Journal Article

Predominant mutation of codon 41 of the β-catenin proto-oncogene in rat colon tumors induced by 1,2-dimethylhydrazine using a complete carcinogenic protocol

Robert Koesters, Margrit A. Hans, Axel Benner, Rüdiger Prosst, Johannes Boehm, Johannes Gahlen and Magnus von Knebel Doeberitz

in Carcinogenesis

Volume 22, issue 11, pages 1885-1890
Published in print November 2001 | ISSN: 0143-3334
Published online November 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.11.1885
Predominant mutation of codon 41 of the β-catenin proto-oncogene in rat colon tumors induced by 1,2-dimethylhydrazine using a complete carcinogenic protocol

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

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 β-catenin gene. Mutations found in the β-catenin gene typically affect one out of four regulatory phosphorylation sites near the N-terminus of the β-catenin protein. Whereas in human colon cancers, however, the majority of β-catenin mutations directly alter threonine 41 or serine 45; the β-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 β-catenin gene in a panel of rat colon tumors induced by long-term (20 weeks) DMH-treatment. We detected β-catenin mutations in 12 of 33 (36%) tumors. Interestingly, only one of the β-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.

Keywords: AOM, azoxymethane; APC, human adenomatous polyposis coli gene;; CTNNB1, human β-catenin gene;; Ctnnb1, mouse/rat β-catenin gene; DMH, 1,2,-dimethylhydrazine

Journal Article.  3316 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.