eIF2α Kinases and the Evolution of Stress Response in Eukaryotes

  • Juan José BerlangaEmail author
  • César de Haro
  • Miguel A. Rodríguez-Gabriel
  • Iván Ventoso


The recognition of the initiation codon in mRNA is a key step of translation. In eukaryotes, this step is regulated by the activity of eIF2, the initiation factor that brings the Met-tRNAi to the small ribosomal subunit. The activity of eIF2 is regulated by phosphorylation of the α subunit at Ser51 in response to stress. This phosphorylation has two apparently opposing effects: general inhibition of protein synthesis and specific activation of stress-specific gene translation. This translation reprogramming is necessary to adapt gene expression to the new conditions, ensuring cell survival under mild stress. There are five different eIF2α kinases (GCN2, HRI, PERK, PKR and PKZ) whose phylogenetic distribution and regulatory domains reflect a growing need of higher eukaryotes to face different types of stress through specialized responses. The acquisition of stress-sensing regulatory domains endowed the primitive eIF2α kinase with the ability to respond to specific stress signals, funneling different stress responses through eIF2 activity and connecting translation activity with the cellular environment. This fact probably boosted the adaptive capacity of metazoans, especially in terms of coping with stress. In this chapter, we will discuss how different stresses have shaped the evolution of eIF2 kinases, possibly fueling the creation of the variety of eIF2α kinases known today.


Endoplasmic Reticulum Stress Kinase Domain Unfold Protein Response Fission Yeast Amino Acid Deprivation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Hinnebusch AG. Mechanism and regulation of initiatior methionyl-tRNA binding to ribosome. In: Sonenberg, N; Hershey, JWB and Mathews, MB, editors. Translational control of gene expression. NY: Cold Spring Harbor Laboratory Press, Cold Spring Harbor; 2000. pp. 185–243.Google Scholar
  2. 2.
    Lee JH, Choi SK, Roll-Mecak A, Burley SK, Dever TE. Universal conservation in translation initiation revealed by human and archaeal homologs of bacterial translation initiation factor IF2. Proc Natl Acad Sci USA. 1999;96:4342–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Roll-Mecak A, Shin BS, Dever TE, Burley SK. Engaging the ribosome: universal IFs of translation. Trends Biochem Sci. 2001;26:705–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Hinnebusch AG. The scanning mechanism of eukaryotic translation initiation. Annu Rev Biochem. 2014;83:779–812. doi: 10.1146/annurev-biochem-060713-035802.CrossRefPubMedGoogle Scholar
  5. 5.
    Gualerzi CO, Pon CL. Initiation of mRNA translation in bacteria: structural and dynamic aspects. Cell Mol Life Sci. 2015;72:4341–67. doi: 10.1007/s00018-015-2010-3.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Asano K, Shalev A, Phan L, Nielsen K, Clayton J, Valasek L, Donahue TF, Hinnebusch AG. Multiple roles for the C-terminal domain of eIF5 in translation initiation complex assembly and GTPase activation. EMBO J. 2001;20:2326–37. doi: 10.1093/emboj/20.9.2326.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Paulin FE, Campbell LE, O’Brien K, Loughlin J, Proud CG. Eukaryotic translation initiation factor 5 (eIF5) acts as a classical GTPase-activator protein. Curr Biol. 2001;11:55–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Konieczny A, Safer B. Purification of the eukaryotic initiation factor 2-eukaryotic initiation factor 2B complex and characterization of its guanine nucleotide exchange activity during protein synthesis initiation. J Biol Chem. 1983;258:3402–8.PubMedGoogle Scholar
  9. 9.
    Alone PV, Dever TE. Direct binding of translation initiation factor eIF2gamma-G domain to its GTPase-activating and GDP-GTP exchange factors eIF5 and eIF2B epsilon. J Biol Chem. 2006;281:12636–44. doi: 10.1074/jbc.M511700200.CrossRefPubMedGoogle Scholar
  10. 10.
    Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11:113–27. doi: 10.1038/nrm2838.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    La Teana A, Benelli D, Londei P, Blasi U. Translation initiation in the crenarchaeon Sulfolobus solfataricus: eukaryotic features but bacterial route. Biochem Soc Trans. 2013;41:350–5. doi: 10.1042/BST20120300.CrossRefPubMedGoogle Scholar
  12. 12.
    Pedulla N, Palermo R, Hasenohrl D, Blasi U, Cammarano P, Londei P. The archaeal eIF2 homologue: functional properties of an ancient translation initiation factor. Nucleic Acids Res. 2005;33:1804–12. doi: 10.1093/nar/gki321.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Dmitriev SE, Stolboushkina EA, Terenin IM, Andreev DE, Garber MB, Shatsky IN. Archaeal translation initiation factor aIF2 can substitute for eukaryotic eIF2 in ribosomal scanning during mammalian 48S complex formation. J Mol Biol. 2011;413:106–14. doi: 10.1016/j.jmb.2011.08.026.CrossRefPubMedGoogle Scholar
  14. 14.
    Dubiez E, Aleksandrov A, Lazennec-Schurdevin C, Mechulam Y, Schmitt E. Identification of a second GTP-bound magnesium ion in archaeal initiation factor 2. Nucleic Acids Res. 2015;43:2946–57. doi: 10.1093/nar/gkv053.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dev K, Santangelo TJ, Rothenburg S, Neculai D, Dey M, Sicheri F, Dever TE, Reeve JN, Hinnebusch AG. Archaeal aIF2B interacts with eukaryotic translation initiation factors eIF2alpha and eIF2Balpha: Implications for aIF2B function and eIF2B regulation. J Mol Biol. 2009;392:701–22. doi: 10.1016/j.jmb.2009.07.030.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Benelli D, Londei P. Translation initiation in Archaea: conserved and domain-specific features. Biochem Soc Trans. 2011;39:89–93. doi: 10.1042/BST0390089.CrossRefPubMedGoogle Scholar
  17. 17.
    Arkhipova V, Stolboushkina E, Kravchenko O, Kljashtorny V, Gabdulkhakov A, Garber M, Nikonov S, Martens B, Blasi U, Nikonov O. Binding of the 5′-Triphosphate End of mRNA to the gamma-Subunit of Translation Initiation Factor 2 of the Crenarchaeon Sulfolobus solfataricus. J Mol Biol. 2015;427:3086–95. doi: 10.1016/j.jmb.2015.07.020.CrossRefPubMedGoogle Scholar
  18. 18.
    Hasenohrl D, Lombo T, Kaberdin V, Londei P, Blasi U. Translation initiation factor a/eIF2(-gamma) counteracts 5′ to 3′ mRNA decay in the archaeon Sulfolobus solfataricus. Proc Natl Acad Sci USA. 2008;105:2146–50. doi: 10.1073/pnas.0708894105.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pestova TV, Lomakin IB, Lee JH, Choi SK, Dever TE, Hellen CU. The joining of ribosomal subunits in eukaryotes requires eIF5B. Nature. 2000;403:332–5. doi: 10.1038/35002118.CrossRefPubMedGoogle Scholar
  20. 20.
    Ben-Asouli Y, Banai Y, Hauser H, Kaempfer R. Recognition of 5′-terminal TAR structure in human immunodeficiency virus-1 mRNA by eukaryotic translation initiation factor 2. Nucleic Acids Res. 2000;28:1011–8.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Tahara M, Ohsawa A, Saito S, Kimura M. In vitro phosphorylation of initiation factor 2 alpha (aIF2 alpha) from hyperthermophilic archaeon Pyrococcus horikoshii OT3. J Biochem. 2004;135:479–85.CrossRefPubMedGoogle Scholar
  22. 22.
    Krishnamoorthy T, Pavitt GD, Zhang F, Dever TE, Hinnebusch AG. Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Mol Cell Biol. 2001;21:5018–30. doi: 10.1128/MCB.21.15.5018-5030.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Soding J, Thompson JD, Higgins DG. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011;7:539. doi: 10.1038/msb.2011.75.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dar AC, Dever TE, Sicheri F. Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Cell. 2005;122:887–900. doi: 10.1016/j.cell.2005.06.044.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhan K, Vattem KM, Bauer BN, Dever TE, Chen JJ, Wek RC. Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses. Mol Cell Biol. 2002;22:7134–46.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Dever TE DA, Sicheri F. The eIF2α kinases. In: Mathews MBSN, Hershey JWB, editors. Translational control in biology and medicine. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press; 2007. pp. 319–344.Google Scholar
  27. 27.
    Benson DA, Karsch-Mizrachi I, Lipman DJ, Ostell J, Wheeler DL. GenBank. Nucleic Acids Res. 2005;33:D34–8. doi: 10.1093/nar/gki063.CrossRefPubMedGoogle Scholar
  28. 28.
    Rothenburg S, Deigendesch N, Dittmar K, Koch-Nolte F, Haag F, Lowenhaupt K, Rich A. A PKR-like eukaryotic initiation factor 2alpha kinase from zebrafish contains Z-DNA binding domains instead of dsRNA binding domains. Proc Natl Acad Sci USA. 2005;102:1602–7. doi: 10.1073/pnas.0408714102.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Bergan V, Jagus R, Lauksund S, Kileng O, Robertsen B. The Atlantic salmon Z-DNA binding protein kinase phosphorylates translation initiation factor 2 alpha and constitutes a unique orthologue to the mammalian dsRNA-activated protein kinase R. FEBS J. 2008;275:184–97. doi: 10.1111/j.1742-4658.2007.06188.x.CrossRefPubMedGoogle Scholar
  30. 30.
    Rothenburg S, Deigendesch N, Dey M, Dever TE, Tazi L. Double-stranded RNA-activated protein kinase PKR of fishes and amphibians: varying the number of double-stranded RNA binding domains and lineage-specific duplications. BMC Biol. 2008;6:12. doi: 10.1186/1741-7007-6-12.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Su J, Zhu Z, Wang Y. Molecular cloning, characterization and expression analysis of the PKZ gene in rare minnow Gobiocypris rarus. Fish Shellfish Immunol. 2008;25:106–13. doi: 10.1016/j.fsi.2008.03.006.CrossRefPubMedGoogle Scholar
  32. 32.
    Yang PJ, Wu CX, Li W, Fan LH, Lin G, Hu CY. Cloning and functional analysis of PKZ (PKR-like) from grass carp (Ctenopharyngodon idellus). Fish Shellfish Immunol. 2011;31:1173–8. doi: 10.1016/j.fsi.2011.10.012.CrossRefPubMedGoogle Scholar
  33. 33.
    Mohrle JJ, Zhao Y, Wernli B, Franklin RM, Kappes B. Molecular cloning, characterization and localization of PfPK4, an eIF-2alpha kinase-related enzyme from the malarial parasite Plasmodium falciparum. Biochem J. 1997;328(Pt 2):677–87.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Narasimhan J, Joyce BR, Naguleswaran A, Smith AT, Livingston MR, Dixon SE, Coppens I, Wek RC, Sullivan WJ Jr. Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii. J Biol Chem. 2008;283:16591–601. doi: 10.1074/jbc.M800681200.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Konrad C, Wek RC, Sullivan WJ Jr. GCN2-like eIF2alpha kinase manages the amino acid starvation response in Toxoplasma gondii. Int J Parasitol. 2014;44:139–46. doi: 10.1016/j.ijpara.2013.08.005.CrossRefPubMedGoogle Scholar
  36. 36.
    Moraes MC, Jesus TC, Hashimoto NN, Dey M, Schwartz KJ, Alves VS, Avila CC, Bangs JD, Dever TE, Schenkman S, Castilho BA. Novel membrane-bound eIF2alpha kinase in the flagellar pocket of Trypanosoma brucei. Eukaryot Cell. 2007;6:1979–91. doi: 10.1128/EC.00249-07.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    da Silva Augusto L, Moretti NS, Ramos TC, de Jesus TC, Zhang M, Castilho BA, Schenkman S. A membrane-bound eIF2 alpha kinase located in endosomes is regulated by heme and controls differentiation and ROS levels in Trypanosoma cruzi. PLoS Pathog. 2015;11:e1004618. doi: 10.1371/journal.ppat.1004618.Google Scholar
  38. 38.
    Deshmukh K, Anamika K, Srinivasan N. Evolution of domain combinations in protein kinases and its implications for functional diversity. Prog Biophys Mol Biol. 2010;102:1–15. doi: 10.1016/j.pbiomolbio.2009.12.009.CrossRefPubMedGoogle Scholar
  39. 39.
    Trifonov EN, Frenkel ZM. Evolution of protein modularity. Curr Opin Struct Biol. 2009;19:335–40. doi: 10.1016/ Scholar
  40. 40.
    Hinnebusch AG. Evidence for translational regulation of the activator of general amino acid control in yeast. Proc Natl Acad Sci USA. 1984;81:6442–6.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol Cell. 2000;6:269–79.CrossRefPubMedGoogle Scholar
  42. 42.
    Garcia-Barrio M, Dong J, Ufano S, Hinnebusch AG. Association of GCN1-GCN20 regulatory complex with the N-terminus of eIF2alpha kinase GCN2 is required for GCN2 activation. EMBO J. 2000;19:1887–99.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wek SA, Zhu S, Wek RC. The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Mol Cell Biol. 1995;15:4497–506.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Berlanga JJ, Ventoso I, Harding HP, Deng J, Ron D, Sonenberg N, Carrasco L, de Haro C. Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses. EMBO J. 2006;25:1730–40.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    del Pino J, Jimenez JL, Ventoso I, Castello A, Munoz-Fernandez MA, de Haro C, Berlanga JJ. GCN2 has inhibitory effect on human immunodeficiency virus-1 protein synthesis and is cleaved upon viral infection. PLoS ONE. 2012;7:e47272. doi: 10.1371/journal.pone.0047272.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Qiu H, Dong J, Hu C, Francklyn CS, Hinnebusch AG. The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation. EMBO J. 2001;20:1425–38.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lu L, Han AP, Chen JJ. Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses. Mol Cell Biol. 2001;21:7971–80. doi: 10.1128/MCB.21.23.7971-7980.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Martin R, Berlanga JJ, de Haro C. New roles of the fission yeast eIF2alpha kinases Hri1 and Gcn2 in response to nutritional stress. J Cell Sci. 2013;126:3010–20. doi: 10.1242/jcs.118067.CrossRefPubMedGoogle Scholar
  49. 49.
    Zhan K, Narasimhan J, Wek RC. Differential activation of eIF2 kinases in response to cellular stresses in Schizosaccharomyces pombe. Genetics. 2004;168:1867–75.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Yang JM, London IM, Chen JJ. Effects of hemin and porphyrin compounds on intersubunit disulfide formation of heme-regulated eIF-2 alpha kinase and the regulation of protein synthesis in reticulocyte lysates. J Biol Chem. 1992;267:20519–24.PubMedGoogle Scholar
  51. 51.
    Yun BG, Matts JA, Matts RL. Interdomain interactions regulate the activation of the heme-regulated eIF 2 alpha kinase. Biochim Biophys Acta. 2005;1725:174–81. doi: 10.1016/j.bbagen.2005.07.011.CrossRefPubMedGoogle Scholar
  52. 52.
    Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397:271–4.CrossRefPubMedGoogle Scholar
  53. 53.
    Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998;18:7499–509.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–32. doi: 10.1038/35014014.CrossRefPubMedGoogle Scholar
  55. 55.
    Ma K, Vattem KM, Wek RC. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J Biol Chem. 2002;277:18728–35. doi: 10.1074/jbc.M200903200.CrossRefPubMedGoogle Scholar
  56. 56.
    Garcia MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M. Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev. 2006;70:1032–60. doi: 10.1128/MMBR.00027-06.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Green SR, Mathews MB. Two RNA-binding motifs in the double-stranded RNA-activated protein kinase. DAI. Genes Dev. 1992;6:2478–90.CrossRefPubMedGoogle Scholar
  58. 58.
    Manche L, Green SR, Schmedt C, Mathews MB. Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol Cell Biol. 1992;12:5238–48.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Schmedt C, Green SR, Manche L, Taylor DR, Ma Y, Mathews MB. Functional characterization of the RNA-binding domain and motif of the double-stranded RNA-dependent protein kinase DAI (PKR). J Mol Biol. 1995;249:29–44. doi: 10.1006/jmbi.1995.0278.CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang L, Wang A. Virus-induced ER stress and the unfolded protein response. Front Plant Sci. 2012;3:293. doi: 10.3389/fpls.2012.00293.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO. Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell. 2000;11:4241–57.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Murray JI, Whitfield ML, Trinklein ND, Myers RM, Brown PO, Botstein D. Diverse and specific gene expression responses to stresses in cultured human cells. Mol Biol Cell. 2004;15:2361–74. doi: 10.1091/mbc.E03-11-0799.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–33.CrossRefPubMedGoogle Scholar
  64. 64.
    Dever TE. Gene-specific regulation by general translation factors. Cell. 2002;108:545–56.CrossRefPubMedGoogle Scholar
  65. 65.
    Harding HP, Calfon M, Urano F, Novoa I, Ron D. Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol. 2002;18:575–99. doi: 10.1146/annurev.cellbio.18.011402.160624.CrossRefPubMedGoogle Scholar
  66. 66.
    Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell. 2001;7:1165–76.CrossRefPubMedGoogle Scholar
  67. 67.
    Hinnebusch AG. Translational regulation of yeast GCN4. A window on factors that control initiator-trna binding to the ribosome. J Biol Chem. 1997;272:21661–4.CrossRefPubMedGoogle Scholar
  68. 68.
    Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci USA. 2004;101:11269–74.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Elde NC, Child SJ, Geballe AP, Malik HS. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature. 2009;457:485–9. doi: 10.1038/nature07529.CrossRefPubMedGoogle Scholar
  70. 70.
    Rothenburg S, Seo EJ, Gibbs JS, Dever TE, Dittmar K. Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nat Struct Mol Biol. 2009;16:63–70. doi: 10.1038/nsmb.1529.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Juan José Berlanga
    • 1
    Email author
  • César de Haro
    • 1
  • Miguel A. Rodríguez-Gabriel
    • 1
  • Iván Ventoso
    • 1
  1. 1.Centro de Biología Molecular Severo Ochoa (CSIC-UAM)Universidad Autónoma de MadridCampus CantoblancoSpain

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