The armadillo repeat domain of Apc suppresses intestinal tumorigenesis.
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.
Crist
Richard C
RC
Department of Microbiology and Immunology, Thomas Jefferson University, 233 South 10th St., BLSB 709, Philadelphia, PA 19107, USA.
Roth
Jacquelyn J
JJ
Baran
Amy A
AA
McEntee
Benjamin J
BJ
Siracusa
Linda D
LD
Buchberg
Arthur M
AM
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D050939:Gene Fusion; D017491:Genes, APC; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015398:Signal Transduction; D001616:beta-Galactosidase / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D051186:Armadillo Domain Proteins; D001616:beta-Galactosidase