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The armadillo repeat domain of Apc suppresses intestinal tumorigenesis

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Abstract

The adenomatous polyposis coli (APC) gene is known to act as a tumor suppressor gene in both sporadic and hereditary colorectal cancer by negatively regulating WNT signaling. Familial adenomatous polyposis (FAP) patients develop intestinal polyps due to the presence of a single germline mutation in APC. The severity of the FAP phenotype is a function of the position of the APC mutation, indicating a complex role for APC that extends beyond the canonical WNT pathway. APC encodes a large protein with multiple functional domains, including an armadillo repeat domain that has been linked to protein–protein interactions. To determine the effect of the armadillo repeat domain on intestinal tumorigenesis, we generated a congenic mouse line (Apc Δ242) carrying a gene trap cassette between exons 7 and 8 of the murine Apc gene. Apc Δ242/+ mice express a truncated Apc product lacking the armadillo repeat domain as part of a fusion protein with β-geo. Expression of the fusion product was confirmed by X-gal staining, ensuring that Apc Δ242 is not a null allele. In contrast, Apc Min/+ mice produce a truncated Apc product that contains an intact armadillo repeat domain. On the C57BL/6J background, Apc Δ242/+ mice develop more polyps than do Apc Min/+ mice along the entire length of the small intestine; however, polyps were significantly smaller in Apc Δ242/+ mice. In addition, polyp multiplicity in Apc Δ242/+ mice is affected by polymorphisms between inbred strains. These data suggest that the armadillo repeat domain of the Apc protein suppresses tumor initiation in the murine intestine while also promoting tumor growth.

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Acknowledgments

We thank Dr. Revati Koratkar for providing the B6C3F1 Apc Min/+ data and Stephanie Nnadi and Jennifer Talarico for critical reading of the manuscript. RCC was supported by NIH training grant T32-CA09678. JJR was supported by NIH training grant T32-CA09683. Research was supported in part by grants from the NCI to AMB and LDS.

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Author notes

  1. Benjamin J. McEntee

    Present address: Sanofi Pasteur, Swiftwater, PA, 18370, USA

Authors and Affiliations

  1. Department of Microbiology and Immunology, Thomas Jefferson University, 233 South 10th St., BLSB 709, Philadelphia, PA, 19107, USA

    Richard C. Crist, Jacquelyn J. Roth, Amy A. Baran, Benjamin J. McEntee, Linda D. Siracusa & Arthur M. Buchberg

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  1. Richard C. Crist
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  2. Jacquelyn J. Roth
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Correspondence to Arthur M. Buchberg.

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R. C. Crist and J. J. Roth contributed equally to this work.

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Crist, R.C., Roth, J.J., Baran, A.A. et al. The armadillo repeat domain of Apc suppresses intestinal tumorigenesis. Mamm Genome 21, 450–457 (2010). https://doi.org/10.1007/s00335-010-9288-0

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