Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene.
Ectopic expression of certain Wnt genes in mouse mammary tissue is tumorigenic, and mutations that stabilize beta-catenin are found in various human cancers including colorectal cancer. To determine the role of stabilized beta-catenin in intestinal tumorigenesis in mice, we constructed by embryonic stem (ES) cell-mediated homologous recombination, a mutant beta-catenin allele whose exon 3 was sandwiched by loxP sequences. When the germline heterozygotes were crossed with mice expressing Cre recombinase in the intestines, the serines and threonine encoded by exon 3 and to be phosphorylated by glycogen synthase kinase 3beta (GSK3beta) were deleted in the offspring intestines, which caused adenomatous intestinal polyps resembling those in Apc(Delta716) knockout mice. Some nascent microadenomas were also found in the colon. These results present experimental genetic evidence that activation of the Wnt signaling pathway can cause intestinal and colonic tumors.
Harada
N
N
Banyu Tsukuba Research Institute (Merck), Tsukuba 300-2611, Japan.
Tamai
Y
Y
Ishikawa
T
T
Sauer
B
B
Takaku
K
K
Oshima
M
M
Taketo
M M
MM
D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018390:Gene Targeting / Q000379:methods; D005799:Genes, Dominant; D019426:Integrases / Q000235:genetics; D007414:Intestinal Neoplasms / Q000235:genetics; D007417:Intestinal Polyps / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells; D015534:Trans-Activators; D014764:Viral Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014764:Viral Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C045073:Cre recombinase; D019426:Integrases