Cellular and Molecular Life Sciences

, Volume 67, Issue 14, pp 2491–2506 | Cite as

Endocytosis of hepatitis C virus non-enveloped capsid-like particles induces MAPK–ERK1/2 signaling events

  • Konstantina Katsarou
  • Alexandros Α. Lavdas
  • Panagiota Tsitoura
  • Elisavet Serti
  • Panagiotis Markoulatos
  • Penelope Mavromara
  • Urania GeorgopoulouEmail author
Research Article


Although HCV is an enveloped virus, naked nucleocapsids have been reported in the serum of infected patients. The HCV core particle serves as a protective capsid shell for the viral genome and recombinant in vitro assembled HCV core particles induce strong specific immunity. We investigated the post-binding mechanism of recombinant core particle uptake and its intracellular fate. In hepatic cells, these particles are internalized, most likely in a clathrin-dependent pathway, reaching early to late endosomes and finally lysosomes. The endocytic acidic milieu is implicated in trafficking process. Using specific phosphoantibodies, signaling pathway inhibitors and chemical agents, ERK1/2 was found to be activated in a sustained way after endocytosis, followed by downstream immediate early genes (c-fos and egr-1) modulation. We propose that the intriguing properties of cellular internalization of HCV non-enveloped particles can induce specific ERK1/2–MAPKs events that could be important in HCV life cycle and pathogenesis of HCV infection.


Hepatitis C virus Non-enveloped particles Endocytosis ERK1/2 c-fos egr-1 



We thank P. Foka for useful discussions and Dr. D. Blaas for critical reading. We also thank our colleague Dr. K. Lazaridis (Department of Biochemistry, Hellenic Pasteur Institute) for assisting in statistical analysis. This work was supported by PENED 03EΔ297, co-financed by E.U.-European Social Fund (75%) and the Greek Ministry of Development-GSRT (25%).

Supplementary material

HCVne particles in HepG2 cells follow an indentical progression from early to late endosomes and lysosomes. Cells were incubated with HCVne particles for 15 minutes or 4 hours and immunostained with anti-core (green) and anti-EEA1/anti-Lamp2 (red). Cells were also transfected with mRFP-Rab7 (red). 24 hours post-transfection HCVne particles were added for 1 hour, and cells were fixed and immunostained for anti-core (green). Colocalization is observed in yellow. Bars:8μm (MPG 3701 kb)

18_2010_351_MOESM2_ESM.mpg (908 kb)
HCVne particles in endosomes use actin filaments and microtubules for their traffic. A) HCVne particles were added for 15 minutes in Huh7 cells which were fixed and immunolabeled with anti-core (green) / anti-EEA1 (blue) antibodies and counterstained with Alexa 546-phalloidin. B) Huh7 cells where transfected with mRFP-Rab5. 24 hours post-transfection, cells were incubated with HCVne for 15 minutes, immunostained with anti-core (green) and anti-α tubulin (blue). Parts of cells are presented and a triple colocalization (white spot) is observed (MPG 908 kb)
18_2010_351_MOESM3_ESM.tif (460 kb)
HCVne particles colocalize with early endosomes. Dual-color live fluorescence microscopy experiment recorded in Huh7 cells transfected with mRFP-Rab5 (red) in the presence of green fluorescent GFP-HCVne particles described in (14). One picture every 10 second was recorded with a 100x objective at 37oC for 20 minutes after recombinant HCVne binding (TIFF 459 kb)
18_2010_351_MOESM4_ESM.tif (1.5 mb)
HCVne particles colocalize with late endosomes. Live Huh7 cells transfected with mRFP-Rab7 (red) and challenged with green fluorescent GFP-HCVne particles (14). Video was recorded 30 minutes after particles were added with 60x objective at 37oC for 30 minutes (one picture every 30 seconds). Time elapsed from the beginning of recording is noted in each frame of figure 2C (TIFF 1582 kb)


  1. 1.
    But DY, Lai CL, Yuen MF (2008) Natural history of hepatitis-related hepatocellular carcinoma. World J Gastroenterol 14:1652–1656CrossRefPubMedGoogle Scholar
  2. 2.
    Andre P, Perlemuter G, Budkowska A, Brechot C, Lotteau V (2005) Hepatitis C virus particles and lipoprotein metabolism. Semin Liver Dis 25:93–104CrossRefPubMedGoogle Scholar
  3. 3.
    Aoyagi K, Ohue C, Iida K, Kimura T, Tanaka E, Kiyosawa K, Yagi S (1999) Development of a simple and highly sensitive enzyme immunoassay for hepatitis C virus core antigen. J Clin Microbiol 37:1802–1808PubMedGoogle Scholar
  4. 4.
    Maillard P, Krawczynski K, Nitkiewicz J, Bronnert C, Sidorkiewicz M, Gounon P, Dubuisson J, Faure G, Crainic R, Budkowska A (2001) Nonenveloped nucleocapsids of hepatitis C virus in the serum of infected patients. J Virol 75:8240–8250CrossRefPubMedGoogle Scholar
  5. 5.
    Bouvier-Alias M, Patel K, Dahari H, Beaucourt S, Larderie P, Blatt L, Hezode C, Picchio G, Dhumeaux D, Neumann AU, McHutchison JG, Pawlotsky JM (2002) Clinical utility of total HCV core antigen quantification: a new indirect marker of HCV replication. Hepatology 36:211–218CrossRefPubMedGoogle Scholar
  6. 6.
    Sansonno D, Tucci F, Ghebrehiwet B, Lauletta G, Peerschke EIB, Condetuca V, Russi S, Gatti P, Sansonno L, Dammacco F (2009) Role of the receptor for the globular domain of C1q protein in the pathogenesis of Hepatitis C virus-related cryoglobulin vascular damage1. J Immunol 183:6013–6020CrossRefPubMedGoogle Scholar
  7. 7.
    Noppornpanth S, Smits SL, Lien TX, Poovorawan Y, Osterhaus AD, Haagmans BL (2007) Characterization of hepatitis C virus deletion mutants circulating in chronically infected patients. J Virol 81:12496–12503CrossRefPubMedGoogle Scholar
  8. 8.
    Sugiyama K, Suzuki K, Nakazawa T, Funami K, Hishiki T, Ogawa K, Saito S, Shimotohno KW, Suzuki T, Shimizu Y, Tobita R, Hijikata M, Takaku H, Shimotohno K (2009) Genetic analysis of hepatitis C virus with defective genome and its infectivity in vitro. J Virol 83:6922–6928CrossRefPubMedGoogle Scholar
  9. 9.
    Iwai A, Marusawa H, Takada Y, Egawa H, Ikeda K, Nabeshima M, Uemoto S, Chiba T (2006) Identification of novel defective HCV clones in liver transplant recipients with recurrent HCV infection. J Viral Hepat 13:523–531CrossRefPubMedGoogle Scholar
  10. 10.
    Lechmann M, Murata K, Satoi J, Vergalla J, Baumert TF, Liang TJ (2001) Hepatitis C virus-like particles induce virus-specific humoral and cellular immune responses in mice. Hepatology 34:417–423CrossRefPubMedGoogle Scholar
  11. 11.
    Acosta-Rivero N, Rodriguez A, Musacchio A, Falcon V, Suarez VM, Martinez G, Guerra I, Paz-Lago D, Morera Y, de la Rosa MC, Morales-Grillo J, Duenas-Carrera S (2004) In vitro assembly into virus-like particles is an intrinsic quality of Pichia pastoris derived HCV core protein. Biochem Biophys Res Commun 325:68–74CrossRefPubMedGoogle Scholar
  12. 12.
    Baumert TF, Vergalla J, Satoi J, Thomson M, Lechmann M, Herion D, Greenberg HB, Ito S, Liang TJ (1999) Hepatitis C virus-like particles synthesized in insect cells as a potential vaccine candidate. Gastroenterology 117:1397–1407CrossRefPubMedGoogle Scholar
  13. 13.
    Tsitoura P, Georgopoulou U, Petres S, Varaklioti A, Karafoulidou A, Vagena D, Politis C, Mavromara P (2007) Evidence for cellular uptake of recombinant hepatitis C virus non-enveloped capsid-like particles. FEBS Lett 581:4049–4057CrossRefPubMedGoogle Scholar
  14. 14.
    Katsarou K, Serti E, Tsitoura P, Lavdas AA, Varaklioti A, Pickl-Herk AM, Blaas D, Oz-Arslan D, Zhu R, Hinterdorfer P, Mavromara P, Georgopoulou U (2009) Green fluorescent protein—tagged HCV non-enveloped capsid like particles: development of a new tool for tracking HCV core uptake. Biochimie 91:903–915CrossRefPubMedGoogle Scholar
  15. 15.
    Pelkmans L, Helenius A (2003) Insider information: what viruses tell us about endocytosis. Curr Opin Cell Biol 15:414–422CrossRefPubMedGoogle Scholar
  16. 16.
    Tsai B (2007) Penetration of nonenveloped viruses into the cytoplasm. Annu Rev Cell Dev Biol 23:23–43CrossRefPubMedGoogle Scholar
  17. 17.
    Smith AE, Helenius A (2004) How viruses enter animal cells. Science 304:237–242CrossRefPubMedGoogle Scholar
  18. 18.
    von Hahn T, Rice CM (2008) Hepatitis C virus entry. J Biol Chem 283:3689–3693CrossRefGoogle Scholar
  19. 19.
    Burlone ME, Budkowska A (2009) Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J Gen Virol 90:1055–1070CrossRefPubMedGoogle Scholar
  20. 20.
    Codran A, Royer C, Jaeck D, Bastien-Valle M, Baumert TF, Kieny MP, Pereira CA, Martin JP (2006) Entry of hepatitis C virus pseudotypes into primary human hepatocytes by clathrin-dependent endocytosis. J Gen Virol 87:2583–2593CrossRefPubMedGoogle Scholar
  21. 21.
    Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouille Y (2006) Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol 80:6964–6972CrossRefPubMedGoogle Scholar
  22. 22.
    Tscherne DM, Jones CT, Evans MJ, Lindenbach BD, McKeating JA, Rice CM (2006) Time- and temperature-dependent activation of hepatitis C virus for low-pH-triggered entry. J Virol 80:1734–1741CrossRefPubMedGoogle Scholar
  23. 23.
    Meertens L, Bertaux C, Dragic T (2006) Hepatitis C virus entry requires a critical postinternalization step and delivery to early endosomes via clathrin-coated vesicles. J Virol 80:11571–11578CrossRefPubMedGoogle Scholar
  24. 24.
    Bayer N, Schober D, Huttinger M, Blaas D, Fuchs R (2001) Inhibition of clathrin-dependent endocytosis has multiple effects on human rhinovirus serotype 2 cell entry. J Biol Chem 276:3952–3962CrossRefPubMedGoogle Scholar
  25. 25.
    Chung SK, Kim JY, Kim IB, Park SI, Paek KH, Nam JH (2005) Internalization and trafficking mechanisms of coxsackievirus B3 in HeLa cells. Virology 333:31–40CrossRefPubMedGoogle Scholar
  26. 26.
    Wang K, Huang S, Kapoor-Munshi A, Nemerow G (1998) Adenovirus internalization and infection require dynamin. J Virol 72:3455–3458PubMedGoogle Scholar
  27. 27.
    Parker JS, Parrish CR (2000) Cellular uptake and infection by canine parvovirus involves rapid dynamin-regulated clathrin-mediated endocytosis, followed by slower intracellular trafficking. J Virol 74:1919–1930CrossRefPubMedGoogle Scholar
  28. 28.
    Miaczynska M, Pelkmans L, Zerial M (2004) Not just a sink: endosomes in control of signal transduction. Curr Opin Cell Biol 16:400–406CrossRefPubMedGoogle Scholar
  29. 29.
    McPherson PS, Kay BK, Hussain NK (2001) Signaling on the endocytic pathway. Traffic 2:375–384CrossRefPubMedGoogle Scholar
  30. 30.
    Greber UF (2002) Signalling in viral entry. Cell Mol Life Sci 59:608–626CrossRefPubMedGoogle Scholar
  31. 31.
    Vonderheit A, Helenius A (2005) Rab7 associates with early endosomes to mediate sorting and transport of Semliki forest virus to late endosomes. PLoS Biol 3:e233CrossRefPubMedGoogle Scholar
  32. 32.
    Cen B, Selvaraj A, Burgess RC, Hitzler JK, Ma Z, Morris SW, Prywes R (2003) Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes. Mol Cell Biol 23:6597–6608CrossRefPubMedGoogle Scholar
  33. 33.
    Mattera R, Bonifacino JS (2008) Ubiquitin binding and conjugation regulate the recruitment of Rabex-5 to early endosomes. EMBO J 27:2484–2494CrossRefPubMedGoogle Scholar
  34. 34.
    Groot M, Boxer LM, Thiel G (2000) Nerve growth factor- and epidermal growth factor-regulated gene transcription in PC12 pheochromocytoma and INS-1 insulinoma cells. Eur J Cell Biol 79:924–935CrossRefPubMedGoogle Scholar
  35. 35.
    Kockar FT, Foka P, Hughes TR, Kousteni S, Ramji DP (2001) Analysis of the Xenopus laevis CCAAT-enhancer binding protein alpha gene promoter demonstrates species-specific differences in the mechanisms for both auto-activation and regulation by Sp1. Nucleic Acids Res 29:362–372CrossRefPubMedGoogle Scholar
  36. 36.
    Li YQ, Tao KS, Ren N, Wang YH (2005) Effect of c-fos antisense probe on prostaglandin E2-induced upregulation of vascular endothelial growth factor mRNA in human liver cancer cells. World J Gastroenterol 11:4427–4430PubMedGoogle Scholar
  37. 37.
    Kim SO, Kwon JI, Jeong YK, Kim GY, Kim ND, Choi YH (2007) Induction of Egr-1 is associated with anti-metastatic and anti-invasive ability of beta-lapachone in human hepatocarcinoma cells. Biosci Biotechnol Biochem 71:2169–2176CrossRefPubMedGoogle Scholar
  38. 38.
    Kong SE, Hall JC, McCauley RD (1999) Estimation of gene expression within the intestinal mucosa using semiquantitative reverse transcriptase-polymerase chain reaction. Anal Biochem 271:111–114CrossRefPubMedGoogle Scholar
  39. 39.
    Stenmark H, Parton RG, Steele-Mortimer O, Lutcke A, Gruenberg J, Zerial M (1994) Inhibition of rab5 GTPase activity stimulates membrane fusion in endocytosis. EMBO J 13:1287–1296PubMedGoogle Scholar
  40. 40.
    Durrbach A, Louvard D, Coudrier E (1996) Actin filaments facilitate two steps of endocytosis. J Cell Sci 109:457–465PubMedGoogle Scholar
  41. 41.
    Girao H, Geli MI, Idrissi FZ (2008) Actin in the endocytic pathway: from yeast to mammals. FEBS Lett 582:2112–2119CrossRefPubMedGoogle Scholar
  42. 42.
    Matteoni R, Kreis TE (1987) Translocation and clustering of endosomes and lysosomes depends on microtubules. J Cell Biol 105:1253–1265CrossRefPubMedGoogle Scholar
  43. 43.
    Gruenberg J, van der Goot FG (2006) Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol 7:495–504CrossRefPubMedGoogle Scholar
  44. 44.
    Ohkuma S, Poole B (1978) Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA 75:3327–3331CrossRefPubMedGoogle Scholar
  45. 45.
    Perez L, Carrasco L (1994) Involvement of the vacuolar H(+)-ATPase in animal virus entry. J Gen Virol 75:2595–2606CrossRefPubMedGoogle Scholar
  46. 46.
    Qiu Z, Hingley ST, Simmons G, Yu C, Das Sarma J, Bates P, Weiss SR (2006) Endosomal proteolysis by cathepsins is necessary for murine coronavirus mouse hepatitis virus type 2 spike-mediated entry. J Virol 80:5768–5776CrossRefPubMedGoogle Scholar
  47. 47.
    Willingham MC, Hanover JA, Dickson RB, Pastan I (1984) Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells. Proc Natl Acad Sci USA 81:175–179CrossRefPubMedGoogle Scholar
  48. 48.
    Heuser JE, Anderson RG (1989) Hypertonic media inhibit receptor-mediated endocytosis by blocking clathrin-coated pit formation. J Cell Biol 108:389–400CrossRefPubMedGoogle Scholar
  49. 49.
    Teis D, Huber LA (2003) The odd couple: signal transduction and endocytosis. Cell Mol Life Sci 60:2020–2033CrossRefPubMedGoogle Scholar
  50. 50.
    English JM, Cobb MH (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23:40–45CrossRefPubMedGoogle Scholar
  51. 51.
    Birukova AA, Birukov KG, Gorshkov B, Liu F, Garcia JG, Verin AD (2005) MAP kinases in lung endothelial permeability induced by microtubule disassembly. Am J Physiol Lung Cell Mol Physiol 289:L75–L84CrossRefPubMedGoogle Scholar
  52. 52.
    Ebisuya M, Kondoh K, Nishida E (2005) The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J Cell Sci 118:2997–3002CrossRefPubMedGoogle Scholar
  53. 53.
    Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28:370–490CrossRefPubMedGoogle Scholar
  54. 54.
    Turjanski AG, Vaque JP, Gutkind JS (2007) MAP kinases and the control of nuclear events. Oncogene 26:3240–3253CrossRefPubMedGoogle Scholar
  55. 55.
    Murphy LO, MacKeigan JP, Blenis J (2004) A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol Cell Biol 24:144–153CrossRefPubMedGoogle Scholar
  56. 56.
    Chalmers CJ, Balmanno K, Hadfield K, Ley R, Cook SJ (2003) Thrombin inhibits Bim (Bcl-2-interacting mediator of cell death) expression and prevents serum-withdrawal-induced apoptosis via protease-activated receptor 1. Biochem J 375:99–109CrossRefPubMedGoogle Scholar
  57. 57.
    Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J (2002) Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol 4:556–564PubMedGoogle Scholar
  58. 58.
    Chu JJ, Ng ML (2004) Infectious entry of West Nile virus occurs through a clathrin-mediated endocytic pathway. J Virol 78:10543–10555CrossRefPubMedGoogle Scholar
  59. 59.
    van der Schaar HM, Rust MJ, Chen C, van der Ende-Metselaar H, Wilschut J, Zhuang X, Smit JM (2008) Dissecting the cell entry pathway of dengue virus by single-particle tracking in living cells. PLoS Pathog 4:e1000244CrossRefPubMedGoogle Scholar
  60. 60.
    Lecot S, Belouzard S, Dubuisson J, Rouille Y (2005) Bovine viral diarrhoea virus entry is dependent on clathrin-mediated endocytosis. J Virol 79:10826–10829CrossRefPubMedGoogle Scholar
  61. 61.
    Pho MT, Ashok A, Atwood WJ (2000) JC virus enters human glial cells by clathrin-dependent receptor-mediated endocytosis. J Virol 74:2288–2292CrossRefPubMedGoogle Scholar
  62. 62.
    Snyers L, Zwickl H, Blaas D (2003) Human rhinovirus type 2 is internalized by clathrin-mediated endocytosis. J Virol 77:5360–5369CrossRefPubMedGoogle Scholar
  63. 63.
    Cooper A, Shaul Y (2006) Clathrin-mediated endocytosis and lysosomal cleavage of hepatitis B virus capsid-like core particles. J Biol Chem 281:16563–16569CrossRefPubMedGoogle Scholar
  64. 64.
    Pelkmans L, Puntener D, Helenius A (2002) Local actin polymerization and dynamin recruitment in SV40-induced internalization of caveolae. Science 296:535–539CrossRefPubMedGoogle Scholar
  65. 65.
    O’Donnell V, LaRocco M, Duque H, Baxt B (2005) Analysis of foot-and-mouth disease virus internalization events in cultured cells. J Virol 79:8506–8518CrossRefPubMedGoogle Scholar
  66. 66.
    Bayer N, Schober D, Prchla E, Murphy RF, Blaas D, Fuchs R (1998) Effect of bafilomycin A1 and nocodazole on endocytic transport in hela cells: implications for viral uncoating and infection. J Virol 72:9645–9655PubMedGoogle Scholar
  67. 67.
    Chandran K, Nibert ML (2003) Animal cell invasion by a large nonenveloped virus: reovirus delivers the goods. Trends Microbiol 11:374–382CrossRefPubMedGoogle Scholar
  68. 68.
    Otto HH, Schirmeister T (1997) Cysteine proteases and their inhibitors. Chem Rev 97:133–172CrossRefPubMedGoogle Scholar
  69. 69.
    Xing R, Addington AK, Mason RW (1998) Quantification of cathepsins B and L in cells. Biochem J 332:499–505PubMedGoogle Scholar
  70. 70.
    Schwartz SL, Cao C, Pylypenko O, Rak A, Wandinger-Ness A (2007) Rab GTPases at a glance. J Cell Sci 120:3905–3910CrossRefPubMedGoogle Scholar
  71. 71.
    Rauma T, Tuukkanen J, Bergelson JM, Denning G, Hautala T (1999) rab5 GTPase regulates adenovirus endocytosis. J Virol 73:9664–9668PubMedGoogle Scholar
  72. 72.
    Stone M, Jia S, Heo WD, Meyer T, Konan KV (2007) Participation of rab5, an early endosome protein, in hepatitis C virus RNA replication machinery. J Virol 81:4551–4563CrossRefPubMedGoogle Scholar
  73. 73.
    Felberbaum-Corti M, Cavalli V, Gruenberg J (2005) Capture of the small GTPase Rab5 by GDI: regulation by p38 MAP kinase. Methods Enzymol 403:367–381CrossRefPubMedGoogle Scholar
  74. 74.
    Hubbard SR, Miller WT (2007) Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol 19:117–123CrossRefPubMedGoogle Scholar
  75. 75.
    Vasquez RJ, Howell B, Yvon AM, Wadsworth P, Cassimeris L (1997) Nanomolar concentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro. Mol Biol Cell 8:973–985PubMedGoogle Scholar
  76. 76.
    Sadowski L, Pilecka I, Miaczynska M (2009) Signaling from endosomes: location makes a difference. Exp Cell Res 315:1601–1609CrossRefPubMedGoogle Scholar
  77. 77.
    Sorkin A, von Zastrow M (2009) Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10:609–622CrossRefPubMedGoogle Scholar
  78. 78.
    Barbieri MA, Fernandez-Pol S, Hunker C, Horazdovsky BH, Stahl PD (2004) Role of rab5 in EGF receptor-mediated signal transduction. Eur J Cell Biol 83:305–314CrossRefPubMedGoogle Scholar
  79. 79.
    Hunker CM, Kruk I, Hall J, Giambini H, Veisaga ML, Barbieri MA (2006) Role of Rab5 in insulin receptor-mediated endocytosis and signaling. Arch Biochem Biophys 449:130–142CrossRefPubMedGoogle Scholar
  80. 80.
    Lu A, Tebar F, Alvarez-Moya B, Lopez-Alcala C, Calvo M, Enrich C, Agell N, Nakamura T, Matsuda M, Bachs O (2009) A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes. J Cell Biol 184:863–879CrossRefPubMedGoogle Scholar
  81. 81.
    Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B (2005) ERK1/2 and MEK1/2 induced by Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol 79:10308–10329CrossRefPubMedGoogle Scholar
  82. 82.
    Panteva M, Korkaya H, Jameel S (2003) Hepatitis viruses and the MAPK pathway: is this a survival strategy? Virus Res 92:131–140CrossRefPubMedGoogle Scholar
  83. 83.
    Zheng Y, Li J, Johnson DL, Ou JH (2003) Regulation of hepatitis B virus replication by the ras-mitogen-activated protein kinase signaling pathway. J Virol 77:7707–7712CrossRefPubMedGoogle Scholar
  84. 84.
    Kermorgant S, Parker PJ (2008) Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation. J Cell Biol 182:855–863CrossRefPubMedGoogle Scholar
  85. 85.
    Giambartolomei S, Covone F, Levrero M, Balsano C (2001) Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 20:2606–2610CrossRefPubMedGoogle Scholar
  86. 86.
    Voisin L, Julien C, Duhamel S, Gopalbhai K, Claveau I, Saba-El-Leil MK, Rodrigue-Gervais IG, Gaboury L, Lamarre D, Basik M, Meloche S (2008) Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC Cancer 8:337CrossRefPubMedGoogle Scholar
  87. 87.
    Sebolt-Leopold JS (2004) MEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors. Curr Pharm Des 10:1907–1914CrossRefPubMedGoogle Scholar
  88. 88.
    Karin M (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270:16483–16486PubMedGoogle Scholar
  89. 89.
    Feo F, Frau M, Tomasi ML, Brozzetti S, Pascale RM (2009) Genetic and epigenetic control of molecular alterations in hepatocellular carcinoma. Exp Biol Med (Maywood) 234:726–736CrossRefGoogle Scholar
  90. 90.
    Vaysberg M, Hatton O, Lambert SL, Snow AL, Wong B, Krams SM, Martinez OM (2008) Tumor-derived variants of Epstein-Barr virus latent membrane protein 1 induce sustained Erk activation and c-Fos. J Biol Chem 283:36573–36585CrossRefPubMedGoogle Scholar
  91. 91.
    Cai Y, Liu Y, Zhang X (2006) Induction of transcription factor Egr-1 gene expression in astrocytoma cells by Murine coronavirus infection. Virology 355:152–163CrossRefPubMedGoogle Scholar
  92. 92.
    Fu ZF, Weihe E, Zheng YM, Schafer MK, Sheng H, Corisdeo S, Rauscher FJ, Koprowski H, Dietzschold B (1993) Differential effects of rabies and borna disease viruses on immediate-early- and late-response gene expression in brain tissues. J Virol 67:6674–6681PubMedGoogle Scholar
  93. 93.
    Romagnoli L, Sariyer IK, Tung J, Feliciano M, Sawaya BE, Del Valle L, Ferrante P, Khalili K, Safak M, White MK (2008) Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter. Virology 375:331–341CrossRefPubMedGoogle Scholar
  94. 94.
    Lee S, Park U, Lee YI (2001) Hepatitis C virus core protein transactivates insulin-like growth factor II gene transcription through acting concurrently on Egr1 and Sp1 sites. Virology 283:167–177CrossRefPubMedGoogle Scholar
  95. 95.
    Eto K, Kaur V, Thomas MK (2006) Regulation of insulin gene transcription by the immediate-early growth response gene Egr-1. Endocrinology 147:2923–2935CrossRefPubMedGoogle Scholar
  96. 96.
    Adamson ED, Mercola D (2002) Egr1 transcription factor: multiple roles in prostate tumor cell growth and survival. Tumour Biol 23:93–102CrossRefPubMedGoogle Scholar
  97. 97.
    Eid MA, Kumar MV, Iczkowski KA, Bostwick DG, Tindall DJ (1998) Expression of early growth response genes in human prostate cancer. Cancer Res 58:2461–2468PubMedGoogle Scholar
  98. 98.
    Li Y, Marzolo MP, van Kerkhof P, Strous GJ, Bu G (2000) The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem 275:17187–17194CrossRefPubMedGoogle Scholar
  99. 99.
    Ruedl C, Schwarz K, Jegerlehner A, Storni T, Manolova V, Bachmann MF (2005) Virus-like particles as carriers for T-cell epitopes: limited inhibition of T-cell priming by carrier-specific antibodies. J Virol 79:717–724CrossRefPubMedGoogle Scholar
  100. 100.
    Acosta-Rivero N, Poutou J, Alvarez-Lajonchere L, Guerra I, Aguilera Y, Musacchio A, Rodriguez A, Aguilar JC, Falcon V, Alvarez-Obregon JC, Soria Y, Torres D, Linares M, Perez A, Morales-Grillo J, Duenas-Carrera S (2009) Recombinant in vitro assembled hepatitis C virus core particles induce strong specific immunity enhanced by formulation with an oil-based adjuvant. Biol Res 42:41–56CrossRefPubMedGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Konstantina Katsarou
    • 1
  • Alexandros Α. Lavdas
    • 2
  • Panagiota Tsitoura
    • 3
  • Elisavet Serti
    • 1
  • Panagiotis Markoulatos
    • 4
  • Penelope Mavromara
    • 1
  • Urania Georgopoulou
    • 1
    Email author
  1. 1.Molecular Virology LaboratoryHellenic Pasteur InstituteAthensGreece
  2. 2.Laboratory of Cellular and Molecular NeurobiologyHellenic Pasteur InstituteAthensGreece
  3. 3.Insect Molecular Genetics and Biotechnology, Institute of BiologyNCSR DemokritosAthensGreece
  4. 4.Department of Biochemistry and BiotechnologyUniversity of ThessalyThessalyGreece

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