title: Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function.
abstract: 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.
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Soumen
authors.initials: S
authors.lastname: Bera
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Frank
authors.initials: F
authors.lastname: Weinberg
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Dede N
authors.initials: DN
authors.lastname: Ekoue
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Kristine
authors.initials: K
authors.lastname: Ansenberger-Fricano
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois. Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois. Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois. adiamond@uic.edu.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Diamond
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D005260:Female; D014644:Genetic Variation; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000201:enzymology; D018384:Oxidative Stress / Q000235:genetics; D011110:Polymorphism, Genetic; D013347:Subcellular Fractions / Q000201:enzymology; D000094765:Glutathione Peroxidase GPX1
chemical_list: D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human