Predominant mutation of codon 41 of the beta-catenin proto-oncogene in rat colon tumors induced by 1,2-dimethylhydrazine using a complete carcinogenic protocol.
Constitutive activation of the wnt-signaling pathway plays an important role during both human and rat colon carcinogenesis and can be brought through mutations in either the adenomatous polyposis coli or the beta-catenin gene. Mutations found in the beta-catenin gene typically affect one out of four regulatory phosphorylation sites near the N-terminus of the beta-catenin protein. Whereas in human colon cancers, however, the majority of beta-catenin mutations directly alter threonine 41 or serine 45; the beta-catenin mutations found in chemically induced rat colon tumors seemed to cluster around codon 33 instead. Unlike previous studies, that have used relatively short-term (2-5 weeks) treatment with one of the alkylating agents 1,2,-dimethylhydrazine (DMH) or azoxymethane, we have investigated the mutational spectrum of the beta-catenin gene in a panel of rat colon tumors induced by long-term (20 weeks) DMH-treatment. We detected beta-catenin mutations in 12 of 33 (36%) tumors. Interestingly, only one of the beta-catenin mutations found affected the previously implicated codon 33 cluster region (Asp32Asn), whereas 11 of 12 (>90%) mutations represented identical C-->T transitions within codon 41 resulting in the common replacement of threonine by isoleucine. We propose a model in which codon 41 mutations bear higher oncogenic potential but are induced by DMH less frequently than mutations in the codon 33 cluster region. Consequently, only after sustained carcinogenic treatment, as is achieved in the long-term DMH-protocol, codon 41 mutations will be induced frequently enough to be present in all developing malignant lesions and, then, because of their higher oncogenic potential, these are selected for.
Koesters
R
R
Department of Surgery, University Hospital of Heidelberg, INF 110, 69120, Heidelberg, Germany. r.koesters@dkfz.de
Hans
M A
MA
Benner
A
A
Prosst
R
R
Boehm
J
J
Gahlen
J
J
Doeberitz
M K
MK
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003062:Codon; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004127:Dimethylhydrazines / Q000633:toxicity*; D011905:Genes, ras / Q000235:genetics / Q000502:physiology; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators; D051176:beta Catenin
D002273:Carcinogens; D003062:Codon; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004127:Dimethylhydrazines; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015534:Trans-Activators; D051176:beta Catenin