Skip to main content
SpringerLink
Log in

Modulation of cell signaling pathways by kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)

  • Review Article
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, has been associated with the development of Kaposi's sarcoma, pleural effusion lymphoma, and multicentric Castleman's disease. KSHV is a double-stranded DNA virus that has been classified as a gammaherpesvirus. The viral genome is approx, 160 kb long and encodes for several genes that are involved in cell signaling pathways. These include genes that are unique to the virus as well as viral homologues of cellular genes. The latter are likely to have been usurped from the host genome and include both virokines and viral receptor proteins. This article reviews how these KSHV proteins modulate cellular signal transduction pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M., et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869.

    PubMed  CAS  Google Scholar 

  2. Ganem, D. (1998) Human herpesvirus 8 and its role in the genesis of Kaposi's sarcoma. Curr. Clin. Top. Infect. Dis. 18, 237–251.

    PubMed  CAS  Google Scholar 

  3. Kedes, D. H., Operskalski, E., Busch, M., Kohn, R., Flood, J., and Ganem, D. (1996) The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma- associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nat. Med. 2, 918–924.

    PubMed  CAS  Google Scholar 

  4. Moore, P. S., and Chang, Y. (1995) Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. New Engl. J. Med. 332, 1181–1185.

    PubMed  CAS  Google Scholar 

  5. Cesarman, E., Chang, Y., Moore, P. S., Said, J. W., and Knowles, D. M. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. New Engl. J. Med. 332, 1186–1191.

    PubMed  CAS  Google Scholar 

  6. Cesarman, E., and Knowles, D. M. (1997) Kaposi's sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Semin. Diagn. Pathol. 14, 54–66.

    PubMed  CAS  Google Scholar 

  7. Albrecht, J. C., Nicholas, J., Biller, D., Cameron, K. R., Biesinger, B., Newman, C., et al. (1992) Primary structure of the herpesvirus saimiri genome. J. Virol. 66, 5047–5058.

    PubMed  CAS  Google Scholar 

  8. Alexander, L., Denenkamp, L., Knapp, A., Auerbach, M., Czajak, S., Damania, B., et al. (2000) The primary sequence of rhesus rhadinovirus isolate 26–95: sequence similarities to Kaposi's sarcoma herpesvirus and rhesus rhadinovirus isolate 17577. J. Virol. 74, 3388–3398.

    PubMed  CAS  Google Scholar 

  9. Searles, R. P., Bergquam, E. P., Axthelm, M. K., and Wong, S. W. (1999) Sequence and genomic analysis of a rhesus macaque rhadinovirus with similarity to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. J. Virol. 73, 3040–3053.

    PubMed  CAS  Google Scholar 

  10. Virgin, H. W. T., Latreille, P., Wamsley, P., Hallsworth, K., Weck, K. E., Dal Canto, A. J., et al. (1997) Complete sequence and genomic analysis of murine gamma herpesvirus 68. J. Virol. 71, 5894–5904.

    PubMed  CAS  Google Scholar 

  11. Moore, P. S., and Chang, Y. (1995) Kaposi's sarcoma findings. Science 270, 5233, 15–16.

    Google Scholar 

  12. Staskus, K. A., Zhong, W., Gebhard, K., Herndier, B., Wang, H., Renne, R., et al. (1997) Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J. Virol. 71, 715–719.

    PubMed  CAS  Google Scholar 

  13. Gessain, A., Sudaka, A., Briere, J., Fouchard, N., Nicola, M. A., Rio, B., et al. (1996) Kaposi sarcoma-associated herpes-like virus (human herpesvirus type 8) DNA sequences in multicentric Castleman's disease: is there any relevant association in non-human immunodeficiency virus-infected patients? Blood 87, 414–416.

    PubMed  CAS  Google Scholar 

  14. Neipel, F., Albrecht, J. C., and Fleckenstein, B. (1998) Human herpesvirus 8—the first human rhadinovirus. J. Natl. Cancer Inst. Monogr. 23, 73–77.

    PubMed  Google Scholar 

  15. Pastore, C., Gloghini, A., Volpe, G., Nomdedeu, J., Leonardo, E., Mazza, U., et al. (1995) Distribution of Kaposi's sarcoma herpesvirus sequences among lymphoid malignancies in Italy and Spain. Br. J. Haematol. 91, 918–920.

    PubMed  CAS  Google Scholar 

  16. Soulier, J., Grollet, L., Oksenhendler, E., Cacoub, P., Cazals-Hatem, D., Babinet, P., et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86, 1276–1280.

    PubMed  CAS  Google Scholar 

  17. Dupin, N., Fisher, C., Kellam, P., Ariad, S., Tulliez, M., Franck, N., et al. (1999) Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc. Natl. Acad. Sci. USA 96, 4546–4551.

    PubMed  CAS  Google Scholar 

  18. Mitterer, M., Mair, W., Gatti, D., Sheldon, J., Vachula, M., Coser, P., et al. (1998) Dendritic cells derived from bone marrow and CD34+ selected blood progenitor cells of myeloma patients, cultured in serum-free media, do not contain the Kaposi sarcoma herpesvirus genome. Br J Haematol 102, 1338–1340.

    PubMed  CAS  Google Scholar 

  19. Whitby, D., Boshoff, C., Luppi, M., and Torelli G. (1997) Kaposi's sarcoma-associated herpesvirus infection and multiple myeloma. Science 278, 1971–1972; discussion 1972–1973.

    PubMed  CAS  Google Scholar 

  20. Knowles, D. M., Inghirami, G., Ubriaco, A., and Dalla-Favera, R. (1989) Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood 73, 792–799.

    PubMed  CAS  Google Scholar 

  21. Boshoff, C., and Weiss, R. A. (1998) Kaposi's sarcoma-associated herpesvirus. Adv Cancer Res 75, 57–86.

    PubMed  CAS  Google Scholar 

  22. Drexler, H. G., Uphoff, C. C., Gaidano, G., and Carbone, A. (1998) Lymphoma cell lines: in vitro models for the study of HHV-8+ primary effusion lymphomas (body cavity-based lymphomas). Leukemia 12, 1507–1517.

    PubMed  CAS  Google Scholar 

  23. Kikuta, H., Itakura, O., Taneichi, K., and Kohno, M. (1997) Tropism of human herpesvirus 8 for peripheral blood lymphocytes in patients with Castleman's disease. Br. J. Haematol. 99, 790–793.

    PubMed  CAS  Google Scholar 

  24. Noel, J. C., Hermans, P., Andre, J., Fayt, I., Simonart, T., Verhest, A., et al. (1996) Herpesvirus-like DNA sequences and Kaposi's sarcoma: relationship with epidemiology, clinical spectrum, and histologic features. Cancer 77, 2132–2136.

    PubMed  CAS  Google Scholar 

  25. Flore, O., Rafii, S., Ely, S., O'Leary, J. J., Hyjek, E. M., and Cesarman, E. (1998) Transformation of primary human endothelial cells by Kaposi's sarcoma- associated herpesvirus. Nature 394, 588–592.

    PubMed  CAS  Google Scholar 

  26. Desrosiers, R. C., Sasseville, V. G., Czajak, S. C., Zhang, X., Mansfield, K. G., Kaur, A., et al. (1997) A herpesvirus of rhesus monkeys related to the human Kaposi's sarcoma-associated herpesvirus. J. Virol. 71, 9764–9769.

    PubMed  CAS  Google Scholar 

  27. Greensill, J., Sheldon, J. A., Renwick, N. M., Beer, B. E., Norley, S., Goudsmit, J. et al. (2000) Two distinct gamma-2 herpesviruses in African green monkeys: a second gamma-2 herpesvirus lineage among old world primates? J. Virol. 74, 1572–1577.

    PubMed  CAS  Google Scholar 

  28. Rose, T. M., Strand, K. B., Schultz, E. R., Schaefer, G., Rankin, Jr., G. W., Thouless, M. E., et al. (1997) Identification of two homologs of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in retroperitoneal fibromatosis of different macaque species. J. Virol. 71, 4138–4144.

    PubMed  CAS  Google Scholar 

  29. Strand, K., Harper, E., Thormahlen, S., Thouless, M. E., Tsai, C., Rose, T., et al. (2000) Two distinct lineages of macaque gamma herpesviruses related to the Kaposi's sarcoma associated herpesvirus. J. Clin. Virol. 16, 253–269.

    PubMed  CAS  Google Scholar 

  30. DeWire, S. M., McVoy, M. A., and Damania, B. (2002) Kinetics of expression of rhesus monkey rhadinovirus (RRV) and identification and characterization of a polycistronic transcript encoding the RRV Orf50/Rta, RRV R8, and R8.1 genes. J. Virol. 76, 9819–9831.

    PubMed  CAS  Google Scholar 

  31. Russo, J. J., Bohenzky, R. A., Chien, M. C., Chen, J., Yan, M., Maddalena, D., et al. (1996) Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc. Natl. Acad. Sci. USA 93, 14862–14867.

    PubMed  CAS  Google Scholar 

  32. Nicholas, J., Zong, J. C., Alcendor, D. J., Ciufo, D. M., Poole, L. J., Sarisky, R. T., et al. (1998) Novel organizational features, captured cellular genes, and strain variability within the genome of KSHV/HHV8. J. Natl. Cancer Inst. Monogr. 23, 79–88.

    PubMed  CAS  Google Scholar 

  33. Damania, B., Choi, J. K., and Jung, J. U. (2000) Signaling activities of gamma herpesvirus membrane proteins. J. Virol. 74, 1593–1601.

    PubMed  CAS  Google Scholar 

  34. Damania, B., and Jung, J. U. (2001) Comparative analysis of the transforming mechanisms of Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and Herpesvirus saimiri. Adv. Cancer Res. 80, 51–82.

    PubMed  CAS  Google Scholar 

  35. Damania, B., H. Lee, and J. U. Jung. (1999) Primate herpesviral oncogenes. Mol. Cells 9, 345–349.

    PubMed  CAS  Google Scholar 

  36. Damania, B., Li, M., Choi, J. K., Alexander, L., Jung, J. U., and Desrosiers, R. C. (1999) Identification of the R1 oncogene and its protein product from the rhadinovirus of Rhesus monkeys. J. Virol. 73, 5123–5131.

    PubMed  CAS  Google Scholar 

  37. Lee, H., Veazey, R., Williams, K., Li, M., Guo, J., Neipel, F., et al. (1998) Deregulation of cell growth by the K1 gene of Kaposi's sarcoma-associated herpesvirus. Nat. Med. 4, 435–440.

    PubMed  CAS  Google Scholar 

  38. Lagunoff, M., and Ganem, D. (1997) The structure and coding organization of the genomic termini of Kaposi's sarcoma-associated herpesvirus. Virology 236, 147–154.

    PubMed  CAS  Google Scholar 

  39. Poole, L. J., Zong, J. C., Ciufo, D. M., Alcendor, D. J., Cannon, J. S., et al. (1999) Comparison of genetic variability at multiple loci across the genomes of the major subtypes of Kaposi's sarcoma-associated herpesvirus reveals evidence for recombination and for two distinct types of open reading frame K15 alleles at the righthand end. J. Virol. 73, 6646–6660.

    PubMed  CAS  Google Scholar 

  40. Zong, J. C., Ciufo, D. M., Alcendor, D. J., Wan, X., Nicholas, J., Browning, P. J., et al. (1999) High-level variability in the ORF-K1 membrane protein gene at the left end of the Kaposi's sarcoma-associated herpesvirus genome defines four major virus subtypes and multiple variants or clades in different human populations. J. Virol. 73, 4156–4170.

    PubMed  CAS  Google Scholar 

  41. Kasolo, F. C., Monze, M., Obel, N., Anderson, R. A., French, C., and Gompels, U. A. (1998) Sequence analyses of human herpesvirus-8 strains from both African human immunodeficiency virus-negative and-positive childhood endemic Kaposi's sarcoma show a close relationship with strains identified in febrile children and high variation in the K1 glycoprotein. J. Gen. Virol. 79, 3055–3065.

    PubMed  CAS  Google Scholar 

  42. Nicholas, J., Ruvolo, V., Zong, J., Ciufo, D., Guo, H. G., Reitz, M. S., et al. (1997) A single 13-kilobase divergent locus in the Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genome contains nine open reading frames that are homologous to or related to cellular proteins. J. Virol. 71, 1963–1974.

    PubMed  CAS  Google Scholar 

  43. Lagunoff, M., Majeti, R., Weiss, A., and Ganem, D. (1999) Deregulated signal transduction by the K1 gene product of Kaposi's sarcoma-associated herpesvirus. Proc. Natl. Acad. Sci. USA 96, 5704–5709.

    PubMed  CAS  Google Scholar 

  44. Lee, H., Guo, J., Li, M., Choi, J. K., DeMaria, M., Rosenzweig, M., et al. (1998) Identification of an immunoreceptor tyrosine-based activation motif of K1 transforming protein of Kaposi's sarcoma-associated herpesvirus. Mol. Cell Biol. 18, 5219–5228.

    PubMed  CAS  Google Scholar 

  45. Samaniego, F., Pati, S., Karp, J., Prakash, O., and Bose, D. (2001) Human herpesvirus 8 k1-associated nuclear factor-kappa b-dependent promoter activity: role in kaposi's sarcoma inflammation? J. Natl. Cancer Inst. Monogr. 28, 15–23.

    PubMed  Google Scholar 

  46. Lagunoff, M., Lukac, D. M., and Ganem, D. (2001) Immunoreceptor tyrosine-based activation motif-dependent signaling by Kaposi's sarcoma-associated herpesvirus K1 protein: effects on lytic viral replication. J. Virol. 75, 5891–5898.

    PubMed  CAS  Google Scholar 

  47. Lee, B. S., Paulose-Murphy, M., Chung, Y. H., Connlole, M., Zeichner, S., and Jung, J. U. (2002) Suppression of tetradecanoyl phorbol acetate-induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus by K1 signal transduction. J. Virol. 76, 12185–12199.

    PubMed  CAS  Google Scholar 

  48. Bowser, B. S., DeWire, S. M., and Damania, B. (2002) Transcriptional regulation of the K1 gene product of Kaposi's sarcoma-associated herpesvirus. J. Virol. 76, 12574–12583.

    PubMed  CAS  Google Scholar 

  49. Tomlinson, C. C. and Damania, B. (2003) The K1 protein of Kaposi's sarcoma-associated herpesvirus activates the Akt signaling pathway and targets the forkhead family of transcription factors. J. Virol. 78, 1918–1927.

    Google Scholar 

  50. Damania, B., DeMaria, M., Jung, J. U., and Desrosiers, R. C. (2000) Activation of lymphocyte signaling by the R1 protein of rhesus monkey rhadinovirus. J. Virol. 74, 2721–2730.

    PubMed  CAS  Google Scholar 

  51. Prakash, O., Tang, Z. Y., Peng, X., Coleman, R., Gill, J., Farr, G., et al. (2002) Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8 k1 gene. J. Natl. Cancer Inst. 94, 926–935.

    PubMed  CAS  Google Scholar 

  52. Choi, J. K., Lee, B. S., Shim, S. N., Li, M., and Jung, J. U. (2000) Identification of the novel K15 gene at the rightmost end of the Kaposi's sarcoma-associated herpesvirus genome. J. Virol. 74, 436–446.

    Article  PubMed  CAS  Google Scholar 

  53. Glenn, M., Rainbow, L., Aurad, F., Davison, A., and Schulz, T. F. (1999) Identification of a spliced gene from Kaposi's sarcoma-associated herpesvirus encoding a protein with similarities to latent membrane proteins 1 and 2A of Epstein-Barr virus. J. Virol. 73, 6953–6963.

    PubMed  CAS  Google Scholar 

  54. Brinkmann, M. M., Glenn, M., Rainbow, L., Keiser, A., Henke-Gendo, C., and Schulz, T. T. (2003) Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein. J. Virol. 77, 9346–9358.

    PubMed  CAS  Google Scholar 

  55. Sharp, T. V., Wang, H. W., Koumi, A., Hollyman, D., Endo, Y., Ye, H., et al. (2002) K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J. Virol. 76, 802–816.

    PubMed  CAS  Google Scholar 

  56. DiMaio, D., Lai, C. C., and Klein, O. (1998) Virocrine transformation: the intersection between viral transforming proteins and cellular signal transduction pathways. Annu. Rev. Microbiol. 52, 397–421.

    PubMed  CAS  Google Scholar 

  57. Cesarman, E., Nador, R. G., Bai, F., Bohenzky, R. A., Russo, J. J., Moore, P. S., et al. (1996) Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J. Virol. 70, 8218–8223.

    PubMed  CAS  Google Scholar 

  58. Guo H. G., Browning, P., Nicholas, J., Hayward, G. S., Tschachler, E., Jiang, Y. W., et al. (1997) Characterization of a chemokine receptor-related gene in human herpesvirus 8 and its expression in Kaposi's sarcoma. Virology 228, 371–378.

    PubMed  CAS  Google Scholar 

  59. Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., and Cesarman, E. (1997) Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385, 347–350.

    PubMed  CAS  Google Scholar 

  60. Gershengorn, M. C., Geras-Raaka, E., Varma, A., and Clark-Lewis, I. (1998) Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture [see comments]. J. Clin. Invest. 102, 1469–1472.

    Article  PubMed  CAS  Google Scholar 

  61. Ho, H. H., Du, D., and Gershengorn, M. C. (1999) The N terminus of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor is necessary for high affinity chemokine binding but not for constitutive activity. J. Biol. Chem. 274, 31327–31332.

    PubMed  CAS  Google Scholar 

  62. Geras-Raaka, E., Arvanitakis, L., Bais, C., Cesarman, E., Mesri, E. A., and Gershengorn, M. C. (1998) Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture. J. Exp. Med. 187, 801–806.

    PubMed  CAS  Google Scholar 

  63. Geras-Raaka, E., Varma, A., Clark-Lewis, I., and Gershengorn, M. C. (1998) Kaposi's sarcoma-associated herpesvirus (KSHV) chemokine vMIP-II and human SDF-1alpha inhibit signaling by KSHV G protein-coupled receptor. Biochem. Biophys. Res. Commun. 253, 725–727.

    PubMed  CAS  Google Scholar 

  64. Geras-Raaka, E., Varma, A., Ho, H., Clark-Lewis, I., and Gershengorn, M. C. (1998) Human interferon-gamma-inducible protein 10 (IP-10) inhibits constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. J. Exp. Med. 188, 405–408.

    PubMed  CAS  Google Scholar 

  65. Bais, C., Santomasso, B., Coso, O., Arvanitakis, L., Raaka, E. G., Gutkind, J. S., et al. (1998) G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391, 86–89.

    PubMed  CAS  Google Scholar 

  66. Bais, C., Van Geelen, A., Eroles, P., Mutlu, A., Chiozzini, C., Dias, S., et al. (2003) Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR. Cancer Cell 3, 131–143.

    PubMed  CAS  Google Scholar 

  67. Couty, J. P., Geras-Raaka, E., Weksler, B. B., and Gershengorn, M. C. (2001) Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells. J. Biol. Chem. 276, 33805–33811.

    PubMed  CAS  Google Scholar 

  68. Montaner, S., Sodhi, A., Molinolo, A., Bugge, T. H., Sawai, E. T., He, Y., et al. (2003) Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23–36.

    PubMed  CAS  Google Scholar 

  69. Montaner, S., Sodhi, A., Pece, S., Mesri, E. A., and Gutkind, J. S. (2001) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B. Cancer Res. 61, 2641–2648.

    PubMed  CAS  Google Scholar 

  70. Munshi, N., Ganju, R. K., Avraham, S., Mesri, E. A., and Groopman, J. E. (1999) Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor activation of c-jun amino-terminal kinase/stress-activated protein kinase and lyn kinase is mediated by related adhesion focal tyrosine kinase/proline-rich tyrosine kinase 2. J. Biol. Chem. 274, 31863–31867.

    PubMed  CAS  Google Scholar 

  71. Pati, S., Cavrois, M., Guo, H. G., Foulke, Jr. J. S., Kim, J., Feldman, R. A., et al. (2001) Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis. J. Virol. 75, 8660–8673.

    PubMed  CAS  Google Scholar 

  72. Schwarz, M., and Murphy, P. M. (2001) Kaposi's sarcoma-associated herpesvirus g protein-coupled receptor constitutively activates nf-kappab and induces proinflammatory cytokine and chemokine production via a c-terminal signaling determinant. J. Immunol. 167, 505–513.

    PubMed  CAS  Google Scholar 

  73. Smit, M. J., Verzijl, D., Casarosa, P., Navis, M., Timmerman, H., and Leurs, R. (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.

    PubMed  CAS  Google Scholar 

  74. Sodhi, A., Montaner, S., Patel, V., Zohar, M., Bais, C., Mesri, E. A., et al. (2000) The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1alpha. Cancer Res. 60, 4873–4880.

    PubMed  CAS  Google Scholar 

  75. Yang, T. Y., Chen, S. C., Leach, M. W., Manfra, D., Homey, B., Wiekowski, M., et al. (2000) Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J. Exp. Med. 191, 445–454.

    PubMed  CAS  Google Scholar 

  76. Guo, H. G., Sadowska, M., Reid, W., Tschachler, E., Hayward, G., and Reitz, M. (2003) Kaposi's sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J. Virol. 77, 2631–2639.

    PubMed  CAS  Google Scholar 

  77. Shepard, L. W., Yang, M., Xie, P., Browning, D. D., Vovno-Yasenetskaya, T., Kozasa, T., et al. (2001) Constitutive activation of NF-kappa B and secretion of interleukin-8 induced by the G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus involve G alpha(13) and RhoA. J. Biol. Chem. 276, 45979–45987.

    PubMed  CAS  Google Scholar 

  78. Polson, A. G., Wang, D., DeRisi, J., and Ganem, D. (2002) Modulation of host gene expression by the constitutively active G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus. Cancer Res. 62, 4525–4530.

    PubMed  CAS  Google Scholar 

  79. Cannon, M., Philpott, N. J., and Cesarman, E. (2003) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J. Virol. 77, 57–67.

    PubMed  CAS  Google Scholar 

  80. Moore, P. S., Boshoff, C., Weiss, R. A., and Chang, Y. (1996) Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 274, 1739–1744.

    PubMed  CAS  Google Scholar 

  81. Neipel, F., Albrecht, J. C., Ensser, A., Huang, Y. Q., Li, J. J., Friedman-Kien, A. E., et al. (1997) Human herpesvirus 8 encodes a homolog of interleukin-6. J. Virol. 71, 839–842.

    PubMed  CAS  Google Scholar 

  82. Nicholas, J., Ruvolo, V. R., Burns, W. H., Sandford, G., Wan, X., Ciufo, D., et al. (1997) Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6. Nat. Med. 3, 287–292.

    PubMed  CAS  Google Scholar 

  83. Chatterjee, M., Osborne, J., Bestetti, G., Chang, Y., and Moore, P. S. (2002) Viral IL-6-induced cell proliferation and immune evasion of interferon activity. Science 298, 1432–1435.

    PubMed  CAS  Google Scholar 

  84. Chow, D., He, X., Snow, A. L., Rose-John, S., and Garcia, K. C. (2001) Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291, 2150–2155.

    PubMed  CAS  Google Scholar 

  85. Hideshima, T., Chauhan, D., Teoh, G., Raje, N., Treon, S. P., Tai, Y. T., et al. (2000) Characterization of signaling cascades triggered by human interleukin-6 versus Kaposi's sarcoma-associated herpes virus-encoded viral interleukin 6. Clin. Cancer Res. 6, 1180–1189.

    PubMed  CAS  Google Scholar 

  86. Klouche, M., Brockmeyer, N., Knabbe, C., and Rose-John, S. (2002) Human herpesvirus 8-derived viral IL-6 induces PTX3 expression in Kaposi's sarcoma cells. AIDS 16, F9-F18.

    PubMed  CAS  Google Scholar 

  87. Li, H., and Nicholas, J. (2002) Identification of amino acid residues of gp130 signal transducer and gp80 alpha receptor subunit that are involved in ligand binding and signaling by human herpesvirus 8-encoded interleukin-6. J. Virol. 76, 5627–5636.

    PubMed  CAS  Google Scholar 

  88. Li, H., Wang, H., and Nicholas, J. (2001) Detection of direct binding of human herpesvirus 8-encoded interleukin- 6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and-independent signaling. J. Virol. 75, 3325–3334.

    PubMed  CAS  Google Scholar 

  89. Molden, J., Chang, Y., You, Y., Moore, P. S., and Goldsmith, M. A. (1997) A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J. Biol. Chem. 272, 19625–19631.

    PubMed  CAS  Google Scholar 

  90. Mullberg, J., Geib, T., Jostock, T., Hoischen, S. H., Vollmer, P., Voltz, N., et al. (2000) IL-6 receptor independent stimulation of human gp130 by viral IL-6. J. Immunol. 164, 4672–4677.

    PubMed  CAS  Google Scholar 

  91. Osborne, J., Moore, P. S., and Chang, Y. (1999) KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways. Hum. Immunol. 60, 921–927.

    PubMed  CAS  Google Scholar 

  92. Wan, X., Wang, H., and Nicholas, J. (1999) Human herpesvirus 8 interleukin-6 (vIL-6) signals through gp130 but has structural and receptor-binding properties distinct from those of human IL-6. J. Virol. 73, 8268–8278.

    PubMed  CAS  Google Scholar 

  93. Foussat, A., Wijdenes, J., Bouchet, L., Gaidano, G., Neipel, F., Balabanian, K., et al. (1999) Human interleukin-6 is in vivo an autocrine growth factor for human herpesvirus-8-infected malignant B lymphocytes. Eur. Cytokine Netw. 10, 501–508.

    PubMed  CAS  Google Scholar 

  94. Mori, Y., Nishimoto, N., Ohno, M., Inagi, R., Dhepakson, P., Amou, K., et al. (2000) Human herpesvirus 8-encoded interleukin-6 homologue (viral IL-6) induces endogenous human IL-6 secretion. J. Med. Virol. 61, 332–335.

    PubMed  CAS  Google Scholar 

  95. Parravinci, C., Corbellino, M., Paulli, M., Magrini, U., Lazzarino, M., Moore, P. S., et al. (1997) Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease. Am. J. Pathol. 151, 1517–1522.

    Google Scholar 

  96. Cannon, J. S., Nicholas, J., Orenstein, J. M., Mann, R. B., Murray, P. G., Browning, P. J., et al. (1999) Heterogeneity of viral IL-6 expression in HHV-8-associated diseases. J. Infect. Dis. 180, 824–828.

    PubMed  CAS  Google Scholar 

  97. Staskus, K. A., Sun, R., Miller, G., Racz, P., Jaslowski, A., Metroka, C., et al. (1999) Cellular tropism and viral interleukin-6 expression distinguish human herpesvirus 8 involvement in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. J. Virol. 73, 4181–4187.

    PubMed  CAS  Google Scholar 

  98. Sun, R., Lin, S. F., Gradoville, L., Yuan, Y., Zhu, F., and Miller, G. (1998) A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc. Natl. Acad. Sci. USA 95, 10866–10871.

    PubMed  CAS  Google Scholar 

  99. Aoki, Y., Jaffe, E. S., Chang, Y., Jones, K., Teruya-Feldstein, J., Moore, P. S., et al. (1999) Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6. Blood 93, 4034–4043.

    PubMed  CAS  Google Scholar 

  100. Liu, C., Okruzhnov, Y., Li, H., and Nicholas, J. (2001) Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects. J. Virol. 75, 10933–10940.

    PubMed  CAS  Google Scholar 

  101. Boshoff, C., Endo, Y., Collins, P. D., Takeuchi, Y., Reeves, J. D., Schweickart, V. L., et al. (1997) Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278, 290–294.

    PubMed  CAS  Google Scholar 

  102. Dairaghi, D. J., Franz-Bacon, K., Callas, E., Cupp, J., Schall, T. J., Tamraz, S. A., et al. (1998) Macrophage inflammatory preotein-1beta induces migration and activation of human thymocytes. Blood 91, 2905–2913.

    PubMed  CAS  Google Scholar 

  103. Haque, N. S., Fallon, J. T., Taubman, M. B., and Harpel, P. C. (2001) The chemokine receptor CCR8 mediates human endothelial cell chemotaxis induced by I-309 and Kaposi sarcoma herpesvirus-encoded vMIP-I and by lipoprotein(a)-stimulated endothelial cell conditioned medium. Blood 97, 39–45.

    PubMed  CAS  Google Scholar 

  104. Sozzani, S., Luini, W., Bianchi, G., Allavena, P., Wells, T. N., Napolitano, M., et al. (1998) The viral chemokine macrophage inflammatory protein-II is a selective Th2 chemoattractant. Blood 92, 4036–4039.

    PubMed  CAS  Google Scholar 

  105. Weber, K. S., Grone, H. J., Rocken, M., Klier, C., Gu, S., Wank, R., et al. (2001) Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II. Eur. J. Immunol. 31, 2458–2466.

    PubMed  CAS  Google Scholar 

  106. Nakano, K., Isegawa, Y., Zou, P., Tadagaki, K., Inagi, R., and Yamanishi, K. (2003) Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded vMIP-I and vMIP-II induce signal transduction and chemotaxis in monocytic cells. Arch. Virol. 148, 871–890.

    PubMed  CAS  Google Scholar 

  107. Kledal, T. N., Rosenkilde, M. M., Coulin, F., Simmons, G., Johnsen, A. H., Alouani, S., et al. (1997) A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science 277, 1656–1659.

    PubMed  CAS  Google Scholar 

  108. Chang, J., Renne, R., Dittmer, D., and Ganem, D. (2000) Inflammatory cytokines and the reactivation of Kaposi's sarcoma-associated herpesvirus lytic replication. Virology 266, 17–25.

    PubMed  CAS  Google Scholar 

  109. Dittmer, D., and Kedes, D. H. (1998) Do viral chemokines modulate Kaposi's sarcoma? Bioessays 20, 367–70.

    PubMed  CAS  Google Scholar 

  110. Burysek, L., and Pitha, P. M. (2001) Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. J. Virol. 75, 2345–2352.

    PubMed  CAS  Google Scholar 

  111. Li, M., Lee, H., Guo, J., Neipel, F., Fleckenstein, B., Ozato, K., et al. (1998) Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor. J. Virol. 72, 5433–5440.

    PubMed  CAS  Google Scholar 

  112. Lubyova, B., and Pitha, P. M. (2000) Characterization of a novel human herpesvirus 8-encoded protein, vIRF-3, that shows homology to viral and cellular interferon regulatory factors. J. Virol. 74, 8194–8201.

    PubMed  CAS  Google Scholar 

  113. Rivas, C., Thlick, A. E., Parravicini, C., Moore, P. S., and Chang, Y. (2001) Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. J. Virol. 75, 429–438.

    PubMed  CAS  Google Scholar 

  114. Zimring, J. C., Goodbourn, S., and Offermann, M. K. (1998) Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription. J. Virol. 72, 701–707.

    PubMed  CAS  Google Scholar 

  115. Gao, S. J., Boshoff, C., Jayachandra, S., Weiss, R. A., Chang, Y., and Moore, P. S. (1997) KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15, 1979–85.

    PubMed  CAS  Google Scholar 

  116. Seo, T., Lee, D., Lee, B., Chung, J. H., and Choe, J. (2000) viral interferon regulatory factor 1 of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) binds to, and inhibits transactivation of, CREB-binding protein. Biochem. Biophys. Res. Commun. 270, 23–27.

    PubMed  CAS  Google Scholar 

  117. Burysek, L., Yeow, W. S., Lubyova, B., Kellum, M., Schafer, S. L., Huang, Y. Q., et al. (1999) Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300. J. Virol. 73, 7334–7342.

    PubMed  CAS  Google Scholar 

  118. Burysek, L., Yeow, W. S., and Pitha, P. M. (1999) Unique properties of a second human herpesvirus 8-encoded interferon regulatory factor (vIRF-2). Hum. Virol. 2, 19–32.

    CAS  Google Scholar 

  119. Jayachandra, S., Low, K. G., Thlick, A. E., Yu, J., Ling, P. D., Chang, Y., et al. (1999) Three unrelated viral transforming proteins (vIRF, EBNA2, and E1A) induce the MYC oncogene through the interferon-responsive PRF element by using different transcription coadaptors. Proc. Natl. Acad. Sci. USA 96, 11566–11571.

    PubMed  CAS  Google Scholar 

  120. Nakamura, H., Li, M., Zarycki, J., and Jung, J. U. (2001) Inhibition of p53 tumor suppressor by viral interferon regulatory factor. J. Virol. 75, 7572–7582.

    PubMed  CAS  Google Scholar 

  121. Dittmer, D. P. (2003) Transcription profile of Kaposi's sarcoma-associated herpesvirus in primary Kaposi's sarcoma lesions as determined by real-time PCR arrays. Cancer Res. 63, 2010–2015.

    PubMed  CAS  Google Scholar 

  122. Ballestas, M. E., Chatis, P. A., and Kaye, K. M. (1999) Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284, 641–644.

    PubMed  CAS  Google Scholar 

  123. Cotter, M. A., 2nd, and Robertson, E. S. (1999) The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology 264, 254–264.

    PubMed  CAS  Google Scholar 

  124. Cotter, M. A., 2nd, Subramanian, C., and Robertson, E. S. (2001) The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen binds to specific sequences at the left end of the viral genome through its carboxy-terminus. Virology 291, 241–259.

    PubMed  CAS  Google Scholar 

  125. Garber, A. C., Hu, J., and Renne, R. (2002) Lana cooperatively binds to two sites within the terminal repeat, both sites contribute to lana's ability to suppress transcription and facilitate DNA replication. J. Biol. Chem. 277, 27401–27411.

    PubMed  CAS  Google Scholar 

  126. Garber, A. C., Shu, M. A., Hu, J., and Renne, R. (2001) DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J. Virol. 75, 7882–7892.

    PubMed  CAS  Google Scholar 

  127. Grundhoff, A., and D. Ganem (2003) The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus permits replication of terminal repeat-containing plasmids. J. Virol. 77, 2779–2783.

    PubMed  CAS  Google Scholar 

  128. Friborg, J., Jr., Kong, W., Hottiger, M. O., and Nabel, G. J. (1999) p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402, 889–894.

    PubMed  CAS  Google Scholar 

  129. Platt, G. M., Simpson, G. R., Mittnacht, S., and Schulz, T. F. (1999) Latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts with RING3, a homolog of the Drosophila female sterile homeotic (fsh) gene. J. Virol. 73, 9789–9795.

    PubMed  CAS  Google Scholar 

  130. Radkov, S. A., Kellam, P., and Boshoff, C. (2000) The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nat. Med. 6, 1121–1127.

    PubMed  CAS  Google Scholar 

  131. Li, M., Lee, H., Yoon, D. W., Albrecht, J. C., Fleckenstein, B., Neipel, F., and Jung, J. U. (1997) Kaposi's sarcoma-associated herpesvirus encodes a functional cyclin. J. Virol. 71, 1984–1991.

    PubMed  CAS  Google Scholar 

  132. Schulze-Gahmen, U., Jung, J. U., and Kim, S. H. (1999) Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6. Structure 7, 245–254.

    PubMed  CAS  Google Scholar 

  133. Ellis, M., Y. P. Chew, L. Fallis, S. Freddersdorf, C. Boshoff, R. A. Weiss, X. Lu, and S. Mittnacht. (1999) Degradation of p27(Kip) cdk inhibitor triggered by Kaposi's sarcoma virus cyclin-cdk6 complex. EMBO J. 18, 644–653.

    PubMed  CAS  Google Scholar 

  134. Godden-Kent, D., Talbot, S. J., Boshoff, C., Chang, Y., Moore, P., Weiss, R. A., et al. (1997) The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. J. Virol. 71, 4193–4198.

    PubMed  CAS  Google Scholar 

  135. Mann, D. J., Child, E. S., Swanton, C., Laman, H., and Jones, N. (1999) Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus. EMBO J. 18, 654–663.

    PubMed  CAS  Google Scholar 

  136. Ojala, P. M., Yamamoto, K., Castanos-Velez, E., Biberfeld, P., Korsmeyer, S. J., and Makela, T. P. (2000) The apoptotic v-cyclin-CDK6 complex phosphorylates and inactivates Bcl-2. Nat. Cell Biol. 2, 819–825.

    PubMed  CAS  Google Scholar 

  137. Lundquist, A., Barre, B., Bienvenu, F., Hermann, J., Avril, S., and Coqueret, O. (2003) Kaposi's sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition. Blood. 101, 4070–4077.

    PubMed  CAS  Google Scholar 

  138. Verschuren, E. W., Klefstrom, J., Evan, G. I., and Jones, N. (2002) The oncogenic potential of Kaposi's sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell 2, 229–241.

    PubMed  CAS  Google Scholar 

  139. Thome, M., Schneider, P., Hofmann, K., Fickenscher, H., Meinl, E., Neipel, F., et al. (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517–521.

    PubMed  CAS  Google Scholar 

  140. Field, N., W. Low, M. Daniels, S. Howell, L. Daviet, C. Boshoff, and M. Collins. (2003) KSHV vFLIP binds to IKK-γ to activate IKK. J. Cell Sci. 116, 3721–3728.

    PubMed  CAS  Google Scholar 

  141. Liu, L., Eby, M. T., Rathore, N., Sinha, S. K., Kumar, A., and Chaudhary, P. M. (2002) The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J. Biol. Chem. 277, 13745–13751.

    PubMed  CAS  Google Scholar 

  142. An, J., Sun, Y., Sun, R., and Rettig, M. B. (2003) Kaposi's sarcoma-associated herpesvirus encoded vFLIP induces cellular IL-6 expression: the role of the NF-kappaB and JNK/AP1 pathways. Oncogene 22, 3371–3385.

    PubMed  CAS  Google Scholar 

  143. Sadler, R., Wu, L., Forghani, B., Renne, R., Zhong, W., Herndier, B., et al. (1999) A complex translational program generates multiple novel proteins from the latently expressed kaposin (K12) locus of Kaposi's sarcoma-associated herpesvirus. J. Virol. 73, 5722–5730.

    PubMed  CAS  Google Scholar 

  144. Kliche, S., Nagel, W., Kremmer, E., Atzler, C., Ege, A., Knorr, T., et al. (2001) Signaling by human herpesvirus 8 kaposin A through direct membrane recruitment of cytohesin-1. Mol. Cell 7, 833–843.

    PubMed  CAS  Google Scholar 

  145. Muralidhar, S., Pumfery, A. M., Hassani, M., Sadaie, M. R., Azumi, N., Kishishita, M., et al. (1998) Identification of kaposin (open reading frame K12) as a human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) transforming gene. J. Virol. 72, 4980–4988.

    PubMed  CAS  Google Scholar 

  146. Muralidhar, S., Veytsmann, G., Chandran, B., Ablashi, D., Doniger, J., and Rosenthal, L. J. (2000) Characterization of the human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) oncogene, kaposin (ORF K12). J. Clin. Virol. 16, 203–213.

    PubMed  CAS  Google Scholar 

  147. Wang, L., Wakisaka, N., Tomlinson, C. C., DeWire, S., Krall, S., Pagano, J. S., and Damania, B. (2004) The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) K1 protein induces expression of angiogenic and invasion factors. Cancer Res. 64, 120–128.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, CB # 7295, University of North Carolina, Chapel Hill, NC

    Blossom Damania

Authors
  1. Blossom Damania
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Blossom Damania.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Damania, B. Modulation of cell signaling pathways by kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). Cell Biochem Biophys 40, 305–322 (2004). https://doi.org/10.1385/CBB:40:3:305

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/CBB:40:3:305

Index Entries

Search

Navigation