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A T/C polymorphism in the GPX4 3 ' UTR affects the selenoprotein expression pattern and cell viability in transfected Caco-2 cells

Lookup NU author(s): Dr Hannah Gautrey, Dr Judith HallORCiD, Professor John Hesketh

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Abstract

Background: Synthesis of selenoproteins such as glutathione peroxidases (GPx) requires a specific tRNA and a stem-loop structure in the 3'untranslated region (3'UTR) of the mRNA. A common single nucleotide polymorphism occurs in the GPX4 gene in a region corresponding to the 3'UTR. Methods: The two variant 3'UTR sequences were linked to sequences from a selenoprotein reporter gene (iodothyronine deiodinase) and expressed in Caco-2 cells. Clones expressing comparable levels of deiodinase (assessed by real-time PCR) were selected and their response to tert-butyl hydroperoxide assessed by cell viability and measurement of reactive oxygen species. Selenoprotein expression was assessed by real-time PCR, enzyme activity and immunoassay. Results: When selenium supply was low, cells overexpressing the C variant 3'UTR showed lower viability after oxidative challenge, increased levels of reactive oxygen species and lower GPx activity and SelH mRNA expression compared to cells overexpressing the T variant. After selenium supplementation, cell viability and GPx4 expression were higher in the cells overexpressing the C variant. Expression of transgenes incorporating the TIC variant GPX4 (rs713041) sequences in Caco-2 cells leads to alterations in both cell viability after an oxidative challenge and selenoprotein expression. This suggests that the two variants compete differently in the selenoprotein hierarchy. General Significance: The data provide evidence that the T/C variant GPX4 (rs713041) alters the pattern of selenoprotein synthesis if selenium intake is low. Further work is required to assess the impact on disease susceptibility. (C) 2011 Elsevier B.V. All rights reserved.

Publication metadata

Author(s): Gautrey H, Nicol F, Sneddon AA, Hall J, Hesketh J

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta: General Subjects

Year: 2011

Volume: 1810

Issue: 6

Pages: 284-291

Print publication date: 01/04/2011

ISSN (print): 0304-4165

ISSN (electronic): 1872-8006

Publisher: Elsevier BV

URL: http://dx.doi.org/10.1016/j.bbagen.2011.03.016

DOI: 10.1016/j.bbagen.2011.03.016

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