Author/Authors :
Zeng، نويسنده , , Xing and Sigoillot، نويسنده , , Frederic and Gaur، نويسنده , , Shantanu and Choi، نويسنده , , Sungwoon and Pfaff، نويسنده , , Kathleen L. and Oh، نويسنده , , Dong-Chan and Hathaway، نويسنده , , Nathaniel and Dimova، نويسنده , , Nevena and Cuny، نويسنده , , Gregory D. and King، نويسنده , , Randall W.، نويسنده ,
Abstract :
Summary
ubule 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.
