title: Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.
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.
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Jamin B
authors.initials: JB
authors.lastname: Hein
authors.affiliation: The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Nilsson
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D015153:Blotting, Western; D064199:Cdc20 Proteins / Q000378:metabolism*; D056751:Cyclin A2 / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D016195:G2 Phase; D006367:HeLa Cells; D006801:Humans; D007399:Interphase / Q000502:physiology*; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation
chemical_list: C503721:CCNA2 protein, human; C534699:CCNB1 protein, human; D064199:Cdc20 Proteins; D056751:Cyclin A2; D056744:Cyclin B1; C577488:CDC20 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2