#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection


KSHV infection of endothelial cells in vivo causes Kaposi's sarcoma and understanding the steps involved in de novo KSHV infection of these cells and the consequences is important to develop therapies to counter KSHV pathogenesis. Infection of endothelial cells in vitro is preceded by the induction of a network of host signaling agents that are necessary for virus entry, gene expression and establishment of latency. Our previous studies have implicated reactive oxygen species (ROS) as part of this network. In the current study, we show that ROS activate Nrf2, a master transcriptional regulator of genes involved in ROS homeostasis, apoptosis, glucose metabolism and angiogenesis. Besides ROS, KSHV utilizes additional aspects of host signaling to induce Nrf2 activity. We also observed that infection of endothelial cells deficient in Nrf2 resulted in downregulation of multiple genes important in KSHV pathogenesis, such as COX-2 and VEGF, and affected proper expression of two hallmark KSHV genes, lytic ORF50 and latent ORF73. Taken together, this study is the first to demonstrate the importance of Nrf2 during de novo KSHV infection of endothelial cells, and establishes Nrf2 as an attractive therapeutic target to control KSHV infection, establishment of latency and the associated cancers.


Vyšlo v časopise: Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004460
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004460

Souhrn

KSHV infection of endothelial cells in vivo causes Kaposi's sarcoma and understanding the steps involved in de novo KSHV infection of these cells and the consequences is important to develop therapies to counter KSHV pathogenesis. Infection of endothelial cells in vitro is preceded by the induction of a network of host signaling agents that are necessary for virus entry, gene expression and establishment of latency. Our previous studies have implicated reactive oxygen species (ROS) as part of this network. In the current study, we show that ROS activate Nrf2, a master transcriptional regulator of genes involved in ROS homeostasis, apoptosis, glucose metabolism and angiogenesis. Besides ROS, KSHV utilizes additional aspects of host signaling to induce Nrf2 activity. We also observed that infection of endothelial cells deficient in Nrf2 resulted in downregulation of multiple genes important in KSHV pathogenesis, such as COX-2 and VEGF, and affected proper expression of two hallmark KSHV genes, lytic ORF50 and latent ORF73. Taken together, this study is the first to demonstrate the importance of Nrf2 during de novo KSHV infection of endothelial cells, and establishes Nrf2 as an attractive therapeutic target to control KSHV infection, establishment of latency and the associated cancers.


Zdroje

1. CesarmanE, ChangY, MoorePS, SaidJW, KnowlesDM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191.

2. ChangY, CesarmanE, PessinMS, LeeF, CulpepperJ, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869.

3. SoulierJ, GrolletL, OksenhendlerE, CacoubP, Cazals-HatemD, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280.

4. CostaJ, RabsonAS (1983) Generalised Kaposi's sarcoma is not a neoplasm. Lancet 1: 58.

5. Ganem D (2007) Ksarcoma-associated herpesvirus. In: D. M. Knipe PMH, D. R. Griffin, R. A. Lamb, M. A. Marin, B. Roizman, and S. E. Straus, editor. Fields Virology 5th ed. Philadelphia: Lippincott Williams & Wilkins.

6. ChandranB (2010) Early events in Kaposi's sarcoma-associated herpesvirus infection of target cells. J Virol 84: 2188–2199.

7. AkulaSM, WangFZ, VieiraJ, ChandranB (2001) Human herpesvirus 8 interaction with target cells involves heparan sulfate. Virology 282: 245–255.

8. WangFZ, AkulaSM, PramodNP, ZengL, ChandranB (2001) Human herpesvirus 8 envelope glycoprotein K8.1A interaction with the target cells involves heparan sulfate. J Virol 75: 7517–7527.

9. HahnA, BirkmannA, WiesE, DorerD, MahrK, et al. (2009) Kaposi's sarcoma-associated herpesvirus gH/gL: glycoprotein export and interaction with cellular receptors. J Virol 83: 396–407.

10. NaranattPP, AkulaSM, ZienCA, KrishnanHH, ChandranB (2003) Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol 77: 1524–1539.

11. WangFZ, AkulaSM, Sharma-WaliaN, ZengL, ChandranB (2003) Human herpesvirus 8 envelope glycoprotein B mediates cell adhesion via its RGD sequence. J Virol 77: 3131–3147.

12. VeettilMV, SadagopanS, Sharma-WaliaN, WangFZ, RaghuH, et al. (2008) Kaposi's sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection. J Virol 82: 12126–12144.

13. KoyanoS, MarEC, StameyFR, InoueN (2003) Glycoproteins M and N of human herpesvirus 8 form a complex and inhibit cell fusion. J Gen Virol 84: 1485–1491.

14. ChakrabortyS, VeettilMV, BotteroV, ChandranB (2012) Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc Natl Acad Sci U S A 109: E1163–1172.

15. BandyopadhyayC, Valiya-VeettilM, DuttaD, ChakrabortyS, ChandranB (2014) CIB1 synergizes with EphrinA2 to regulate Kaposi's sarcoma-associated herpesvirus macropinocytic entry in human microvascular dermal endothelial cells. PLoS Pathog 10: e1003941.

16. BotteroV, ChakrabortyS, ChandranB (2013) Reactive oxygen species are induced by Kaposi's sarcoma-associated herpesvirus early during primary infection of endothelial cells to promote virus entry. J Virol 87: 1733–1749.

17. DuttaD, ChakrabortyS, BandyopadhyayC, Valiya VeettilM, AnsariMA, et al. (2013) EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog 9: e1003510.

18. KrishnanHH, Sharma-WaliaN, StreblowDN, NaranattPP, ChandranB (2006) Focal adhesion kinase is critical for entry of Kaposi's sarcoma-associated herpesvirus into target cells. J Virol 80: 1167–1180.

19. Sharma-WaliaN, NaranattPP, KrishnanHH, ZengL, ChandranB (2004) Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein gB induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements. J Virol 78: 4207–4223.

20. Valiya VeettilM, SadagopanS, KerurN, ChakrabortyS, ChandranB (2010) Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus. PLoS Pathog 6: e1001238.

21. VeettilMV, Sharma-WaliaN, SadagopanS, RaghuH, SivakumarR, et al. (2006) RhoA-GTPase facilitates entry of Kaposi's sarcoma-associated herpesvirus into adherent target cells in a Src-dependent manner. J Virol 80: 11432–11446.

22. BotteroV, KerurN, SadagopanS, PatelK, Sharma-WaliaN, et al. (2011) Phosphorylation and polyubiquitination of transforming growth factor beta-activated kinase 1 are necessary for activation of NF-kappaB by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. J Virol 85: 1980–1993.

23. SadagopanS, Sharma-WaliaN, VeettilMV, RaghuH, SivakumarR, et al. (2007) Kaposi's sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression. J Virol 81: 3949–3968.

24. Sharma-WaliaN, KrishnanHH, NaranattPP, ZengL, SmithMS, et al. (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: 10308–10329.

25. Sharma-WaliaN, RaghuH, SadagopanS, SivakumarR, VeettilMV, et al. (2006) Cyclooxygenase 2 induced by Kaposi's sarcoma-associated herpesvirus early during in vitro infection of target cells plays a role in the maintenance of latent viral gene expression. J Virol 80: 6534–6552.

26. KrishnanHH, NaranattPP, SmithMS, ZengL, BloomerC, et al. (2004) Concurrent expression of latent and a limited number of lytic genes with immune modulation and antiapoptotic function by Kaposi's sarcoma-associated herpesvirus early during infection of primary endothelial and fibroblast cells and subsequent decline of lytic gene expression. J Virol 78: 3601–3620.

27. LiX, FengJ, SunR (2011) Oxidative stress induces reactivation of Kaposi's sarcoma-associated herpesvirus and death of primary effusion lymphoma cells. J Virol 85: 715–724.

28. YeF, GaoSJ (2011) A novel role of hydrogen peroxide in Kaposi sarcoma-associated herpesvirus reactivation. Cell Cycle 10: 3237–3238.

29. YeF, ZhouF, BedollaRG, JonesT, LeiX, et al. (2011) Reactive oxygen species hydrogen peroxide mediates Kaposi's sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog 7: e1002054.

30. MoiP, ChanK, AsunisI, CaoA, KanYW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91: 9926–9930.

31. KansanenE, KuosmanenSM, LeinonenH, LevonenAL (2013) The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biol 1: 45–49.

32. MitsuishiY, MotohashiH, YamamotoM (2012) The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol 2: 200.

33. TaguchiK, MotohashiH, YamamotoM (2011) Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16: 123–140.

34. KenslerTW, WakabayashiN, BiswalS (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47: 89–116.

35. ZhangDD, LoSC, CrossJV, TempletonDJ, HanninkM (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24: 10941–10953.

36. ItohK, WakabayashiN, KatohY, IshiiT, IgarashiK, et al. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13: 76–86.

37. KatohY, ItohK, YoshidaE, MiyagishiM, FukamizuA, et al. (2001) Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6: 857–868.

38. NioiP, NguyenT, SherrattPJ, PickettCB (2005) The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol 25: 10895–10906.

39. JainAK, BloomDA, JaiswalAK (2005) Nuclear import and export signals in control of Nrf2. J Biol Chem 280: 29158–29168.

40. ChowdhryS, ZhangY, McMahonM, SutherlandC, CuadradoA, et al. (2013) Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32: 3765–3781.

41. HayesJD, FlanaganJU, JowseyIR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45: 51–88.

42. MoinovaHR, MulcahyRT (1999) Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element. Biochem Biophys Res Commun 261: 661–668.

43. PresteraT, TalalayP, AlamJ, AhnYI, LeePJ, et al. (1995) Parallel induction of heme oxygenase-1 and chemoprotective phase 2 enzymes by electrophiles and antioxidants: regulation by upstream antioxidant-responsive elements (ARE). Mol Med 1: 827–837.

44. PrimianoT, KenslerTW, KuppusamyP, ZweierJL, SutterTR (1996) Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemopreventive dithiolethiones. Carcinogenesis 17: 2291–2296.

45. ThimmulappaRK, MaiKH, SrisumaS, KenslerTW, YamamotoM, et al. (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62: 5196–5203.

46. HayashiA, SuzukiH, ItohK, YamamotoM, SugiyamaY (2003) Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun 310: 824–829.

47. MaherJM, DieterMZ, AleksunesLM, SlittAL, GuoG, et al. (2007) Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46: 1597–1610.

48. HirotsuY, KatsuokaF, FunayamaR, NagashimaT, NishidaY, et al. (2012) Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 40: 10228–10239.

49. MitsuishiY, TaguchiK, KawataniY, ShibataT, NukiwaT, et al. (2012) Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22: 66–79.

50. NitureSK, JaiswalAK (2012) Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem 287: 9873–9886.

51. NitureSK, JaiswalAK (2013) Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med 57: 119–131.

52. KimTH, HurEG, KangSJ, KimJA, ThapaD, et al. (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res 71: 2260–2275.

53. ZhangZ, WangQ, MaJ, YiX, ZhuY, et al. (2013) Reactive oxygen species regulate FSH-induced expression of vascular endothelial growth factor via Nrf2 and HIF1alpha signaling in human epithelial ovarian cancer. Oncol Rep 29: 1429–1434.

54. ZhouS, YeW, ZhangM, LiangJ (2012) The effects of nrf2 on tumor angiogenesis: a review of the possible mechanisms of action. Crit Rev Eukaryot Gene Expr 22: 149–160.

55. PanH, WangH, ZhuL, MaoL, QiaoL, et al. (2013) The role of Nrf2 in migration and invasion of human glioma cell U251. World Neurosurg 80: 363–370.

56. NguyenT, NioiP, PickettCB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284: 13291–13295.

57. CullinanSB, GordanJD, JinJ, HarperJW, DiehlJA (2004) The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol 24: 8477–8486.

58. KobayashiA, KangMI, OkawaH, OhtsujiM, ZenkeY, et al. (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24: 7130–7139.

59. ZhangDD (2006) Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38: 769–789.

60. ZhangDD, HanninkM (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23: 8137–8151.

61. BairdL, LleresD, SwiftS, Dinkova-KostovaAT (2013) Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci U S A 110: 15259–15264.

62. BairdL, SwiftS, LleresD, Dinkova-KostovaAT (2014) Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol Adv

63. FurukawaM, XiongY (2005) BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 25: 162–171.

64. McMahonM, ItohK, YamamotoM, HayesJD (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 278: 21592–21600.

65. Dinkova-KostovaAT, HoltzclawWD, ColeRN, ItohK, WakabayashiN, et al. (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 99: 11908–11913.

66. NitureSK, KhatriR, JaiswalAK (2014) Regulation of Nrf2-an update. Free Radic Biol Med 66: 36–44.

67. HuangHC, NguyenT, PickettCB (2002) Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem 277: 42769–42774.

68. LeeJM, HansonJM, ChuWA, JohnsonJA (2001) Phosphatidylinositol 3-kinase, not extracellular signal-regulated kinase, regulates activation of the antioxidant-responsive element in IMR-32 human neuroblastoma cells. J Biol Chem 276: 20011–20016.

69. MengX, SunG, YeJ, XuH, WangH, et al. (2014) Notoginsenoside R1-mediated neuroprotection involves estrogen receptor-dependent crosstalk between Akt and ERK1/2 pathways: a novel mechanism of Nrf2/ARE signaling activation. Free Radic Res 48: 445–460.

70. MengXB, SunGB, WangM, SunJ, QinM, et al. (2013) P90RSK and Nrf2 Activation via MEK1/2-ERK1/2 Pathways Mediated by Notoginsenoside R2 to Prevent 6-Hydroxydopamine-Induced Apoptotic Death in SH-SY5Y Cells. Evid Based Complement Alternat Med 2013: 971712.

71. NakasoK, YanoH, FukuharaY, TakeshimaT, Wada-IsoeK, et al. (2003) PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett 546: 181–184.

72. NumazawaS, IshikawaM, YoshidaA, TanakaS, YoshidaT (2003) Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress. Am J Physiol Cell Physiol 285: C334–342.

73. KesicMJ, SimmonsSO, BauerR, JaspersI (2011) Nrf2 expression modifies influenza A entry and replication in nasal epithelial cells. Free Radic Biol Med 51: 444–453.

74. KosmiderB, MessierEM, JanssenWJ, NahreiniP, WangJ, et al. (2012) Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus. Respir Res 13: 43.

75. YagetaY, IshiiY, MorishimaY, MasukoH, AnoS, et al. (2011) Role of Nrf2 in host defense against influenza virus in cigarette smoke-exposed mice. J Virol 85: 4679–4690.

76. LeeJ, KohK, KimYE, AhnJH, KimS (2013) Upregulation of Nrf2 expression by human cytomegalovirus infection protects host cells from oxidative stress. J Gen Virol 94: 1658–1668.

77. BurdetteD, OlivarezM, WarisG (2010) Activation of transcription factor Nrf2 by hepatitis C virus induces the cell-survival pathway. J Gen Virol 91: 681–690.

78. DayoubR, VogelA, SchuettJ, LupkeM, SpiekerSM, et al. (2013) Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration. Mol Med 19: 237–244.

79. IvanovAV, SmirnovaOA, IvanovaON, MasalovaOV, KochetkovSN, et al. (2011) Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS One 6: e24957.

80. LeeJC, TsengCK, YoungKC, SunHY, WangSW, et al. (2014) Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells. Br J Pharmacol 171: 237–252.

81. EdwardsMR, JohnsonB, MireCE, XuW, ShabmanRS, et al. (2014) The Marburg Virus VP24 Protein Interacts with Keap1 to Activate the Cytoprotective Antioxidant Response Pathway. Cell Rep 6: 1017–1025.

82. PageA, VolchkovaVA, ReidSP, MateoM, Bagnaud-BauleA, et al. (2014) Marburgvirus hijacks nrf2-dependent pathway by targeting nrf2-negative regulator keap1. Cell Rep 6: 1026–1036.

83. MallerySR, PeiP, LandwehrDJ, ClarkCM, BradburnJE, et al. (2004) Implications for oxidative and nitrative stress in the pathogenesis of AIDS-related Kaposi's sarcoma. Carcinogenesis 25: 597–603.

84. PaulAG, ChandranB, Sharma-WaliaN (2013) Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies. Transl Res 162: 77–92.

85. PaulAG, ChandranB, Sharma-WaliaN (2013) Concurrent targeting of eicosanoid receptor 1/eicosanoid receptor 4 receptors and COX-2 induces synergistic apoptosis in Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus associated non-Hodgkin lymphoma cell lines. Transl Res 161: 447–468.

86. KwakMK, ItohK, YamamotoM, KenslerTW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22: 2883–2892.

87. MaQ, HeX (2012) Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol Rev 64: 1055–1081.

88. HayakawaM, MiyashitaH, SakamotoI, KitagawaM, TanakaH, et al. (2003) Evidence that reactive oxygen species do not mediate NF-kappaB activation. EMBO J 22: 3356–3366.

89. StuehrDJ, FasehunOA, KwonNS, GrossSS, GonzalezJA, et al. (1991) Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs. FASEB J 5: 98–103.

90. LeeOH, JainAK, PapushaV, JaiswalAK (2007) An auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance. J Biol Chem 282: 36412–36420.

91. FarahCA, SossinWS (2012) The role of C2 domains in PKC signaling. Adv Exp Med Biol 740: 663–683.

92. NewtonAC (1995) Protein kinase C: structure, function, and regulation. J Biol Chem 270: 28495–28498.

93. WebbBL, HirstSJ, GiembyczMA (2000) Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis. Br J Pharmacol 130: 1433–1452.

94. BalaK, BoscoR, GramolelliS, HaasDA, KatiS, et al. (2012) Kaposi's sarcoma herpesvirus K15 protein contributes to virus-induced angiogenesis by recruiting PLCgamma1 and activating NFAT1-dependent RCAN1 expression. PLoS Pathog 8: e1002927.

95. SadagopanS, Valiya VeettilM, PaudelN, BotteroV, ChandranB (2011) Kaposi's sarcoma-associated herpesvirus-induced angiogenin plays roles in latency via the phospholipase C gamma pathway: blocking angiogenin inhibits latent gene expression and induces the lytic cycle. J Virol 85: 2666–2685.

96. SmitMJ, VerzijlD, CasarosaP, NavisM, TimmermanH, et al. (2002) Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via G(i) and phospholipase C-dependent signaling pathways. J Virol 76: 1744–1752.

97. PaulAG, Sharma-WaliaN, ChandranB (2011) Targeting KSHV/HHV-8 latency with COX-2 selective inhibitor nimesulide: a potential chemotherapeutic modality for primary effusion lymphoma. PLoS One 6: e24379.

98. AokiY, TosatoG (2001) Vascular endothelial growth factor/vascular permeability factor in the pathogenesis of primary effusion lymphomas. Leuk Lymphoma 41: 229–237.

99. DaiL, BratoevaM, TooleBP, QinZ, ParsonsC (2012) KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction. Int J Cancer 131: 834–843.

100. GasperiniP, SakakibaraS, TosatoG (2008) Contribution of viral and cellular cytokines to Kaposi's sarcoma-associated herpesvirus pathogenesis. J Leukoc Biol 84: 994–1000.

101. HamdenKE, WhitmanAG, FordPW, SheltonJG, McCubreyJA, et al. (2005) Raf and VEGF: emerging therapeutic targets in Kaposi's sarcoma-associated herpesvirus infection and angiogenesis in hematopoietic and nonhematopoietic tumors. Leukemia 19: 18–26.

102. HaywardGS (2003) Initiation of angiogenic Kaposi's sarcoma lesions. Cancer Cell 3: 1–3.

103. NishiJ, MaruyamaI (2000) Increased expression of vascular endothelial growth factor (VEGF) in Castleman's disease: proposed pathomechanism of vascular proliferation in the affected lymph node. Leuk Lymphoma 38: 387–394.

104. SivakumarR, Sharma-WaliaN, RaghuH, VeettilMV, SadagopanS, et al. (2008) Kaposi's sarcoma-associated herpesvirus induces sustained levels of vascular endothelial growth factors A and C early during in vitro infection of human microvascular dermal endothelial cells: biological implications. J Virol 82: 1759–1776.

105. LiuD, JiL, WangY, ZhengL (2012) Cyclooxygenase-2 expression, prostacyclin production and endothelial protection of high-density lipoprotein. Cardiovasc Hematol Disord Drug Targets 12: 98–105.

106. George PaulA, Sharma-WaliaN, KerurN, WhiteC, ChandranB (2010) Piracy of prostaglandin E2/EP receptor-mediated signaling by Kaposi's sarcoma-associated herpes virus (HHV-8) for latency gene expression: strategy of a successful pathogen. Cancer Res 70: 3697–3708.

107. ShelbyBD, LaMarcaHL, McFerrinHE, NelsonAB, LaskyJA, et al. (2007) Kaposi's sarcoma associated herpesvirus G-protein coupled receptor activation of cyclooxygenase-2 in vascular endothelial cells. Virol J 4: 87.

108. Sharma-WaliaN, George PaulA, PatelK, ChandranK, AhmadW, et al. (2010) NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2). J Virol 84: 12733–12753.

109. Sharma-WaliaN, PatelK, ChandranK, MargineanA, BotteroV, et al. (2012) COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP. Oncogenesis 1: e5.

110. ArltA, SebensS, KrebsS, GeismannC, GrossmannM, et al. (2013) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32: 4825–4835.

111. KobayashiA, KangMI, WataiY, TongKI, ShibataT, et al. (2006) Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26: 221–229.

112. FujimuroM, LiuJ, ZhuJ, YokosawaH, HaywardSD (2005) Regulation of the interaction between glycogen synthase kinase 3 and the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen. J Virol 79: 10429–10441.

113. NaranattPP, KrishnanHH, SvojanovskySR, BloomerC, MathurS, et al. (2004) Host gene induction and transcriptional reprogramming in Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)-infected endothelial, fibroblast, and B cells: insights into modulation events early during infection. Cancer Res 64: 72–84.

114. MarquezRT, XuL (2012) Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2: 214–221.

115. Sharma-WaliaN, PaulAG, BotteroV, SadagopanS, VeettilMV, et al. (2010) Kaposi's sarcoma associated herpes virus (KSHV) induced COX-2: a key factor in latency, inflammation, angiogenesis, cell survival and invasion. PLoS Pathog 6: e1000777.

116. AkulaSM, PramodNP, WangFZ, ChandranB (2002) Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108: 407–419.

117. VartRJ, NikitenkoLL, LagosD, TrotterMW, CannonM, et al. (2007) Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res 67: 4042–4051.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2014 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#