Inactivation of hCDC4 can cause chromosomal instability

Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century; 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...

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Bibliographic Details
Published in:Nature 2004-03, Vol.428 (6978), p.77-81
Main Authors: Lengauer, Christoph, Rajagopalan, Harith, Jallepalli, Prasad V, Rago, Carlo, Velculescu, Victor E, Kinzler, Kenneth W, Vogelstein, Bert
Format: Article
Language:English
Subjects:
Aneuploidy
Archipelagoes
Biological and medical sciences
CDC4 gene
Cell Cycle Proteins - chemistry
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell cycle, cell proliferation
Cell Line, Tumor
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Chromosomes
Colorectal carcinoma
Colorectal Neoplasms - genetics
Cyclin E - genetics
Cyclin E - metabolism
F-Box Proteins - chemistry
F-Box Proteins - genetics
F-Box Proteins - metabolism
F-Box-WD Repeat-Containing Protein 7
Fundamental and applied biological sciences. Psychology
Gene Deletion
Genomic Instability - genetics
Humanities and Social Sciences
Humans
In Situ Hybridization, Fluorescence
Inactivation
letter
Micronuclei, Chromosome-Defective - genetics
Models, Molecular
Molecular and cellular biology
multidisciplinary
Mutation
Mutation - genetics
Protein Conformation
RNA, Messenger - genetics
RNA, Messenger - metabolism
Science
Science (multidisciplinary)
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - deficiency
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century; 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature02313