Regulation of selenoprotein expression

Abstract

Studies on selenoprotein expression are revealing three distinct patterns of selenium regulation. In rats, selenium deficiency can result in >90% decreases in both glutathione peroxidase-1 (GPx1) activity and mRNA, whereas glutathione peroxidase-4 activity and mRNA decrease 60% and <10%, respectively. Our recent work with thioredoxin reductase reveals activity decreases of ∼90% but with mRNA decreases <30%. This selenium regulation of gene expression could occur potentially at any of six points. Regulation of selenoprotein translation by selenium, mediated by Sec-tRNA availability, regulates the level of all selenoproteins. For optimum translation of a selenoprotein, its mRNA appears to require an optimum UGA location, an optimum UGA context and SECIS element(s) in the 3′-untranslated region (3′-UTR) which optimize Sec incorporation. The unique and specific regulation of GPx1 expression by selenium is mediated by regulation of GPx1 mRNA stability, and involves nonsense-mediated mRNA decay. This regulation, too, requires a functional SECIS element and a UGA codon, and the UGA must be followed by an intron. Our recent results indicate that GPx1 mRNA in selenium-deficient rat liver is moderately abundant, and that GPx1 mRNA in rat liver increases more than 20-fold with selenium supplementation. We hypothesize that this selenium regulation of GPx1 expression is a major component of GPx1 function in higher animals, and that in this role, GPx1 serves as a biological selenium buffer that maintains modest selenium stores for future selenoprotein synthesis.