Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry

Nat Commun. 2016 Mar 10;7:10975. doi: 10.1038/ncomms10975.

Abstract

Proper cell-cycle progression requires tight temporal control of the Anaphase Promoting Complex/Cyclosome (APC/C), a large ubiquitin ligase that is activated by one of two co-activators, Cdh1 or Cdc20. APC/C and Cdc20 are already present during interphase but APC/C-Cdc20 regulation during this window of the cell cycle, if any, is unknown. Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity. Preventing Cdc20 phosphorylation results in pre-mature activation of the APC/C-Cdc20 and several substrates, including cyclin B1 and A2, are destabilized which lengthens G2 and slows mitotic entry. Expressing non-degradable cyclin A2 but not cyclin B1 restores mitotic entry in these cells. We have thus uncovered a novel positive feedback loop centred on cyclin A2-Cdk2 inhibition of interphase APC/C-Cdc20 to allow further cyclin A2 accumulation and mitotic entry.

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / metabolism*
  • Blotting, Western
  • Cdc20 Proteins / metabolism*
  • Cyclin A2 / metabolism*
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism*
  • G2 Phase
  • HeLa Cells
  • Humans
  • Interphase / physiology*
  • Mitosis / physiology
  • Phosphorylation

Substances

  • CCNA2 protein, human
  • CCNB1 protein, human
  • Cdc20 Proteins
  • Cyclin A2
  • Cyclin B1
  • CDC20 protein, human
  • Anaphase-Promoting Complex-Cyclosome
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2