Cell Cycle Proteins
  • F-Box Proteins
  • FBXO5 protein, human
  • FZR1 protein, human
  • Mitogens
  • Retinoblastoma Protein
  • Anaphase-Promoting Complex-Cyclosome