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Wnt-driven intestinal tumourigenesis is suppressed by Chk1 deficiency but enhanced by conditional haploinsufficiency

Oncogene volume 33, pages 4089–4096 (2014)Cite this article

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Abstract

Chk1 is essential in maintaining genomic stability due to its role in cell cycle regulation. Several recent studies have indicated that the abrogation of checkpoints in tumourigenesis through the inhibition of Chk1 may be of therapeutic value. To further investigate the role of Chk1 in the mouse small intestine and its potential role as a therapy for colorectal cancer, we simultaneously deleted Chk1 and Apc in the mouse small intestine. We found that homozygous loss of Chk1 is not compatible with Wnt-driven proliferation and resulted in the suppression of Wnt-driven tumourigenesis in the mouse small intestine. In contrast, heterozygous loss of Chk1 in a Wnt-driven background resulted in an increase in DNA damage and apoptosis and accelerated both tumour development and progression.

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Acknowledgements

This work was supported by Cancer Research UK. Particular thanks go to Mark Bishop, Lucie Pietzka and Derek Scarborough for technical assistance. The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Cardiff School of Biosciences, Cardiff University, Cardiff, UK

    K R Greenow, A R Clarke & R Jones

  2. School of Medicine, Cardiff University, Cardiff, UK

    G T Williams

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  1. K R Greenow
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  2. A R Clarke
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  3. G T Williams
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  4. R Jones
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Correspondence to A R Clarke.

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Supplementary Information accompanies this paper on the Oncogene website

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Greenow, K., Clarke, A., Williams, G. et al. Wnt-driven intestinal tumourigenesis is suppressed by Chk1 deficiency but enhanced by conditional haploinsufficiency. Oncogene 33, 4089–4096 (2014). https://doi.org/10.1038/onc.2013.371

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