Frequent mutations of the rat beta-catenin gene in colon cancers induced by methylazoxymethanol acetate plus 1-hydroxyanthraquinone.
Recent evidence suggests that the beta-catenin gene (CTNNB1) acts as an oncogene, and some human colon tumors with an intact APC gene have activating mutations in CTNNB1. In this study, mutations in the region corresponding to N-terminal phosphorylation sites (codons 1-51) of the rat Ctnnb1 gene were investigated in 20 colon tumors associated with ulcerative colitis and induced with methylazoxymethanol acetate and 1-hydroxyanthraquinone. Ninety percent (18 of 20) of the tumors induced in male F344 rats harbored mutations, which were detected in three of four adenomas (75%) and 15 of 16 adenocarcinomas (94%). Of 18 total missense mutations, 13 (72%) were G-->A transitions at position 101, three were G-->A transitions at position 94, and two were C-->T transitions at position 122, resulting in the amino acid substitutions Gly34-->Glu, Asp32-->Asn, and Thr41-->Ile, respectively. Although there were no mutations in the Apc gene, as we previously reported in the same tumor samples, the results obtained in this study strongly implicate the Apc-beta-catenin-T-cell factor (Tcf) signaling pathway in methylazoxymethanol acetate, 1-hydroxyanthraquinone-induced colon carcinogenesis.
Suzui
M
M
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Ushijima
T
T
Dashwood
R H
RH
Yoshimi
N
N
Sugimura
T
T
Mori
H
H
Nagao
M
M
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000880:Anthraquinones; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D008746:Methylazoxymethanol Acetate; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D015534:Trans-Activators; D051176:beta Catenin
D000880:Anthraquinones; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003062:Codon; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D008746:Methylazoxymethanol Acetate; C061208:1-hydroxyanthraquinone