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

Background and aims: The glutathione peroxidase 2 (GPx2) is a selenoenzyme, that is expressed at crypt bases of the intestinal epithelium and in tumor tissue. The GPx2 promoter is activated by the Wnt pathway, which might be the reason for this expression pattern of GPx2. Together with additional selenoproteins that are putative Wnt targets, namely TrxR2 and TrxR3, Wnt-dependent GPx2 expression was analysed using different cell culture models and mice.

Results: Two human cell culture models for either an activated Wnt pathway (3T3 cells with Wnt3a) or for inhibition of a constitutively active Wnt pathway (HT-29 APC cells) were analysed. The endogenous expression of all three selenoproteins was consistently dependent on the activity status of the Wnt pathway. To provide physiological relevance for this finding, the mRNA expression of GPx2, TrxR2, and TrxR3 was analysed in isolated epithelial cells of the jejunum and colon of mice. Selenoproteins analysed were higher expressed in the proliferative crypt compartment, characterised by an active Wnt pathway, compared to cells of the villus or crypt table, respectively. An inducible knockout of beta-catenin in isolated colonic crypt base cells reduced GPx2 expression.

Conclusions: We have demonstrated the regulation of GPx2 expression by the Wnt pathway in vitro and in vivo and proved for the first time the relevance of this regulatory mechanism in vivo. Furthermore TrxR2 and TrxR3 have been identified as novel Wnt targets.