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Complete deletion of Apc results in severe polyposis in mice

Oncogene volume 29, pages 1857–1864 (2010)Cite this article

Abstract

The adenomatous polyposis coli (APC) gene product is mutated in the vast majority of human colorectal cancers. APC negatively regulates the WNT pathway by aiding in the degradation of β-catenin, which is the transcription factor activated downstream of WNT signaling. APC mutations result in β-catenin stabilization and constitutive WNT pathway activation, leading to aberrant cellular proliferation. APC mutations associated with colorectal cancer commonly fall in a region of the gene termed the mutation cluster region and result in expression of an N-terminal fragment of the APC protein. Biochemical and molecular studies have revealed localization of APC/Apc to different sub-cellular compartments and various proteins outside of the WNT pathway that associate with truncated APC/Apc. These observations and genotype–phenotype correlations have led to the suggestion that truncated APC bears neomorphic and/or dominant-negative function that support tumor development. To analyze this possibility, we have generated a novel allele of Apc in the mouse that yields complete loss of Apc protein. Our studies reveal that whole-gene deletion of Apc results in more rapid tumor development than the APC multiple intestinal neoplasia (ApcMin) truncation. Furthermore, we found that adenomas bearing truncated Apc had increased β-catenin activity when compared with tumors lacking Apc protein, which could lead to context-dependent inhibition of tumorigenesis.

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Acknowledgements

We thank members of the Jacks labs, Keara Lane in particular, for experimental advice and assistance. This work was supported by the Howard Hughes Medical Institute and partially by the Cancer Center Support (core) Grant P30-CA14051 from the National Cancer Institute. TJ is a Howard Hughes Investigator and a Daniel K Ludwig Scholar.

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Authors and Affiliations

  1. Koch Institute and Department of Biology, MIT, Cambridge, MA, USA

    A F Cheung, A M Carter, K K Kostova, J F Woodruff, D Crowley & T Jacks

  2. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA

    D Crowley & T Jacks

  3. Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, Boston, MA, USA

    R T Bronson

  4. Harvard Medical School Department of Pathology, Masschusetts General Hospital Cancer Center, Charlestown, MA, USA

    K M Haigis

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  1. A F Cheung
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Correspondence to T Jacks.

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

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Cheung, A., Carter, A., Kostova, K. et al. Complete deletion of Apc results in severe polyposis in mice. Oncogene 29, 1857–1864 (2010). https://doi.org/10.1038/onc.2009.457

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