Journal Article

Cyclin D1 over-expression correlates with β-<i>catenin</i> activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3β and ERK1/2 in mouse hepatic carcinogenesis

Junichi Gotoh, Masahiko Obata, Masumi Yoshie, Shinichi Kasai and Katsuhiro Ogawa

in Carcinogenesis

Volume 24, issue 3, pages 435-442
Published in print March 2003 | ISSN: 0143-3334
Published online March 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.3.435
Cyclin D1 over-expression correlates with β-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3β and ERK1/2 in mouse hepatic carcinogenesis

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Mutational activation of β-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated β-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either β-catenin or cyclin D1 may be activated by various pathways independently of β-catenin mutations. In this study, we investigated β-catenin activation and mutations, cyclin D1 expression, H-ras mutations and phosphorylation of extracellular signal regulated protein kinases 1/2 (ERK1/2), Akt and glycogen synthetase kinase 3β (GSK3β) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of β-catenin, a sign of β-catenin activation, was frequently observed in association with the high nuclear cyclin D1 labeling index in the hepatic tumors at the late stage of carcinogenesis. The β-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear β-catenin/TCF4 complex together with cyclin D1 over-expression. However, the fact that only 31.8% (7/22) of the lesions with the nuclear/cytoplasmic β-catenin staining showed β-catenin mutations indicated that β-catenin was activated not only by its own mutations but also by other reason(s). On the other hand, there was no correlation between the β-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3β and ERK1/2, although GSK3β was frequently over-expressed in the tumors. These results indicate that, although β-catenin and cyclin D1 activation are well correlated, the Akt/GSK3β and ras/ERK1/2 pathways may not play a major role in the β-catenin/cyclin D1 activation.

Keywords: DEN, diethylnitrosamine; ERK, extracellular signal regulated kinase; GSK3β, glycogen synthetase kinase-3β; HCC, hepatocellular carcinoma; Igf, insulin like growth factor; L.I., labeling index; PI3K, phosphatidyl inositoside 3-phosphate kinase; SSCP, single strand conformation polymorphism; TCF, T cell factor.

Journal Article.  6653 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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