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.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anaphase-Promoting Complex-Cyclosome
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Animals
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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HeLa Cells
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Humans
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Metaphase / drug effects
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Microtubules / drug effects
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Microtubules / metabolism
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Mitosis / drug effects*
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Mutant Proteins / metabolism
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Prodrugs / pharmacology
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Binding / drug effects
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Protein Biosynthesis / drug effects
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Spindle Apparatus / drug effects*
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Spindle Apparatus / pathology*
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Tosylarginine Methyl Ester / pharmacology*
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Ubiquitin-Protein Ligase Complexes / antagonists & inhibitors*
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Ubiquitin-Protein Ligase Complexes / metabolism
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Xenopus
Substances
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Enzyme Inhibitors
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Mutant Proteins
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Prodrugs
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Proteasome Inhibitors
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Tosylarginine Methyl Ester
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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Proteasome Endopeptidase Complex