Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice.
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 Cdc20(AAA/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.
Li
Min
M
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Fang
Xiao
X
Wei
Zhubo
Z
York
J Philippe
JP
Zhang
Pumin
P
D000595:Amino Acid Sequence; D000782:Aneuploidy; D000818:Animals; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D043171:Chromosomal Instability; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D018816:Genes, cdc; D006801:Humans; D007621:Karyotyping; D064246:Mad2 Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015739:Nocodazole / Q000378:metabolism; D017354:Point Mutation; D016415:Sequence Alignment; D008941:Spindle Apparatus / Q000378:metabolism*; D050257:Tubulin Modulators / Q000378:metabolism
D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D050257:Tubulin Modulators; D015739:Nocodazole