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Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells

Oncogene volume 26, pages 3511–3520 (2007)Cite this article

Abstract

Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate β-catenin/T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or β-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signal-activated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear β-catenin, ABI was significantly higher than in those without. These results collectively indicate that β-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.

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Acknowledgements

We thank M Maekawa for excellent technical assistance, Dr M Sonoshita for the retrovirus method, and Dr A Shimizu for the flow cytometry service. We also thank Drs S Yamashita, E Sonoda and S Takeda for fruitful discussions, and Dr J Moneypenny for comments on the paper. We thank Drs H Clevers (Utrecht) and T Akiyama (Tokyo) for providing us the dominant-negative TCF constructs, and Dr P Vogt (San Diego) for the TCF4-VP16 constructs. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and from Sagawa Cancer Research Fund. KA is a 21st Century COE Program postdoctoral fellow at Graduate School of Medicine, Kyoto University.

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Authors and Affiliations

  1. Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    K Aoki, M Aoki, H Miyoshi, M Oshima & M M Taketo

  2. Center for Molecular Biology and Genetics, Kyoto University, Kyoto, Japan

    M Sugai

  3. Banyu Tsukuba Research Institute (Merck), Ibaraki, Japan

    N Harada

  4. Division of Oncological Pathology, Aichi Cancer Center Research Institute, Aichi, Japan

    T Tsukamoto, T Mizoshita & M Tatematsu

  5. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    H Seno & T Chiba

  6. Department of Urology, University of Southern California, Los Angeles, CA, USA

    C-L Hsieh

  7. Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA

    C-L Hsieh

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  1. K Aoki
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Correspondence to M M Taketo.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Aoki, K., Aoki, M., Sugai, M. et al. Chromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells. Oncogene 26, 3511–3520 (2007). https://doi.org/10.1038/sj.onc.1210141

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  • DOI: https://doi.org/10.1038/sj.onc.1210141

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