Browsing by Author "Oh, Dong-Chan"
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Item Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage(Cancer Cell, 10/19/2011) Zeng, Xing; Sigoillot, Frederic; Gaur, Shantanu; Choi, Sungwoon; Pfaff, Kathleen L.; Oh, Dong-Chan; Hathaway, Nathaniel; Dimova, Nevena; Cuny, Gregory D.; King, Randall W.Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindleassembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promotingcomplex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to theAPC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase withoutperturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest inducedby a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is requiredto inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positivefeedback loop that amplifies the ability of TAME to induce mitotic arrest.