[PDF][PDF] Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage
X Zeng, F Sigoillot, S Gaur, S Choi, KL Pfaff, DC Oh… - Cancer cell, 2010 - cell.com
X Zeng, F Sigoillot, S Gaur, S Choi, KL Pfaff, DC Oh, N Hathaway, N Dimova, GD Cuny…
Cancer cell, 2010•cell.comMicrotubule inhibitors are important cancer drugs that induce mitotic arrest by activating the
spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the
anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine
methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and
Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but
nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a …
spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the
anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine
methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and
Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but
nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a …
Summary
Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is required to inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest.
cell.com