Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.
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, Blotting, Western, Cdc20 Proteins, Cyclin A2, Cyclin B1, Cyclin-Dependent Kinase 2, G2 Phase, HeLa Cells, Humans, Interphase, Mitosis, Phosphorylation
Anaphase-Promoting Complex-Cyclosome, Blotting, Western, Cdc20 Proteins, Cyclin A2, Cyclin B1, Cyclin-Dependent Kinase 2, G2 Phase, HeLa Cells, Humans, Interphase, Mitosis, Phosphorylation
Nat Commun
Date: Mar. 11, 2016
PubMed ID: 26960431
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