期刊
MOLECULAR BIOLOGY OF THE CELL
卷 20, 期 9, 页码 2381-2388出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-12-1206
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- Department of Pathology and Cell Biology
- Columbia University College of Physicians and Surgeons
- American Cancer Society Research Scholar [RSG-09-02701-CCG]
- March of Dimes Birth Defects Foundation
The majority of colorectal tumors are aneuploid because of the underlying chromosome instability (CIN) phenotype, in which a defective mitotic checkpoint is implicated. Adenomatous polyposis coli (APC), a tumor suppressor gene that is commonly mutated in colon cancers, has been suggested in causing CIN; however, the molecular mechanism remains unresolved. In this study, we report an interaction of tumor-associated N-terminal APC fragments (N-APC) with Mad2, an essential mitotic checkpoint protein, providing a direct molecular support for linking APC mutations to the generation of CIN. N-APC interacts with Mad2 in Xenopus egg extracts, colon cancer cells, and in vitro with purified components. The interaction between N-APC and Mad2 decreases the soluble pool of Mad2, which is essential for Mad2 cycling and releasing from unattached kinetochores to produce a diffusible wait anaphase signal. Addition of such an N-APC mutant of egg extracts inactivates the mitotic checkpoint. Expressing a tumor-associated N-APC mutant in mammalian cells with an intact mitotic checkpoint produces premature anaphase onset with missegregated chromosomes.
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