Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century1; however, the mechanisms responsible for this abnormality have remained elusive. Here we report the identification of mutations in hCDC4 (also known as Fbw7 or Archipelago) in both human colorectal cancers and their precursor lesions. We show that genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability. This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E—a protein that is regulated by hCDC4 (refs 2–4). Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion.
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We thank L. Meszler and L. Morsberger for technical assistance; A. Rosen and S. White for reagents; and the members of our Center for Cancer Genetics and Therapeutics for help and support. This work was supported by the Clayton Fund, NIH grants, and a Translational Research Award from the Virginia and D. K. Ludwig Fund for Cancer Research.
The authors declare that they have no competing financial interests.
Time-lapse video-microscopy images of a dividing HCT116 hCDC4-/- cell expressing histone-GFP (see Methods). (PDF 109 kb)
Summary of hCDC4 mutations in colorectal neoplasms. (PDF 57 kb)
Formation of micronuclei. (PDF 41 kb)
Time-lapse videomicroscopy movie of a dividing HCT116 hCDC4-/- cell shows a failure of chromosomes to properly align on metaphase plate. Mitosis results in an unequal segregation of nuclear material. (MOV 727 kb)
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