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.

中文翻译：

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由 APC/CCdc20 的小分子抑制剂诱导的矛盾有丝分裂退出。

后期促进复合物/环体 (APC/C) 是一种泛素连接酶，可启动后期和有丝分裂退出。APC/C 被 Cdc20 激活并被有丝分裂检查点复合体 (MCC) 抑制，当纺锤体装配检查点 (SAC) 被激活时，MCC 会延迟有丝分裂退出。我们之前将 apcin 鉴定为 Cdc20 的小分子配体，可抑制 APC/CCdc20 并延长有丝分裂。在这里，我们发现当 SAC 活性高时，apcin 反而会缩短有丝分裂。apcin 的这些相反作用源于靶向 Cdc20 中底物泛素化和 MCC 依赖性 APC/C 抑制所需的共同结合位点。此外，我们发现apcin 与p31comet 合作以减轻APC/C 的MCC 依赖性抑制。因此，Apcin 会导致 APC/C 净抑制，当 SAC 活性低时会延长有丝分裂，