Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Nov;70(11):8218–8223. doi: 10.1128/jvi.70.11.8218-8223.1996

Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma.

E Cesarman 1, R G Nador 1, F Bai 1, R A Bohenzky 1, J J Russo 1, P S Moore 1, Y Chang 1, D M Knowles 1
PMCID: PMC190906  PMID: 8892957

Abstract

A new human herpesvirus was recently identified in all forms of Kaposi's sarcoma (Kaposi's sarcoma-associated herpesvirus [KSHV] or human herpesvirus 8), as well as in primary effusion (body cavity-based) lymphomas (PELs). A 12.3-kb-long KSHV clone was obtained from a PEL genomic library. Sequencing of this clone revealed extensive homology and colinearity with the right end of the herpesvirus saimiri (HVS) genome and more limited homology to the left end of the Epstein-Barr virus genome. Four open reading frames (ORFs) were sequenced and characterized; these are homologous to the following viral and/or cellular genes: (i) Epstein-Barr virus membrane antigen p140 and HVS p160, (ii) HVS and cellular type D cyclins, (iii) HVS and cellular G protein-coupled receptors, and (iv) HVS. Since there is considerable evidence that cyclin D1 and some G protein-coupled receptors contribute to the development of specific cancers, the presence of KSHV homologs of these genes provides support for a role for KSHV in malignant transformation. All ORFs identified are transcribed in PELs and Kaposi's sarcoma tissues, further suggesting an active role for KSHV in these diseases.

Full Text

The Full Text of this article is available as a PDF (211.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahuja S. K., Murphy P. M. Molecular piracy of mammalian interleukin-8 receptor type B by herpesvirus saimiri. J Biol Chem. 1993 Oct 5;268(28):20691–20694. [PubMed] [Google Scholar]
  2. Albrecht J. C., Nicholas J., Biller D., Cameron K. R., Biesinger B., Newman C., Wittmann S., Craxton M. A., Coleman H., Fleckenstein B. Primary structure of the herpesvirus saimiri genome. J Virol. 1992 Aug;66(8):5047–5058. doi: 10.1128/jvi.66.8.5047-5058.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Allen L. F., Lefkowitz R. J., Caron M. G., Cotecchia S. G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha 1B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11354–11358. doi: 10.1073/pnas.88.24.11354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  5. Ambroziak J. A., Blackbourn D. J., Herndier B. G., Glogau R. G., Gullett J. H., McDonald A. R., Lennette E. T., Levy J. A. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients. Science. 1995 Apr 28;268(5210):582–583. doi: 10.1126/science.7725108. [DOI] [PubMed] [Google Scholar]
  6. Arnold A., Kim H. G., Gaz R. D., Eddy R. L., Fukushima Y., Byers M. G., Shows T. B., Kronenberg H. M. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest. 1989 Jun;83(6):2034–2040. doi: 10.1172/JCI114114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Arvanitakis L., Yaseen N., Sharma S. Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. J Immunol. 1995 Aug 1;155(3):1047–1056. [PubMed] [Google Scholar]
  8. Baer R., Bankier A. T., Biggin M. D., Deininger P. L., Farrell P. J., Gibson T. J., Hatfull G., Hudson G. S., Satchwell S. C., Séguin C. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature. 1984 Jul 19;310(5974):207–211. doi: 10.1038/310207a0. [DOI] [PubMed] [Google Scholar]
  9. Biesinger B., Müller-Fleckenstein I., Simmer B., Lang G., Wittmann S., Platzer E., Desrosiers R. C., Fleckenstein B. Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3116–3119. doi: 10.1073/pnas.89.7.3116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Birkenbach M., Josefsen K., Yalamanchili R., Lenoir G., Kieff E. Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J Virol. 1993 Apr;67(4):2209–2220. doi: 10.1128/jvi.67.4.2209-2220.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Boshoff C., Whitby D., Hatziioannou T., Fisher C., van der Walt J., Hatzakis A., Weiss R., Schulz T. Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet. 1995 Apr 22;345(8956):1043–1044. doi: 10.1016/s0140-6736(95)90780-7. [DOI] [PubMed] [Google Scholar]
  12. Cameron K. R., Stamminger T., Craxton M., Bodemer W., Honess R. W., Fleckenstein B. The 160,000-Mr virion protein encoded at the right end of the herpesvirus saimiri genome is homologous to the 140,000-Mr membrane antigen encoded at the left end of the Epstein-Barr virus genome. J Virol. 1987 Jul;61(7):2063–2070. doi: 10.1128/jvi.61.7.2063-2070.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cesarman E., Chang Y., Moore P. S., Said J. W., Knowles D. M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995 May 4;332(18):1186–1191. doi: 10.1056/NEJM199505043321802. [DOI] [PubMed] [Google Scholar]
  14. Cesarman E., Moore P. S., Rao P. H., Inghirami G., Knowles D. M., Chang Y. In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood. 1995 Oct 1;86(7):2708–2714. [PubMed] [Google Scholar]
  15. Chang Y., Cesarman E., Pessin M. S., Lee F., Culpepper J., Knowles D. M., Moore P. S. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994 Dec 16;266(5192):1865–1869. doi: 10.1126/science.7997879. [DOI] [PubMed] [Google Scholar]
  16. Chang Y., Moore P. S., Talbot S. J., Boshoff C. H., Zarkowska T., Godden-Kent, Paterson H., Weiss R. A., Mittnacht S. Cyclin encoded by KS herpesvirus. Nature. 1996 Aug 1;382(6590):410–410. doi: 10.1038/382410a0. [DOI] [PubMed] [Google Scholar]
  17. Chang Y., Ziegler J., Wabinga H., Katangole-Mbidde E., Boshoff C., Schulz T., Whitby D., Maddalena D., Jaffe H. W., Weiss R. A. Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group. Arch Intern Med. 1996 Jan 22;156(2):202–204. [PubMed] [Google Scholar]
  18. Dobner T., Wolf I., Emrich T., Lipp M. Differentiation-specific expression of a novel G protein-coupled receptor from Burkitt's lymphoma. Eur J Immunol. 1992 Nov;22(11):2795–2799. doi: 10.1002/eji.1830221107. [DOI] [PubMed] [Google Scholar]
  19. Dupin N., Gorin I., Deleuze J., Agut H., Huraux J. M., Escande J. P. Herpes-like DNA sequences, AIDS-related tumors, and Castleman's disease. N Engl J Med. 1995 Sep 21;333(12):798–799. [PubMed] [Google Scholar]
  20. Dupin N., Grandadam M., Calvez V., Gorin I., Aubin J. T., Havard S., Lamy F., Leibowitch M., Huraux J. M., Escande J. P. Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet. 1995 Mar 25;345(8952):761–762. doi: 10.1016/s0140-6736(95)90642-8. [DOI] [PubMed] [Google Scholar]
  21. Ensser A., Fleckenstein B. Alcelaphine herpesvirus type 1 has a semaphorin-like gene. J Gen Virol. 1995 Apr;76(Pt 4):1063–1067. doi: 10.1099/0022-1317-76-4-1063. [DOI] [PubMed] [Google Scholar]
  22. Federsppiel B., Melhado I. G., Duncan A. M., Delaney A., Schappert K., Clark-Lewis I., Jirik F. R. Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen. Genomics. 1993 Jun;16(3):707–712. doi: 10.1006/geno.1993.1251. [DOI] [PubMed] [Google Scholar]
  23. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  24. Francia di Celle P., Mariani S., Riera L., Stacchini A., Reato G., Foa R. Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion. Blood. 1996 May 15;87(10):4382–4389. [PubMed] [Google Scholar]
  25. Frank D., Cesarman E., Liu Y. F., Michler R. E., Knowles D. M. Posttransplantation lymphoproliferative disorders frequently contain type A and not type B Epstein-Barr virus. Blood. 1995 Mar 1;85(5):1396–1403. [PubMed] [Google Scholar]
  26. Gessain A., Sudaka A., Brière J., Fouchard N., Nicola M. A., Rio B., Arborio M., Troussard X., Audouin J., Diebold J. 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. 1996 Jan 1;87(1):414–416. [PubMed] [Google Scholar]
  27. Gutkind J. S., Novotny E. A., Brann M. R., Robbins K. C. Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4703–4707. doi: 10.1073/pnas.88.11.4703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Herzog H., Hort Y. J., Shine J., Selbie L. A. Molecular cloning, characterization, and localization of the human homolog to the reported bovine NPY Y3 receptor: lack of NPY binding and activation. DNA Cell Biol. 1993 Jul-Aug;12(6):465–471. doi: 10.1089/dna.1993.12.465. [DOI] [PubMed] [Google Scholar]
  29. Honess R. W., Gompels U. A., Barrell B. G., Craxton M., Cameron K. R., Staden R., Chang Y. N., Hayward G. S. Deviations from expected frequencies of CpG dinucleotides in herpesvirus DNAs may be diagnostic of differences in the states of their latent genomes. J Gen Virol. 1989 Apr;70(Pt 4):837–855. doi: 10.1099/0022-1317-70-4-837. [DOI] [PubMed] [Google Scholar]
  30. Jackson T. R., Blair L. A., Marshall J., Goedert M., Hanley M. R. The mas oncogene encodes an angiotensin receptor. Nature. 1988 Sep 29;335(6189):437–440. doi: 10.1038/335437a0. [DOI] [PubMed] [Google Scholar]
  31. Jazin E. E., Yoo H., Blomqvist A. G., Yee F., Weng G., Walker M. W., Salon J., Larhammar D., Wahlestedt C. A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells. Regul Pept. 1993 Sep 22;47(3):247–258. doi: 10.1016/0167-0115(93)90392-l. [DOI] [PubMed] [Google Scholar]
  32. Julius D., Livelli T. J., Jessell T. M., Axel R. Ectopic expression of the serotonin 1c receptor and the triggering of malignant transformation. Science. 1989 Jun 2;244(4908):1057–1062. doi: 10.1126/science.2727693. [DOI] [PubMed] [Google Scholar]
  33. Jung J. U., Stäger M., Desrosiers R. C. Virus-encoded cyclin. Mol Cell Biol. 1994 Nov;14(11):7235–7244. doi: 10.1128/mcb.14.11.7235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Karcher D. S., Alkan S. Herpes-like DNA sequences, AIDS-related tumors, and Castleman's disease. N Engl J Med. 1995 Sep 21;333(12):797–799. doi: 10.1056/NEJM199509213331211. [DOI] [PubMed] [Google Scholar]
  35. Merico F., Bergui L., Gregoretti M. G., Ghia P., Aimo G., Lindley I. J., Caligaris-Cappio F. Cytokines involved in the progression of multiple myeloma. Clin Exp Immunol. 1993 Apr;92(1):27–31. doi: 10.1111/j.1365-2249.1993.tb05943.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mesri E. A., Cesarman E., Arvanitakis L., Rafii S., Moore M. A., Posnett D. N., Knowles D. M., Asch A. S. Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus is a new transmissible virus that infects B cells. J Exp Med. 1996 May 1;183(5):2385–2390. doi: 10.1084/jem.183.5.2385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miller G., Rigsby M. O., Heston L., Grogan E., Sun R., Metroka C., Levy J. A., Gao S. J., Chang Y., Moore P. Antibodies to butyrate-inducible antigens of Kaposi's sarcoma-associated herpesvirus in patients with HIV-1 infection. N Engl J Med. 1996 May 16;334(20):1292–1297. doi: 10.1056/NEJM199605163342003. [DOI] [PubMed] [Google Scholar]
  38. Moore P. S., Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995 May 4;332(18):1181–1185. doi: 10.1056/NEJM199505043321801. [DOI] [PubMed] [Google Scholar]
  39. Moore P. S., Gao S. J., Dominguez G., Cesarman E., Lungu O., Knowles D. M., Garber R., Pellett P. E., McGeoch D. J., Chang Y. Primary characterization of a herpesvirus agent associated with Kaposi's sarcomae. J Virol. 1996 Jan;70(1):549–558. doi: 10.1128/jvi.70.1.549-558.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Moore P. S., Kingsley L. A., Holmberg S. D., Spira T., Gupta P., Hoover D. R., Parry J. P., Conley L. J., Jaffe H. W., Chang Y. Kaposi's sarcoma-associated herpesvirus infection prior to onset of Kaposi's sarcoma. AIDS. 1996 Feb;10(2):175–180. doi: 10.1097/00002030-199602000-00007. [DOI] [PubMed] [Google Scholar]
  41. Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
  42. Murphy P. M., Tiffany H. L. Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science. 1991 Sep 13;253(5025):1280–1283. doi: 10.1126/science.1891716. [DOI] [PubMed] [Google Scholar]
  43. Nicholas J., Cameron K. R., Honess R. W. Herpesvirus saimiri encodes homologues of G protein-coupled receptors and cyclins. Nature. 1992 Jan 23;355(6358):362–365. doi: 10.1038/355362a0. [DOI] [PubMed] [Google Scholar]
  44. Noel J. C. Kaposi's sarcoma and KSHV. Lancet. 1995 Nov 18;346(8986):1359–1359. [PubMed] [Google Scholar]
  45. Nomura H., Nielsen B. W., Matsushima K. Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors. Int Immunol. 1993 Oct;5(10):1239–1249. doi: 10.1093/intimm/5.10.1239. [DOI] [PubMed] [Google Scholar]
  46. Parma J., Duprez L., Van Sande J., Cochaux P., Gervy C., Mockel J., Dumont J., Vassart G. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature. 1993 Oct 14;365(6447):649–651. doi: 10.1038/365649a0. [DOI] [PubMed] [Google Scholar]
  47. Peters G. The D-type cyclins and their role in tumorigenesis. J Cell Sci Suppl. 1994;18:89–96. doi: 10.1242/jcs.1994.supplement_18.13. [DOI] [PubMed] [Google Scholar]
  48. Renne R., Zhong W., Herndier B., McGrath M., Abbey N., Kedes D., Ganem D. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med. 1996 Mar;2(3):342–346. doi: 10.1038/nm0396-342. [DOI] [PubMed] [Google Scholar]
  49. Russo D., Arturi F., Schlumberger M., Caillou B., Monier R., Filetti S., Suárez H. G. Activating mutations of the TSH receptor in differentiated thyroid carcinomas. Oncogene. 1995 Nov 2;11(9):1907–1911. [PubMed] [Google Scholar]
  50. Sampei G., Mizobuchi K. The organization of the purL gene encoding 5'-phosphoribosylformylglycinamide amidotransferase of Escherichia coli. J Biol Chem. 1989 Dec 15;264(35):21230–21238. [PubMed] [Google Scholar]
  51. Schalling M., Ekman M., Kaaya E. E., Linde A., Biberfeld P. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med. 1995 Jul;1(7):707–708. doi: 10.1038/nm0795-707. [DOI] [PubMed] [Google Scholar]
  52. Sciacca F. L., Stürzl M., Bussolino F., Sironi M., Brandstetter H., Zietz C., Zhou D., Matteucci C., Peri G., Sozzani S. Expression of adhesion molecules, platelet-activating factor, and chemokines by Kaposi's sarcoma cells. J Immunol. 1994 Nov 15;153(10):4816–4825. [PubMed] [Google Scholar]
  53. Shingadia D., Howard M. R., Brink N. S., Gibb D., Klein N., Tedder R., Novelli V. Kaposi's sarcoma and KSHV. Lancet. 1995 Nov 18;346(8986):1359–1360. [PubMed] [Google Scholar]
  54. Soulier J., Grollet L., Oksenhendler E., Cacoub P., Cazals-Hatem D., Babinet P., d'Agay M. F., Clauvel J. P., Raphael M., Degos L. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995 Aug 15;86(4):1276–1280. [PubMed] [Google Scholar]
  55. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  56. Strader C. D., Fong T. M., Tota M. R., Underwood D., Dixon R. A. Structure and function of G protein-coupled receptors. Annu Rev Biochem. 1994;63:101–132. doi: 10.1146/annurev.bi.63.070194.000533. [DOI] [PubMed] [Google Scholar]
  57. Telford E. A., Watson M. S., Aird H. C., Perry J., Davison A. J. The DNA sequence of equine herpesvirus 2. J Mol Biol. 1995 Jun 9;249(3):520–528. doi: 10.1006/jmbi.1995.0314. [DOI] [PubMed] [Google Scholar]
  58. Tiong S. Y., Nash D. The adenosine2 gene of Drosophila melanogaster encodes a formylglycineamide ribotide amidotransferase. Genome. 1993 Oct;36(5):924–934. doi: 10.1139/g93-122. [DOI] [PubMed] [Google Scholar]
  59. Tsujimoto Y., Finger L. R., Yunis J., Nowell P. C., Croce C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984 Nov 30;226(4678):1097–1099. doi: 10.1126/science.6093263. [DOI] [PubMed] [Google Scholar]
  60. Whitby D., Howard M. R., Tenant-Flowers M., Brink N. S., Copas A., Boshoff C., Hatzioannou T., Suggett F. E., Aldam D. M., Denton A. S. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet. 1995 Sep 23;346(8978):799–802. doi: 10.1016/s0140-6736(95)91619-9. [DOI] [PubMed] [Google Scholar]
  61. Wilson R., Ainscough R., Anderson K., Baynes C., Berks M., Bonfield J., Burton J., Connell M., Copsey T., Cooper J. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature. 1994 Mar 3;368(6466):32–38. doi: 10.1038/368032a0. [DOI] [PubMed] [Google Scholar]
  62. Young D., Waitches G., Birchmeier C., Fasano O., Wigler M. Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell. 1986 Jun 6;45(5):711–719. doi: 10.1016/0092-8674(86)90785-3. [DOI] [PubMed] [Google Scholar]
  63. Zhang Y. J., Jiang W., Chen C. J., Lee C. S., Kahn S. M., Santella R. M., Weinstein I. B. Amplification and overexpression of cyclin D1 in human hepatocellular carcinoma. Biochem Biophys Res Commun. 1993 Oct 29;196(2):1010–1016. doi: 10.1006/bbrc.1993.2350. [DOI] [PubMed] [Google Scholar]
  64. Zhong W., Wang H., Herndier B., Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6641–6646. doi: 10.1073/pnas.93.13.6641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. di Celle P. F., Carbone A., Marchis D., Zhou D., Sozzani S., Zupo S., Pini M., Mantovani A., Foa R. Cytokine gene expression in B-cell chronic lymphocytic leukemia: evidence of constitutive interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein. Blood. 1994 Jul 1;84(1):220–228. [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES