Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice

Min Li, Xiao Fang, Zhubo Wei, J. Philippe York, Pumin Zhang

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Genomic instability is a hallmark of human cancers. Spindle assembly checkpoint (SAC) is a critical cellular mechanism that prevents chromosome missegregation and therefore aneuploidy by blocking premature separation of sister chromatids. Thus, SAC, much like the DNA damage checkpoint, is essential for genome stability. In this study, we report the generation and analysis of mice carrying a Cdc20 allele in which three residues critical for the interaction with Mad2 were mutated to alanine. The mutant Cdc20 protein (AAA-Cdc20) is no longer inhibited by Mad2 in response to SAC activation, leading to the dysfunction of SAC and aneuploidy. The dysfunction could not be rescued by the additional expression of another Cdc20 inhibitor, BubR1. Furthermore, we found that Cdc20AAA/AAA mice died at late gestation, but Cdc20+/AAA mice were viable. Importantly, Cdc20+/AAA mice developed spontaneous tumors at highly accelerated rates, indicating that the SAC-mediated inhibition of Cdc20 is an important tumor-suppressing mechanism.

Original languageEnglish (US)
Pages (from-to)983-994
Number of pages12
JournalJournal of Cell Biology
Volume185
Issue number6
DOIs
StatePublished - Jun 15 2009

ASJC Scopus subject areas

  • Cell Biology

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