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XB-ART-42263
Cancer Cell 2010 Oct 19;184:382-95. doi: 10.1016/j.ccr.2010.08.010.
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Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage.

Zeng X , Sigoillot F , Gaur S , Choi S , Pfaff KL , Oh DC , Hathaway N , Dimova N , Cuny GD , King RW .


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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.

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Species referenced: Xenopus
Genes referenced: cdc20 cdh1

References [+] :
Bekier, Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit. 2009, Pubmed