Inactivation of hCDC4 can cause chromosomal instability

Harith Rajagopalan, Prasad V. Jallepalli, Carlo Rago, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein and Christoph Lengauer ()
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Harith Rajagopalan: Johns Hopkins University School of Medicine
Prasad V. Jallepalli: Johns Hopkins University School of Medicine
Carlo Rago: Johns Hopkins University School of Medicine
Victor E. Velculescu: Johns Hopkins University School of Medicine
Kenneth W. Kinzler: Johns Hopkins University School of Medicine
Bert Vogelstein: Johns Hopkins University School of Medicine
Christoph Lengauer: Johns Hopkins University School of Medicine

Nature, 2004, vol. 428, issue 6978, 77-81

Abstract: Abstract 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.

Date: 2004
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DOI: 10.1038/nature02313

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