Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage

Xing Zeng, Frederic Sigoillot, Shantanu Gaur, Sungwoon Choi, Kathleen L. Pfaff, Dong Chan Oh, Nathaniel Hathaway, Nevena Dimova, Gregory D. Cuny, Randall W. King

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)382-395
Number of pages14
JournalCancer Cell
Volume18
Issue number4
DOIs
StatePublished - Oct 19 2010
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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