title: Complete deletion of Apc results in severe polyposis in mice.
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 beta-catenin, which is the transcription factor activated downstream of WNT signaling. APC mutations result in beta-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(Min)) truncation. Furthermore, we found that adenomas bearing truncated Apc had increased beta-catenin activity when compared with tumors lacking Apc protein, which could lead to context-dependent inhibition of tumorigenesis.
authors.affiliation: Koch Institute and Department of Biology, MIT, Cambridge, MA, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Cheung
authors.forename: A M
authors.initials: AM
authors.lastname: Carter
authors.forename: K K
authors.initials: KK
authors.lastname: Kostova
authors.forename: J F
authors.initials: JF
authors.lastname: Woodruff
authors.forename: D
authors.initials: D
authors.lastname: Crowley
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: K M
authors.initials: KM
authors.lastname: Haigis
authors.forename: T
authors.initials: T
authors.lastname: Jacks
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000517:prevention & control; D000818:Animals; D003062:Codon / Q000235:genetics; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D017353:Gene Deletion; D017491:Genes, APC; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D051176:beta Catenin / Q000378:metabolism
chemical_list: D003062:Codon; D018389:Codon, Nonsense; D051176:beta Catenin