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Mutations in the APC tumour suppressor gene cause chromosomal instability

Nature Cell Biology volume 3, pages 433–438 (2001)Cite this article

Abstract

Two forms of genetic instability have been described in colorectal cancer1: microsatellite instability and chromosomal instability. Microsatellite instability results from mutations in mismatch repair genes; chromosomal instability is the hallmark of many colorectal cancers, although it is not completely understood at the molecular level. As truncations of the Adenomatous Polyposis Coli (APC) gene are found in most colorectal tumours, we thought that mutations in APC might be responsible for chromosomal instability. To test this hypothesis, we examined mouse embryonic stem (ES) cells homozygous for Min (multiple intestinal neoplasia) or Apc1638T alleles. Here we show that Apc mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation. Consistent with this, APC accumulates at the kinetochore during mitosis. Apc mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores. This phenotype is recapitulated by the induced expression of a 253-amino-acid carboxy-terminal fragment of APC in microsatellite unstable colorectal cancer cells. We conclude that loss of APC sequences that lie C-terminal to the β-catenin regulatory domain contributes to chromosomal instability in colorectal cancer.

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Figure 1: Representation of the full-length APC protein and of the truncated Min and Apc1638T polypeptides.
Figure 2: Multicolour FISH analysis (COBRA) of APC-deficient and wild-type ES cell lines.
Figure 3: Subcellular localization of the APC protein in mitotic ES cells.
Figure 4: Spindle (green) and CREST/kinetochore (red) staining of mitotic wild-type and Apc mutant cells.

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Acknowledgements

We thank C. Cornelisse and N. Kuiper for assistance with FACS; P. Poddighe for karyotyping colorectal cell lines; I. J. Slats for help with confocal microscopy; and M. van den Burg for assistance with multi-colour FISH. A. G. Jochemsen kindly donated the pCMV-Bcl-2 expression vector. The chromosome-specific mouse libraries were a gift from N. Carter.

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Author notes

  1. Carla Rosenberg, Ron Smits and Menno Kielman: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Human and Clinical Genetics, and Center for Biomedical Genetics, Leiden University Medical Center, PO Box 9503, Leiden, 2300, RA, The Netherlands

    Riccardo Fodde, Ron Smits, Menno Kielman, Claudia Gaspar & Cor Breukel

  2. Department of Immunology, and Center for Biomedical Genetics, University Medical Center Utrecht, PO Box 85500, Utrecht, 3508, GA, The Netherlands

    Jeroen Kuipers, Johan H. van Es, Rachel H. Giles & Hans Clevers

  3. Department of Molecular Cell Biology, and Center for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Jeroen Kuipers, Carla Rosenberg & Joop Wiegant

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  1. Riccardo Fodde
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Corresponding authors

Correspondence to Riccardo Fodde or Hans Clevers.

Supplementary information

Figure S1

Cell-cycle analysis of ES cells. (PDF 27 kb)

Figure S2

Analysis of Bcl-2-transfected ES cells. (PDF 381 kb)

Figure S3

Centrosome abnormalities in APC mutant cells. (PDF 44 kb)

Figure S4

Near-tetraploidy in DLD-1 colorectal carcinoma cells. (PDF 25 kb)

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Fodde, R., Kuipers, J., Rosenberg, C. et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3, 433–438 (2001). https://doi.org/10.1038/35070129

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