Myc deletion rescues Apc deficiency in the small intestine (original) (raw)

Nature volume 446, pages 676–679 (2007) Cite this article

Abstract

The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome1. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers2,3, and its loss results in constitutive activity of the β-catenin–Tcf4 transcription complex3. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro4, in normal crypts in vivo5 and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene6; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear β-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.

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Acknowledgements

This work was supported by the CR-UK. Thanks to D. Scarborough and Beatson technology services (T. Gilby, M. O’Prey and A. Dawson) for help with histology, M. Bishop for genotyping and K. Vousden for comments. Thanks also to Y. Hey and the PICR for microarray analysis.

Author Contribution: O.J.S., V.S.M., V.M., K.R.R., T.J.P. J.A.W., J.K.V. and D.A. conducted research for the paper. O.J.S., H.C. and A.R.C. wrote the paper. All authors discussed the results and read the paper.

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Authors and Affiliations

  1. The Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK,
    Owen J. Sansom, Julie A. Wilkins, J. Keith Vass & Dimitris Athineos
  2. Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3US, UK,
    Valerie S. Meniel, Toby J. Phesse, Karen R. Reed & Alan R. Clarke
  3. Hubrecht Laboratory, Nederlands Institute for Developmental Biology, Upsalalaan 8, 3584 CT Utrecht, The Netherlands,
    Vanesa Muncan & Hans Clevers

Authors

  1. Owen J. Sansom
  2. Valerie S. Meniel
  3. Vanesa Muncan
  4. Toby J. Phesse
  5. Julie A. Wilkins
  6. Karen R. Reed
  7. J. Keith Vass
  8. Dimitris Athineos
  9. Hans Clevers
  10. Alan R. Clarke

Corresponding author

Correspondence toOwen J. Sansom.

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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Sansom, O., Meniel, V., Muncan, V. et al. Myc deletion rescues Apc deficiency in the small intestine.Nature 446, 676–679 (2007). https://doi.org/10.1038/nature05674

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