Complete deletion of Apc results in severe polyposis in mice
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Jacks_Complete deletion.pdf
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Author(s)
Bronson, Roderick T.
Haigis, Kevin M.
Cheung, Ann
Carter, Alia
Kostova, Kamena K.
Woodruff, Joe
Crowley, Denise G.
Jacks, Tyler E
Date Issued
December 2009
Journal
Oncogene
Publisher
Nature Publishing Group
Citation
Cheung, A F, A M Carter, K K Kostova, J F Woodruff, D Crowley, R T Bronson, K M Haigis, and T Jacks. “Complete deletion of Apc results in severe polyposis in mice.” Oncogene 29, no. 12 (December 14, 2009): 1857-1864.
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Author's final manuscript
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 (Apc[superscript Min]) 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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike 3.0
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DOI of Published Version
https://doi.org/10.1038/onc.2009.457
