Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20.
Nat Chem Biol
; 16(5): 546-555, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-32152539
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carbamatos
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Diaminas
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Ciclossomo-Complexo Promotor de Anáfase
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Proteínas Cdc20
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Mitose
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article