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Anna Kipp, Antje Banning, Regina Brigelius-Flohé
Activation of the glutathione peroxidase 2 (GPx2) promoter by ?-catenin
Keywords: ß-catenin, carcinogenesis, gastrointestinal glutathione peroxidase, GPx2, proliferation, selenoproteins, transcriptional, regulation
GPx2, formerly called gastrointestinal GPx, is highly expressed in the proliferative area of the intestinal crypt-to-villus axis and in Paneth cells. Additionally, GPx2 is transiently upregulated during development of gastrointestinal adenocarcinomas. Since both, normal proliferation and differentiation of intestinal epithelial cells as well as carcinogenesis are regulated by the Wnt pathway it was tested whether GPx2 might be a target of the ?-catenin/TCF complex which transfers wnt signals. The GPx2 promoter contains five putative ?-catenin/TCF binding sites. Accordingly, the promoter was active in two cell lines with a constitutively active Wnt pathway, HepG2 and SW480, but not in BHK-21 cells in which the pathway is silent. Overexpression of ?-catenin/TCF activated the GPx2 promoter in all three cell lines. Overexpression of wild-type APC in SW480 cells which harbour a mutated APC gene, decreased basal GPx2 promoter activity. Truncation of the promoter identified one ?-catenin/TCF binding site that was sufficient for activation. Mutation of this site reduced the response to ?-catenin/TCF by more than 50%. These findings suggest a function of GPx2 in the maintenance of normal renewal of the intestinal epithelium. Whether its up-regulation during carcinogenesis supports tumor growth or can rather be considered as counteracting effect remains to be investigated.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 2007
Pages: -