BACKGROUND: The glutathione peroxidase 2 (GPx2) is expressed at crypt bases of the intestinal epithelium and in tumour tissue. The GPx2 promoter is activated by the Wnt pathway, which might be the reason for the specific expression pattern of GPx2. Together with additional selenoproteins, thioredoxin reductases TrxR2 and TrxR3, which are putative Wnt targets based on microarray analysis, Wnt-dependent GPx2 expression was analysed. METHODS: Two cell culture models for either an activated (3T3 cells with Wnt3a overexpression) or an inhibited Wnt pathway (HT-29 APC cells) were analysed. To provide physiological relevance, crypt base epithelial cells of the jejunum and colon of mice were compared to cells of the villus or crypt table, respectively. In addition, β-catenin was deleted in crypt base cells ex vivo. RESULTS: In cancer cell lines, the endogenous expression of all three selenoproteins was consistently dependent on Wnt pathway activity. Expression was higher in the proliferative crypt compartment, where also the Wnt pathway is active. An inducible knockout of β-catenin in isolated colonic crypt base cells reduced basal GPx2 expression. We, thus, demonstrated the regulation of GPx2 expression by the Wnt pathway in vitro and in vivo. Furthermore, the selenoproteins TrxR2 and TrxR3 have been identified as novel Wnt targets. This may imply a role of GPx2, TrxR2 and TrxR3 in proliferation, apoptosis and, therefore, also during cancer development. GENERAL SIGNIFICANCE: Selenium which is essential for the biosynthesis of Wnt-dependent selenoproteins might be important for the renewal of the intestinal epithelium and during carcinogenesis.
BACKGROUND: The glutathione peroxidase 2 (GPx2) is expressed at crypt bases of the intestinal epithelium and in tumour tissue. The GPx2 promoter is activated by the Wnt pathway, which might be the reason for the specific expression pattern of GPx2. Together with additional selenoproteins, thioredoxin reductases TrxR2 and TrxR3, which are putative Wnt targets based on microarray analysis, Wnt-dependent GPx2 expression was analysed. METHODS: Two cell culture models for either an activated (3T3 cells with Wnt3a overexpression) or an inhibited Wnt pathway (HT-29 APC cells) were analysed. To provide physiological relevance, crypt base epithelial cells of the jejunum and colon of mice were compared to cells of the villus or crypt table, respectively. In addition, β-catenin was deleted in crypt base cells ex vivo. RESULTS: In cancer cell lines, the endogenous expression of all three selenoproteins was consistently dependent on Wnt pathway activity. Expression was higher in the proliferative crypt compartment, where also the Wnt pathway is active. An inducible knockout of β-catenin in isolated colonic crypt base cells reduced basal GPx2 expression. We, thus, demonstrated the regulation of GPx2 expression by the Wnt pathway in vitro and in vivo. Furthermore, the selenoproteins TrxR2 and TrxR3 have been identified as novel Wnt targets. This may imply a role of GPx2, TrxR2 and TrxR3 in proliferation, apoptosis and, therefore, also during cancer development. GENERAL SIGNIFICANCE: Selenium which is essential for the biosynthesis of Wnt-dependent selenoproteins might be important for the renewal of the intestinal epithelium and during carcinogenesis.
Authors: Xin Gen Lei; Jian-Hong Zhu; Wen-Hsing Cheng; Yongping Bao; Ye-Shih Ho; Amit R Reddi; Arne Holmgren; Elias S J Arnér Journal: Physiol Rev Date: 2016-01 Impact factor: 37.312
Authors: Kalishwaralal Kalimuthu; Chenicheri K Keerthana; Manikandan Mohan; Jaison Arivalagan; Johnson Retnaraj Samuel Selvan Christyraj; Michael A Firer; Mohammad Haroon Asif Choudry; Ruby John Anto; Yong J Lee Journal: J Cell Biochem Date: 2021-12-21 Impact factor: 4.429
Authors: Young-Mi Go; James R Roede; Douglas I Walker; Duc M Duong; Nicholas T Seyfried; Michael Orr; Yongliang Liang; Kurt D Pennell; Dean P Jones Journal: Mol Cell Proteomics Date: 2013-08-14 Impact factor: 5.911
Authors: Petra A Tsuji; Bradley A Carlson; Salvador Naranjo-Suarez; Min-Hyuk Yoo; Xue-Ming Xu; Dmitri E Fomenko; Vadim N Gladyshev; Dolph L Hatfield; Cindy D Davis Journal: PLoS One Date: 2012-12-04 Impact factor: 3.240
Authors: Mike F Müller; Simone Florian; Stefanie Pommer; Martin Osterhoff; R Steven Esworthy; Fong-Fong Chu; Regina Brigelius-Flohé; Anna P Kipp Journal: PLoS One Date: 2013-08-19 Impact factor: 3.240