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Cancer Lett. 2003 Nov 25;201(2):203-10.

p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells.

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  • 1Department of Biology, Research Institute for Basic Sciences, Kyung Hee University, Hoegi-dong Dongdaemoon-gu, Seoul 130-701, South Korea.

Abstract

Nondisjunction of chromosomes results in aneuploidy in mammalian cells causing genomic instability. The spindle checkpoint, one of the surveillance systems to maintain genomic stability, prevents missegregation of chromosomes until all the kinetochores are properly attached with bipolar spindles. When this condition is not met, MAD2, a component of the spindle checkpoint complex, associates with p55CDC/hCDC20 to inhibit ubiquitination of substrates by the anaphase-promoting complex (APC). In this study, we have focused on the biological role of the MAD2-binding domain in p55CDC/hCDC20 in the maintenance of genomic stability. Based on previous studies, we constructed a truncated p55CDC/hCDC20 mutant (F2) that harbors only the MAD2-binding domain. Interestingly, we found that in the yeast two-hybrid system, the interaction of F2 and MAD2 was stronger than that of intact p55CDC/hCDC20. We also found that in the presence of the microtubule-disrupting drug, nocodazole, U2OS cells expressing p55CDC/hCDC20 mutants bypassed the mitotic arrest and showed apoptotic morphologies, whereas cells harboring vector alone arrested at metaphase. In particular, the apoptotic phenomena were dramatically enhanced in the F2-expressing cells. These mitotic catastrophes also occurred in cells treated with other microtubule disrupting agents, such as taxol and vinblastine. In addition, the mutant cells exhibited chromosomal missegregation during mitosis, even in the absence of nocodazole. Taken together, these results suggest that agents blocking the spindle checkpoint response may induce tumor cells to become more sensitive to spindle poison drugs, providing a powerful tool to improve chemotherapy.

PMID:
14607335
[PubMed - indexed for MEDLINE]
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