Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage
Copyright policy )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.
- University of North Carolina at Chapel Hill United States
- Harvard University United States
- Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School United States
- Brigham and Women's Faulkner Hospital United States
- Harvard Medical School United States
Cancer Research, Proteasome Endopeptidase Complex, Xenopus, Mitosis, Spindle Apparatus, Microtubules, Anaphase-Promoting Complex-Cyclosome, Animals, Humans, Prodrugs, Enzyme Inhibitors, Metaphase, Ubiquitin-Protein Ligase Complexes, Cell Biology, Tosylarginine Methyl Ester, Enzyme Activation, Oncology, Protein Biosynthesis, Mutant Proteins, Proteasome Inhibitors, HeLa Cells, Protein Binding
Cancer Research, Proteasome Endopeptidase Complex, Xenopus, Mitosis, Spindle Apparatus, Microtubules, Anaphase-Promoting Complex-Cyclosome, Animals, Humans, Prodrugs, Enzyme Inhibitors, Metaphase, Ubiquitin-Protein Ligase Complexes, Cell Biology, Tosylarginine Methyl Ester, Enzyme Activation, Oncology, Protein Biosynthesis, Mutant Proteins, Proteasome Inhibitors, HeLa Cells, Protein Binding
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