Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage.
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.
Mesh Terms:
Animals, Enzyme Activation, Enzyme Inhibitors, HeLa Cells, Humans, Metaphase, Microtubules, Mitosis, Mitotic Spindle Apparatus, Mutant Proteins, Prodrugs, Proteasome Endopeptidase Complex, Protein Binding, Protein Biosynthesis, Tosylarginine Methyl Ester, Ubiquitin-Protein Ligase Complexes, Xenopus
Animals, Enzyme Activation, Enzyme Inhibitors, HeLa Cells, Humans, Metaphase, Microtubules, Mitosis, Mitotic Spindle Apparatus, Mutant Proteins, Prodrugs, Proteasome Endopeptidase Complex, Protein Binding, Protein Biosynthesis, Tosylarginine Methyl Ester, Ubiquitin-Protein Ligase Complexes, Xenopus
Cancer Cell
Date: Oct. 19, 2010
PubMed ID: 20951947
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