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 Eāa protein that is regulated by hCDC4 (refs 2ā4). 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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References
Boveri, T. Zur Frage der Enstehung maligner Tumoren (Gustav Fischer, Jena, Germany, 1914)
Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J. & Harper, J. W. A family of mammalian F-box proteins. Curr. Biol. 9, 1180ā1182 (1999)
Schwab, M. & Tyers, M. Cell cycle. Archipelago of destruction. Nature 413, 268ā269 (2001)
Bartek, J. & Lukas, J. Cell cycle. Order from destruction. Science 294, 66ā67 (2001)
Moberg, K. H., Bell, D. W., Wahrer, D. C., Haber, D. A. & Hariharan, I. K. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413, 311ā316 (2001)
Spruck, C. H. et al. hCDC4 gene mutations in endometrial cancer. Cancer Res. 62, 4535ā4539 (2002)
Strohmaier, H. et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413, 316ā322 (2001)
Orlicky, S., Tang, X., Willems, A., Tyers, M. & Sicheri, F. Structural basis for phosphodependent substrate selection and orientation by the SCFCdc4 ubiquitin ligase. Cell 112, 243ā256 (2003)
Guex, N. & Peitsch, M. C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714ā2723 (1997)
Koepp, D. M. et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 294, 173ā177 (2001)
Spruck, C. H., Won, K. A. & Reed, S. I. Deregulated cyclin E induces chromosome instability. Nature 401, 297ā300 (1999)
Nash, P. et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414, 514ā521 (2001)
Goh, P. Y. & Surana, U. Cdc4, a protein required for the onset of S phase, serves an essential function during G2/M transition in Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 5512ā5522 (1999)
Jallepalli, P. V. et al. Securin is required for chromosomal stability in human cells. Cell 105, 445ā457 (2001)
Kanda, T., Sullivan, K. F. & Wahl, G. M. HistoneāGFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr. Biol. 8, 377ā385 (1998)
Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623ā627 (1997)
Savage, J. R. Acentric chromosomal fragments and micronuclei: the time-displacement factor. Mutat. Res. 225, 171ā173 (1989)
Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643ā649 (1998)
Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300ā303 (1998)
Thiagalingam, S. Evaluation of chromosome 18q in colorectal cancers. Nature Genet. 13, 343ā346 (1996)
Pihan, G. A. et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res. 58, 3974ā3985 (1998)
Rajagopalan, H., Nowak, M. A., Vogelstein, B. & Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nature Rev. Cancer 3, 695ā701 (2003)
Sieber, O. M., Heinimann, K. & Tomlinson, I. P. Genomic instabilityāthe engine of tumorigenesis? Nature Rev. Cancer 3, 701ā708 (2003)
Nowak, M. A. et al. The role of chromosomal instability in tumor initiation. Proc. Natl Acad. Sci. USA 99, 16226ā16231 (2002)
Sieber, O. M. et al. Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC. Proc. Natl Acad. Sci. USA 99, 16910ā16915 (2002)
Shih, I. M. et al. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 61, 818ā822 (2001)
Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003)
Shirasuna, K., Sato, M. & Miyazaki, T. A neoplastic epithelial duct cell line established from an irradiated human salivary gland. Cancer 48, 745ā752 (1981)
Acknowledgements
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.
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Supplementary information
Supplementary Figure 1
Time-lapse video-microscopy images of a dividing HCT116Ā hCDC4-/- cell expressing histone-GFP (see Methods). (PDF 109 kb)
Supplementary Table 1
Summary of hCDC4 mutations in colorectal neoplasms. (PDF 57 kb)
Supplementary Table 2
Formation of micronuclei. (PDF 41 kb)
Supplementary Movie 1
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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Rajagopalan, H., Jallepalli, P., Rago, C. et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 428, 77ā81 (2004). https://doi.org/10.1038/nature02313
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DOI: https://doi.org/10.1038/nature02313
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