Complete deletion of Apc results in severe polyposis in mice
Author(s)
Bronson, Roderick T.; Haigis, Kevin M.; Cheung, Ann; Carter, Alia; Kostova, Kamena K.; Woodruff, Joe; Crowley, Denise G.; Jacks, Tyler E; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/84641/Jacks_Complete%20deletion.pdf.jpg?sequence=4&isAllowed=y)
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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.
Date issued
2009-12Department
Koch Institute for Integrative Cancer Research at MITJournal
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.
Version: Author's final manuscript
ISSN
0950-9232
1476-5594