title: Oncogenic Adenomatous polyposis coli mutants impair the mitotic checkpoint through direct interaction with Mad2.
abstract: 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 |P;wait anaphase|P' 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.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Zhang
authors.forename: Roberto
authors.initials: R
authors.lastname: Neisa
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Mao
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000705:Anaphase; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002457:Cell Extracts; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D064246:Mad2 Proteins; D008938:Mitosis; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009857:Oncogenes; D010063:Ovum / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D002457:Cell Extracts; D004268:DNA-Binding Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; C499480:Mad2 protein, Xenopus; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins