@article{389d72f93dad423b872eafe774c838af,
title = "Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage",
abstract = "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.",
author = "Xing Zeng and Frederic Sigoillot and Shantanu Gaur and Sungwoon Choi and Pfaff, {Kathleen L.} and Oh, {Dong Chan} and Nathaniel Hathaway and Nevena Dimova and Cuny, {Gregory D.} and King, {Randall W.}",
note = "Funding Information: We thank Mike Aguiar and Steve Gygi for assistance with mass spectrometry and Jonathan Iaconelli for technical assistance. We thank Daniel Finley, David Pellman, and Tom Rapoport for comments on the manuscript. This work was supported by NIH Grant GM66492 to R.W.K. and a grant from the Stewart Trust. R.W.K. is a member of the Dana Farber-Harvard Cancer Center Breast Cancer SPORE, supported by NIH grant CA089393. K.L.P. was supported by fellowship GM085923. Immunofluorescence microscopy data for this study were acquired in the Nikon Imaging Center at Harvard Medical School. The authors declare no financial conflict of interest. ",
year = "2010",
month = oct,
day = "19",
doi = "10.1016/j.ccr.2010.08.010",
language = "English (US)",
volume = "18",
pages = "382--395",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}