The selenoproteins GPx2, TrxR2 and TrxR3 are regulated by Wnt signalling in the intestinal epithelium.
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.


CONCLUSIONS
Selenium which is essential for the biosynthesis of Wnt-dependent selenoproteins might be important for the renewal of the intestinal epithelium and during carcinogenesis.
Department Biochemistry of Micronutrients, German Institute of Human Nutrition, Potsdam-Rehbruecke, D-14558 Nuthetal, Germany. annakipp@dife.de
Anna P
AP
Kipp
Mike F
MF
Müller
Eva M
EM
Göken
Stefanie
S
Deubel
Regina
R
Brigelius-Flohé
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D051140:Selenoproteins / Q000235:genetics / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics* / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D051140:Selenoproteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase; C516127:TXNRD2 protein, human; C500519:TXNRD3 protein, human; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase