title: Cytoplasmic and nuclear accumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma.
abstract: Beta-catenin plays an important role in the Wnt signaling pathway by activating T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-regulated gene transcription. The level of beta-catenin is regulated through GSK-3beta phosphorylation of specific serine and threonine residues, all of which are encoded for in exon 3 of the beta-catenin gene (CTNNB1). Mutations altering the GSK-3beta phosphorylation sites lead to cellular accumulation of beta-catenin and constitutive transcription of Tcf/Lef target genes. Such mutations have previously been found in melanoma cell lines. In our study, primary melanomas and their corresponding metastases were screened for CTNNB1 exon 3 mutations using single-strand conformation polymorphism and nucleotide sequence analysis. One of 31 primary tumors and 1 of 37 metastases, both originating from the same patient, had a TCT to TTT mutation at codon 45, changing serine to phenylalanine. Immunohistochemical analysis revealed membranous localization of beta-catenin in a majority of the samples. The mutated primary tumor and metastasis, however, displayed widespread cytoplasmic and nuclear expression of beta-catenin. An additional 30% of the primary tumors showed focal cytoplasmic and nuclear staining. Thus, beta-catenin exon 3 mutations are rare in primary as well as metastatic melanomas and do not explain the abnormal cytoplasmic and nuclear localization of beta-catenin found in a relatively large fraction of primary melanomas.
authors.affiliation: Cancer Centre Karolinska, Department of Oncology-Pathology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Omholt
authors.forename: A
authors.initials: A
authors.lastname: Platz
authors.forename: U
authors.initials: U
authors.lastname: Ringborg
authors.forename: J
authors.initials: J
authors.lastname: Hansson
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism*; D003062:Codon; D003593:Cytoplasm / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010649:Phenylalanine / Q000737:chemistry; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D012694:Serine / Q000737:chemistry; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators; D014158:Transcription, Genetic; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003062:Codon; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D012694:Serine; D010649:Phenylalanine