Regulation of the extracellular antioxidant selenoprotein plasma glutathione peroxidase (GPx-3) in mammalian cells

  • Filomena G. Ottaviano
  • Shiow-Shih Tang
  • Diane E. Handy
  • Joseph Loscalzo


Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon as a selenocysteine codon and requires signals in the 3′-untranslated region (UTR), including a selenocysteine insertion sequence (SECIS), as well as specific translational cofactors. To ascertain regulatory determinants of GPx-3 expression and function, we generated recombinant GPx-3 (rGPX-3) constructs with various 3′-UTR, as well as a Sec73Cys mutant. In transfected Cos7 cells, the Sec73Cys mutant was expressed at higher levels than the wild type rGPx-3, although the wild type rGPx-3 had higher specific activity, similar to plasma purified GPx-3. A 3′-UTR with only the SECIS was insufficient for wild type rGPx-3 protein expression. Selenocompound supplementation and co-transfection with SECIS binding protein 2 increased wild type rGPx-3 expression. These results demonstrate the importance of translational mechanisms in GPx-3 expression.


Antioxidant Selenocysteine 3′-untranslated region Regulation 



Plasma glutathione peroxidase


3′-Untranslated region


Selenocysteine insertion sequence


Recombinant GPx-3


Glutathione peroxidase






Sec-elongation factor


SECIS binding protein 2


Qualitative real-time polymerase chain reaction


Human selenophosphate synthetase D


Glyceraldehyde-3-phosphate dehydrogenase


Recombinant Lac Z





This work is supported by the National Institutes of Health grants HL61795, HL58976, HL28178, and HL81587. The authors would like to acknowledge and thank Barbara Voestch and Ying-Yi Zhang for their helpful advice and suggestions, and Stephanie Tribuna for excellent secretarial assistance.


  1. 1.
    Gromer S, Eubel JK, Lee BL, Jacob J (2005) Human selenoproteins at a glance. Cell Mol Life Sci 62:2414–2437. doi: 10.1007/s00018-005-5143-y PubMedCrossRefGoogle Scholar
  2. 2.
    Behne D, Kyriakopoulos A (2001) Mammalian selenium-containing proteins. Annu Rev Nutr 21:453–473. doi: 10.1146/annurev.nutr.21.1.453 PubMedCrossRefGoogle Scholar
  3. 3.
    Ghyselinck NB, Dufaure I, Lareyre JJ, Rigaudiere N, Mattei MG, Dufaure JP (1993) Structural organization and regulation of the gene for the androgen-dependent glutathione peroxidase-like protein specific to the mouse epididymis. Mol Endocrinol 7:258–272. doi: 10.1210/me.7.2.258 PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshimura S, Suemizu H, Taniguchi Y, Arimori K, Kawabe N, Moriuchi T (1994) The human plasma glutathione peroxidase-encoding gene: organization, sequence and localization to chromosome 5q32. Gene 145:293–297. doi: 10.1016/0378-1119(94)90023-X PubMedCrossRefGoogle Scholar
  5. 5.
    Avissar N, Eisenmann C, Breen JG, Horowitz S, Miller RK, Cohen HJ (1994) Human placenta makes extracellular glutathione peroxidase and secretes it into maternal circulation. Am J Physiol 267:E68–E76PubMedGoogle Scholar
  6. 6.
    Avissar N, Slemmon JR, Palmer IS, Cohen HJ (1991) Partial sequence of human plasma glutathione peroxidase and immunologic identification of milk glutathione peroxidase as the plasma enzyme. J Nutr 121:1243–1249PubMedGoogle Scholar
  7. 7.
    Chu FF, Esworthy RS, Doroshow JH, Doan K, Liu XF (1992) Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung, and breast in humans and rodents. Blood 79:3233–3238PubMedGoogle Scholar
  8. 8.
    Tham DM, Whitin JC, Kim KK, Zhu SX, Cohen HJ (1998) Expression of extracellular glutathione peroxidase in human and mouse gastrointestinal tract. Am J Physiol 275:G1463–G1471PubMedGoogle Scholar
  9. 9.
    Comhair SA, Bhathena PR, Farver C, Thunnissen FB, Erzurum SC (2001) Extracellular glutathione peroxidase induction in asthmatic lungs: evidence for redox regulation of expression in human airway epithelial cells. FASEB J 15:70–78. doi: 10.1096/fj.00-0085com PubMedCrossRefGoogle Scholar
  10. 10.
    Maeda K, Okubo K, Shimomura I, Mizuno K, Matsuzawa Y, Matsubara K (1997) Analysis of an expression profile of genes in the human adipose tissue. Gene 190:227–235. doi: 10.1016/S0378-1119(96)00730-5 PubMedCrossRefGoogle Scholar
  11. 11.
    Avissar N, Finkelstein JN, Horowitz S, Willey JC, Coy E, Frampton MW, Watkins RH, Khullar P, Xu YL, Cohen HJ (1996) Extracellular glutathione peroxidase in human lung epithelial lining fluid and in lung cells. Am J Physiol 270:L173–L182PubMedGoogle Scholar
  12. 12.
    Haung W, Koralewska-Makar A, Bauer B, Akesson B (1997) Extracellular glutathione peroxidase and ascorbic acid in aqueous humor and serum of patients operated on for cataract. Clin Chim Acta 261:117–130. doi: 10.1016/S0009-8981(97)06520-0 PubMedCrossRefGoogle Scholar
  13. 13.
    Oshima G, Kunimoto M, Nakagawa Y (2000) Appearance of extracellular glutathione peroxidase (eGPx) in the ascite fluid of casein-elicited rats. Biol Pharm Bull 23:532–536PubMedGoogle Scholar
  14. 14.
    Whitin JC, Bhamre S, Tham DM, Cohen HJ (2002) Extracellular glutathione peroxidase is secreted basolaterally by human renal proximal tubule cells. Am J Physiol Renal Physiol 283:F20–F28PubMedGoogle Scholar
  15. 15.
    Avissar N, Kerl EA, Baker SS, Cohen HJ (1994) Extracellular glutathione peroxidase mRNA and protein in human cell lines. Arch Biochem Biophys 309:239–246. doi: 10.1006/abbi.1994.1108 PubMedCrossRefGoogle Scholar
  16. 16.
    Whitin JC, Tham DM, Bhamre S, Ornt DB, Scandling JD, Tune BM, Salvatierra O, Avissar N, Cohen HJ (1998) Plasma glutathione peroxidase and its relationship to renal proximal tubule function. Mol Genet Metab 65:238–245. doi: 10.1006/mgme.1998.2760 PubMedCrossRefGoogle Scholar
  17. 17.
    Freedman JE, Frei B, Welch GN, Loscalzo J (1995) Glutathione peroxidase potentiates the inhibition of platelet function by S-nitrosothiols. J Clin Invest 96:394–400. doi: 10.1172/JCI118047 PubMedCrossRefGoogle Scholar
  18. 18.
    Freedman JE, Loscalzo J, Benoit SE, Valeri CR, Barnard MR, Michelson AD (1996) Decreased platelet inhibition by nitric oxide in two brothers with a history of arterial thrombosis. J Clin Invest 97:979–987. doi: 10.1172/JCI118522 PubMedCrossRefGoogle Scholar
  19. 19.
    Kenet G, Freedman J, Shenkman B, Regina E, Brok-Simoni F, Holzman F, Vavva F, Brand N, Michelson A, Trolliet M, Loscalzo J, Inbal A (1999) Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke. Arterioscler Thromb Vasc Biol 19:2017–2023PubMedGoogle Scholar
  20. 20.
    Voetsch B, Jin RC, Bierl C, Benke KS, Kenet G, Simioni P, Ottaviano F, Damasceno BP, Annichino-Bizacchi JM, Handy DE, Loscalzo J (2007) Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children. Stroke 38:41–49. doi: 10.1161/01.STR.0000252027.53766.2b PubMedCrossRefGoogle Scholar
  21. 21.
    Brigelius-Flohe R, Banning A, Schnurr K (2003) Selenium-dependent enzymes in endothelial cell function. Antioxid Redox Signal 5:205–215. doi: 10.1089/152308603764816569 PubMedCrossRefGoogle Scholar
  22. 22.
    Bierl C, Voetsch B, Jin RC, Handy DE, Loscalzo J (2004) Determinants of human plasma glutathione peroxidase (GPx-3) expression. J Biol Chem 279:26839–26845. doi: 10.1074/jbc.M401907200 PubMedCrossRefGoogle Scholar
  23. 23.
    Comhair SA, Erzurum SC (2005) The regulation and role of extracellular glutathione peroxidase. Antioxid Redox Signal 7:72–79. doi: 10.1089/ars.2005.7.72 PubMedCrossRefGoogle Scholar
  24. 24.
    Driscoll DM, Copeland PR (2003) Mechanism and regulation of selenoprotein synthesis. Annu Rev Nutr 23:17–40. doi: 10.1146/annurev.nutr.23.011702.073318 PubMedCrossRefGoogle Scholar
  25. 25.
    Low SC, Grundner-Culemann E, Harney JW, Berry MJ (2000) SECIS-SBP2 interactions dictate selenocysteine incorporation efficiency and selenoprotein hierarchy. EMBO J 19:6882–6890. doi: 10.1093/emboj/19.24.6882 PubMedCrossRefGoogle Scholar
  26. 26.
    Copeland PR, Stepanik VA, Driscoll DM (2001) Insight into mammalian selenocysteine insertion: domain structure and ribosome binding properties of Sec insertion sequence binding protein 2. Mol Cell Biol 21:1491–1498. doi: 10.1128/MCB.21.5.1491-1498.2001 PubMedCrossRefGoogle Scholar
  27. 27.
    Fagegaltier D, Hubert N, Yamada K, Mizutani T, Carbon P, Krol A (2000) Characterization of mSelB, a novel mammalian elongation factor for selenoprotein translation. EMBO J 19:4796–4805. doi: 10.1093/emboj/19.17.4796 PubMedCrossRefGoogle Scholar
  28. 28.
    Low SC, Harney JW, Berry MJ (1995) Cloning and functional characterization of human selenophosphate synthetase, an essential component of selenoprotein synthesis. J Biol Chem 270:21659–21664. doi: 10.1074/jbc.270.37.21659 PubMedCrossRefGoogle Scholar
  29. 29.
    Lee BJ, Rajagopalan M, Kim YS, You KH, Jacobson KB, Hatfield D (1990) Selenocysteine tRNA[Ser]Sec gene is ubiquitous within the animal kingdom. Mol Cell Biol 10:1940–1949PubMedGoogle Scholar
  30. 30.
    Copeland PR, Fletcher JE, Carlson BA, Hatfield D, Driscoll DM (2000) A novel RNA binding protein, SBP2, is required for the translation of mammalian selenoprotein mRNAs. EMBO J 19:304–314. doi: 10.1093/emboj/19.2.306 CrossRefGoogle Scholar
  31. 31.
    Maddipati KR, Marnett LJ (1987) Characterization of the major hydroperoxide-reducing activity of human plasma. Purification and properties of a selenium-dependent glutathione peroxidase. J Biol Chem 262:17398–17403PubMedGoogle Scholar
  32. 32.
    Lin CL, Chen HJ, Hou WC (2002) Activity staining of glutathione peroxidase after electrophoresis on native and sodium dodecyl sulfate polyacrylamide gels. Electrophoresis 23:513–516. doi: 10.1002/1522-2683(200202)23:4<513::AID-ELPS513>3.0.CO;2-J PubMedCrossRefGoogle Scholar
  33. 33.
    Handy DE, Zhang Y, Loscalzo J (2005) Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J Biol Chem 280:15518–15525. doi: 10.1074/jbc.M501452200 PubMedCrossRefGoogle Scholar
  34. 34.
    Weiss Sachdev S, Sunde RA (2001) Selenium regulation of transcript abundance and translational efficiency of glutathione peroxidase-1 and -4 in rat liver. Biochem J 357:851–858. doi: 10.1042/0264-6021:3570851 PubMedCrossRefGoogle Scholar
  35. 35.
    Ren B, Huang W, Akesson B, Ladenstein R (1997) The crystal structure of seleno-glutathione peroxidase from human plasma at 2.9 A resolution. J Mol Biol 268:869–885. doi: 10.1006/jmbi.1997.1005 PubMedCrossRefGoogle Scholar
  36. 36.
    Takahashi K, Avissar N, Whitin J, Cohen H (1987) Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme. Arch Biochem Biophys 256:677–686. doi: 10.1016/0003-9861(87)90624-2 PubMedCrossRefGoogle Scholar
  37. 37.
    Bjornstedt M, Xue J, Huang W, Akesson B, Holmgren A (1994) The thioredoxin and glutaredoxin systems are efficient electron donors to human plasma glutathione peroxidase. J Biol Chem 269:29382–29384PubMedGoogle Scholar
  38. 38.
    Muller C, Wingler K, Brigelius-Flohe R (2003) 3′UTRs of glutathione peroxidases differentially affect selenium-dependent mRNA stability and selenocysteine incorporation efficiency. Biol Chem 384:11–18. doi: 10.1515/BC.2003.002 PubMedCrossRefGoogle Scholar
  39. 39.
    Wingler K, Bocher M, Flohe L, Kollmus H, Brigelius-Flohe R (1999) mRNA stability and selenocysteine insertion sequence efficiency rank gastrointestinal glutathione peroxidase high in the hierarchy of selenoproteins. Eur J Biochem 259:149–157. doi: 10.1046/j.1432-1327.1999.00012.x PubMedCrossRefGoogle Scholar
  40. 40.
    Bermano G, Arthur JR, Hesketh JE (1996) Role of the 3′ untranslated region in the regulation of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase gene expression by selenium supply. Biochem J 320:891–895PubMedGoogle Scholar
  41. 41.
    Avissar N, Whitin JC, Allen PZ, Wagner DD, Liegey P, Cohen HJ (1989) Plasma selenium-dependent glutathione peroxidase. Cell of origin and secretion. J Biol Chem 264:15850–15855PubMedGoogle Scholar
  42. 42.
    Axley MJ, Bock A, Stadtman TC (1991) Catalytic properties of an Escherichia coli formate dehydrogenase mutant in which sulfur replaces selenium. Proc Natl Acad Sci USA 88:8450–8454. doi: 10.1073/pnas.88.19.8450 PubMedCrossRefGoogle Scholar
  43. 43.
    Berry MJ, Kieffer JD, Harney JW, Larsen PR (1991) Selenocysteine confers the biochemical properties characteristic of the type I iodothyronine deiodinase. J Biol Chem 266:14155–14158PubMedGoogle Scholar
  44. 44.
    Berry MJ, Kieffer JD, Larsen PR (1991) Evidence that cysteine, not selenocysteine, is in the catalytic site of type II iodothyronine deiodinase. Endocrinology 129:550–552PubMedCrossRefGoogle Scholar
  45. 45.
    Berry MJ, Maia AL, Kieffer JD, Harney JW, Larsen PR (1992) Substitution of cysteine for selenocysteine in type I iodothyronine deiodinase reduces the catalytic efficiency of the protein but enhances its translation. Endocrinology 131:1848–1852. doi: 10.1210/en.131.4.1848 PubMedCrossRefGoogle Scholar
  46. 46.
    Berry MJ, Banu L, Chen YY, Mandel SJ, Kieffer JD, Harney JW, Larsen PR (1991) Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3′ untranslated region. Nature 353:273–276. doi: 10.1038/353273a0 PubMedCrossRefGoogle Scholar
  47. 47.
    Kim IY, Guimaraes MJ, Zlotnik A, Bazan JF, Stadtman TC (1997) Fetal mouse selenophosphate synthetase 2 (SPS2): characterization of the cysteine mutant form overproduced in a baculovirus-insect cell system. Proc Natl Acad Sci USA 94:418–421. doi: 10.1073/pnas.94.2.418 PubMedCrossRefGoogle Scholar
  48. 48.
    Patterson BH, Levander OA (1997) Naturally occurring selenium compounds in cancer chemoprevention trials: a workshop summary. Cancer Epidemiol Biomarkers Prev 6:63–69PubMedGoogle Scholar
  49. 49.
    Ip C (1998) Lessons from basic research in selenium and cancer prevention. J Nutr 128:1845–1854PubMedGoogle Scholar
  50. 50.
    Saito Y, Yoshida Y, Akazawa T, Takahashi K, Niki E (2003) Cell death caused by selenium deficiency and protective effect of antioxidants. J Biol Chem 278:39428–39434. doi: 10.1074/jbc.M305542200 PubMedCrossRefGoogle Scholar
  51. 51.
    Zhong W, Oberley TD (2001) Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line. Cancer Res 61:7071–7078PubMedGoogle Scholar
  52. 52.
    Zhao R, Domann FE, Zhong W (2006) Apoptosis induced by selenomethionine and methioninase is superoxide mediated and p53 dependent in human prostate cancer cells. Mol Cancer Ther 5:3275–3284. doi: 10.1158/1535-7163.MCT-06-0400 PubMedCrossRefGoogle Scholar
  53. 53.
    Bermano G, Nicol F, Dyer JA, Sunde RA, Beckett GJ, Arthur JR, Hesketh JE (1995) Tissue-specific regulation of selenoenzyme gene expression during selenium deficiency in rats. Biochem J 311:425–430PubMedGoogle Scholar
  54. 54.
    Christensen MJ, Burgener KW (1992) Dietary selenium stabilizes glutathione peroxidase mRNA in rat liver. J Nutr 122:1620–1626PubMedGoogle Scholar
  55. 55.
    Suzuki KT, Ishiwata K, Ogra Y (1999) Incorporation of selenium into selenoprotein P and extracellular glutathione peroxidase: HPLC-ICPMS data with enriched selenite. Analyst (Lond) 124:1749–1753. doi: 10.1039/a906521k CrossRefGoogle Scholar
  56. 56.
    Reszka E, Gromadzinska J, Stanczyk M, Wasowicz W (2005) Effect of selenium on expression of selenoproteins in mouse fibrosarcoma cells. Biol Trace Elem Res 104:165–172. doi: 10.1385/BTER:104:2:165 PubMedCrossRefGoogle Scholar
  57. 57.
    Chavatte L, Brown BA, Driscoll DM (2005) Ribosomal protein L30 is a component of the UGA-selenocysteine recoding machinery in eukaryotes. Nat Struct Mol Biol 12:408–416. doi: 10.1038/nsmb922 PubMedCrossRefGoogle Scholar
  58. 58.
    Shen Q, Fan L, Newburger PE (2006) Nuclease sensitive element binding protein 1 associates with the selenocysteine insertion sequence and functions in mammalian selenoprotein translation. J Cell Physiol 207:775–783. doi: 10.1002/jcp.20619 PubMedCrossRefGoogle Scholar
  59. 59.
    Mehta A, Rebsch CM, Kinzy SA, Fletcher JE, Copeland PR (2004) Efficiency of mammalian selenocysteine incorporation. J Biol Chem 279:37852–37859. doi: 10.1074/jbc.M404639200 PubMedCrossRefGoogle Scholar
  60. 60.
    Berry MJ, Harney JW, Ohama T, Hatfield DL (1994) Selenocysteine insertion or termination: factors affecting UGA codon fate and complementary anticodon:codon mutations. Nucleic Acids Res 22:3753–3759. doi: 10.1093/nar/22.18.3753 PubMedCrossRefGoogle Scholar
  61. 61.
    Dumitrescu AM, Liao XH, Abdullah MS, Lado-Abeal J, Majed FA, Moeller LC, Boran G, Schomburg L, Weiss RE, Refetoff S (2005) Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 37:1247–1252. doi: 10.1038/ng1654 PubMedCrossRefGoogle Scholar
  62. 62.
    Squires JE, Stoytchev I, Forry EP, Berry MJ (2007) SBP2 binding affinity is a major determinant in differential selenoprotein mRNA translation and sensitivity to nonsense-mediated decay. Mol Cell Biol 27:7848–7855. doi: 10.1128/MCB.00793-07 PubMedCrossRefGoogle Scholar
  63. 63.
    Shen Q, Chu FF, Newburger PE (1993) Sequences of the 3′-untranslated region of the human cellular glutathone peroxidase gene are necessary and sufficient for selenocysteine incorporation at the UGA codon. J Biol Chem 268:11463–11469PubMedGoogle Scholar
  64. 64.
    Lesoon A, Mehta A, Singh R, Chisolm GM, Driscoll DM (1997) An RNA-binding protein recognizes a mammalian selenocysteine insertion sequence element required for cotranslational incorporation of selenocysteine. Mol Cell Biol 17:1977–1985PubMedGoogle Scholar
  65. 65.
    Grundner-Culemann E, GW Martin, Harney JW, Berry MJ (1999) Two distinct SECIS structures capable of directing selenocysteine incorporation in eukaryotes. RNA 5:625–635. doi: 10.1017/S1355838299981542 PubMedCrossRefGoogle Scholar
  66. 66.
    Martin GW, Harney JW, Berry MJ (1996) Selenocysteine incorporation in eukaryotes: insights into mechanism and efficiency from sequence, structure, and spacing proximity studies of the type1 deiodinase SECIS element. RNA 2:171–182PubMedGoogle Scholar
  67. 67.
    Fujiwara N, Fujii T, Fujii J, Taniguchi N (1999) Functional expression of rat thioredoxin reductase: selenocysteine insertion sequence element for the active enzyme. Biochem J 340:439–444. doi: 10.1042/0264-6021:3400439 PubMedCrossRefGoogle Scholar
  68. 68.
    Copeland PR, Driscoll DM (1999) Purification, redox sensitivity, and RNA binding properties of SECIS-binding protein 2, a protein involved in selenoprotein biosynthesis. J Biol Chem 274:25447–25454. doi: 10.1074/jbc.274.36.25447 PubMedCrossRefGoogle Scholar
  69. 69.
    Ambrogelly A, Palioura S, Soll D (2007) Natural expansion of the genetic code. Nat Chem Biol 3:29–35. doi: 10.1038/nchembio847 PubMedCrossRefGoogle Scholar
  70. 70.
    Cantin AM, North SL, Hubbard RC, Crystal RG (1987) Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol 63:152–157PubMedGoogle Scholar
  71. 71.
    Avissar N, Whitin JC, Allen PZ, Palmer IS, Cohen HJ (1989) Antihuman plasma glutathione peroxidase antibodies: immunologic investigations to determine plasma glutathione peroxidase protein and selenium content in plasma. Blood 73:318–323PubMedGoogle Scholar
  72. 72.
    Martin JL (1995) Thioredoxin-a fold for all reasons. Structure 3:245–250. doi: 10.1016/S0969-2126(01)00154-X PubMedCrossRefGoogle Scholar
  73. 73.
    Takebe G, Yarimizu J, Saito Y, Hayashi T, Nakamura H, Yodoi J, Nagasawa S, Takahashi K (2002) A comparative study on the hydroperoxide and thiol specificity of the glutathione peroxidase family and selenoprotein P. J Biol Chem 277:41254–41258. doi: 10.1074/jbc.M202773200 PubMedCrossRefGoogle Scholar
  74. 74.
    Chen K, Detwiler TC, Essex DW (1995) Characterization of protein disulphide isomerase released from activated platelets. Br J Haematol 90:425–431. doi: 10.1111/j.1365-2141.1995.tb05169.x PubMedCrossRefGoogle Scholar
  75. 75.
    Kroning H, Kahne T, Ittenson A, Franke A, Ansorge S (1994) Thiol-proteindisulfide-oxidoreductase (proteindisulfide isomerase): a new plasma membrane constituent of mature human B lymphocytes. Scand J Immunol 39:346–350. doi: 10.1111/j.1365-3083.1994.tb03384.x PubMedCrossRefGoogle Scholar
  76. 76.
    Martin H, Dean M (1991) Identification of a thioredoxin-related protein associated with plasma membranes. Biochem Biophys Res Commun 175:123–128. doi: 10.1016/S0006-291X(05)81209-4 PubMedCrossRefGoogle Scholar
  77. 77.
    Schallreuter KU, Wood JM (1988) The activity and purification of membrane-associated thioredoxin reductase from human metastatic melanotic melanoma. Biochim Biophys Acta 967:103–109PubMedGoogle Scholar
  78. 78.
    Ottaviano FG, Handy DE, Loscalzo J (2008) Redox regulation in the extracellular environment. Circ J 72:1–16. doi: 10.1253/circj.72.1 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Filomena G. Ottaviano
    • 1
    • 2
  • Shiow-Shih Tang
    • 2
  • Diane E. Handy
    • 2
  • Joseph Loscalzo
    • 2
  1. 1.Whitaker Cardiovascular Institute and Evans Department of MedicineBoston University School of MedicineBostonUSA
  2. 2.Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations