Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20.

The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase that initiates anaphase and mitotic exit. APC/C is activated by Cdc20 and inhibited by the mitotic checkpoint complex (MCC), which delays mitotic exit when the spindle assembly checkpoint (SAC) is activated. We previously identified apcin as a small molecule ligand of Cdc20 ...
that inhibits APC/CCdc20 and prolongs mitosis. Here we find that apcin paradoxically shortens mitosis when SAC activity is high. These opposing effects of apcin arise from targeting of a common binding site in Cdc20 required for both substrate ubiquitination and MCC-dependent APC/C inhibition. Furthermore, we found that apcin cooperates with p31comet to relieve MCC-dependent inhibition of APC/C. Apcin therefore causes either net APC/C inhibition, prolonging mitosis when SAC activity is low, or net APC/C activation, shortening mitosis when SAC activity is high, demonstrating that a small molecule can produce opposing biological effects depending on regulatory context.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Anaphase-Promoting Complex-Cyclosome, Binding Sites, Carbamates, Cdc20 Proteins, Cell Cycle Proteins, Cyclin B1, Diamines, HCT116 Cells, HeLa Cells, Humans, Mitosis, Nocodazole, Nuclear Proteins, Spindle Apparatus, Telomerase, Time-Lapse Imaging, Ubiquitination
Nat Chem Biol
Date: Dec. 01, 2019
Download Curated Data For This Publication
226731
Switch View:
  • Interactions 44