Glutathione peroxidase 1 (GPx-1) has been implicated in the etiology of several common diseases due to the association between specific allelic variations and
cancer risk. The most common among these variations are the
codon 198 polymorphism that results in either a
leucine or
proline and the number of
alanine repeat
codons in the coding sequence. The molecular and
biologic consequences of these variations remain to be characterized. Toward achieving this goal, we have examined the cellular location of GPx-1 encoded by allelic variants by ectopically expressing these genes in MCF-7 human
breast carcinoma cells that produce undetectable levels of GPx-1, thus achieving exclusive expression in the same cellular environment. A differential distribution between the cytoplasm and mitochondria was observed, with the allele expressing the leucine-198 polymorphism and 7
alanine repeats being more cytoplasmically located than the other alleles examined. To assess whether the distribution of GPx-1 between the cytoplasm and mitochondria had a
biologic consequence, we engineered derivative GPx-1
proteins that were targeted to the mitochondria by the addition of a mitochondria targeting sequence and expressed these
proteins in MCF-7 cells. These cells were examined for their response to oxidative stress, energy metabolism, and impact on
cancer-associated signaling molecules. The results obtained indicated that both primary GPx-1 sequence and cellular location have a profound impact on cellular biology and offer feasible hypotheses about how expression of distinct GPx-1 alleles can affect
cancer risk.
Cancer Res; 74(18); 5118-26. ©2014 AACR.