Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1993 Sep;67(9):5522–5528. doi: 10.1128/jvi.67.9.5522-5528.1993

Activation of the human T-cell leukemia virus type I enhancer is mediated by binding sites for Elf-1 and the pets factor.

N M Clark 1, M J Smith 1, J M Hilfinger 1, D M Markovitz 1
PMCID: PMC237955  PMID: 8350410

Abstract

Infection with human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell lymphoma/leukemia. This disease occurs in only a small minority of people infected with HTLV-I and manifests itself many years after infection. Therefore, it appears that a fine balance exists between HTLV-I and the host T-cell factors with which it interacts. HTLV-I encodes a transactivating protein, Tax, which activates viral transcription via cellular mechanisms which are incompletely understood. As viral gene expression is negligible during latency, it is doubtful that Tax controls the initial transition to the replicative state. Tax-independent cellular factors which control HTLV-I transcription, and presumably latency, have received little study. Recently, the product of the chicken proto-oncogene ets-1 has been shown to bind to the HTLV-I enhancer and modestly activate transcription in certain cell types (S. C. Gitlin, R. Bosselut, A. Gégonne, J. Ghysdael, and J. N. Brady, J. Virol. 65:5513-5523, 1991). However, the functional significance of the ets-binding site in the intact enhancer has not previously been shown. We now demonstrate that site-specific mutation of the purine-rich ets-binding site significantly diminishes inducible enhancer function, but not Tax response, in the human Jurkat T-cell line. Similarly, mutation of the peri-ets (pets) site, not previously noted in the HTLV-I enhancer, markedly inhibits inducible enhancer function but not Tax response. Further, we show that the predominant protein binding the purine-rich HTLV-I enhancer element in human T cells is not ets-1 but Elf-1, a member of the ets family which is very similar to the Drosophila morphogen E74. Regulation of HTLV-I through Elf-1/pets enhancer motifs resembles that seen with human immunodeficiency virus type 2 (D. M. Markovitz, M. Smith, J. Hilfinger, M. C. Hannibal, B. Petryniak, and G. J. Nabel, J. Virol. 66:5479-5484, 1992; J. M. Leiden, C.-W. Wang, B. Petryniak, M. Smith, D. M. Markovitz, G. J. Nabel, and C. B. Thompson, J. Virol. 66:5890-5897, 1992), another human pathogenic retrovirus with a relatively long incubation period.

Full text

PDF
5522

Images in this article

5525Image
on p.5525
5525Image
on p.5525
5526Image
on p.5526

Selected References

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

  1. Ben-David Y., Giddens E. B., Letwin K., Bernstein A. Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev. 1991 Jun;5(6):908–918. doi: 10.1101/gad.5.6.908. [DOI] [PubMed] [Google Scholar]
  2. Bhat N. K., Thompson C. B., Lindsten T., June C. H., Fujiwara S., Koizumi S., Fisher R. J., Papas T. S. Reciprocal expression of human ETS1 and ETS2 genes during T-cell activation: regulatory role for the protooncogene ETS1. Proc Natl Acad Sci U S A. 1990 May;87(10):3723–3727. doi: 10.1073/pnas.87.10.3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blattner W. A. Human T-lymphotrophic viruses and diseases of long latency. Ann Intern Med. 1989 Jul 1;111(1):4–6. doi: 10.7326/0003-4819-111-1-4. [DOI] [PubMed] [Google Scholar]
  4. Bosselut R., Duvall J. F., Gégonne A., Bailly M., Hémar A., Brady J., Ghysdael J. The product of the c-ets-1 proto-oncogene and the related Ets2 protein act as transcriptional activators of the long terminal repeat of human T cell leukemia virus HTLV-1. EMBO J. 1990 Oct;9(10):3137–3144. doi: 10.1002/j.1460-2075.1990.tb07511.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davis M. G., Kenney S. C., Kamine J., Pagano J. S., Huang E. S. Immediate-early gene region of human cytomegalovirus trans-activates the promoter of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8642–8646. doi: 10.1073/pnas.84.23.8642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  8. Gitlin S. D., Bosselut R., Gégonne A., Ghysdael J., Brady J. N. Sequence-specific interaction of the Ets1 protein with the long terminal repeat of the human T-lymphotropic virus type I. J Virol. 1991 Oct;65(10):5513–5523. doi: 10.1128/jvi.65.10.5513-5523.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Golemis E. A., Speck N. A., Hopkins N. Alignment of U3 region sequences of mammalian type C viruses: identification of highly conserved motifs and implications for enhancer design. J Virol. 1990 Feb;64(2):534–542. doi: 10.1128/jvi.64.2.534-542.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  12. Gunther C. V., Nye J. A., Bryner R. S., Graves B. J. Sequence-specific DNA binding of the proto-oncoprotein ets-1 defines a transcriptional activator sequence within the long terminal repeat of the Moloney murine sarcoma virus. Genes Dev. 1990 Apr;4(4):667–679. doi: 10.1101/gad.4.4.667. [DOI] [PubMed] [Google Scholar]
  13. Gégonne A., Bosselut R., Bailly R. A., Ghysdael J. Synergistic activation of the HTLV1 LTR Ets-responsive region by transcription factors Ets1 and Sp1. EMBO J. 1993 Mar;12(3):1169–1178. doi: 10.1002/j.1460-2075.1993.tb05758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hall W. W., Liu C. R., Schneewind O., Takahashi H., Kaplan M. H., Röupe G., Vahlne A. Deleted HTLV-I provirus in blood and cutaneous lesions of patients with mycosis fungoides. Science. 1991 Jul 19;253(5017):317–320. doi: 10.1126/science.1857968. [DOI] [PubMed] [Google Scholar]
  15. Hilfinger J. M., Clark N., Smith M., Robinson K., Markovitz D. M. Differential regulation of the human immunodeficiency virus type 2 enhancer in monocytes at various stages of differentiation. J Virol. 1993 Jul;67(7):4448–4453. doi: 10.1128/jvi.67.7.4448-4453.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ho I. C., Bhat N. K., Gottschalk L. R., Lindsten T., Thompson C. B., Papas T. S., Leiden J. M. Sequence-specific binding of human Ets-1 to the T cell receptor alpha gene enhancer. Science. 1990 Nov 9;250(4982):814–818. doi: 10.1126/science.2237431. [DOI] [PubMed] [Google Scholar]
  17. Jeang K. T., Boros I., Brady J., Radonovich M., Khoury G. Characterization of cellular factors that interact with the human T-cell leukemia virus type I p40x-responsive 21-base-pair sequence. J Virol. 1988 Dec;62(12):4499–4509. doi: 10.1128/jvi.62.12.4499-4509.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kanki P. J. Clinical significance of HIV-2 infection in West Africa. AIDS Clin Rev. 1989:95–108. [PubMed] [Google Scholar]
  19. Kim J. H., Durack D. T. Manifestations of human T-lymphotropic virus type I infection. Am J Med. 1988 May;84(5):919–928. doi: 10.1016/0002-9343(88)90072-1. [DOI] [PubMed] [Google Scholar]
  20. Kingsley C., Winoto A. Cloning of GT box-binding proteins: a novel Sp1 multigene family regulating T-cell receptor gene expression. Mol Cell Biol. 1992 Oct;12(10):4251–4261. doi: 10.1128/mcb.12.10.4251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  22. LaMarco K., Thompson C. C., Byers B. P., Walton E. M., McKnight S. L. Identification of Ets- and notch-related subunits in GA binding protein. Science. 1991 Aug 16;253(5021):789–792. doi: 10.1126/science.1876836. [DOI] [PubMed] [Google Scholar]
  23. Leiden J. M., Wang C. Y., Petryniak B., Markovitz D. M., Nabel G. J., Thompson C. B. A novel Ets-related transcription factor, Elf-1, binds to human immunodeficiency virus type 2 regulatory elements that are required for inducible trans activation in T cells. J Virol. 1992 Oct;66(10):5890–5897. doi: 10.1128/jvi.66.10.5890-5897.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Leung K., Nabel G. J. HTLV-1 transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor. Nature. 1988 Jun 23;333(6175):776–778. doi: 10.1038/333776a0. [DOI] [PubMed] [Google Scholar]
  25. Mann D. L., DeSantis P., Mark G., Pfeifer A., Newman M., Gibbs N., Popovic M., Sarngadharan M. G., Gallo R. C., Clark J. HTLV-I--associated B-cell CLL: indirect role for retrovirus in leukemogenesis. Science. 1987 May 29;236(4805):1103–1106. doi: 10.1126/science.2883731. [DOI] [PubMed] [Google Scholar]
  26. Markovitz D. M., Hannibal M. C., Smith M. J., Cossman R., Nabel G. J. Activation of the human immunodeficiency virus type 1 enhancer is not dependent on NFAT-1. J Virol. 1992 Jun;66(6):3961–3965. doi: 10.1128/jvi.66.6.3961-3965.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Markovitz D. M., Hannibal M., Perez V. L., Gauntt C., Folks T. M., Nabel G. J. Differential regulation of human immunodeficiency viruses (HIVs): a specific regulatory element in HIV-2 responds to stimulation of the T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9098–9102. doi: 10.1073/pnas.87.23.9098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Markovitz D. M. Infection with the human immunodeficiency virus type 2. Ann Intern Med. 1993 Feb 1;118(3):211–218. doi: 10.7326/0003-4819-118-3-199302010-00010. [DOI] [PubMed] [Google Scholar]
  29. Markovitz D. M., Smith M. J., Hilfinger J., Hannibal M. C., Petryniak B., Nabel G. J. Activation of the human immunodeficiency virus type 2 enhancer is dependent on purine box and kappa B regulatory elements. J Virol. 1992 Sep;66(9):5479–5484. doi: 10.1128/jvi.66.9.5479-5484.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Marriott S. J., Boros I., Duvall J. F., Brady J. N. Indirect binding of human T-cell leukemia virus type I tax1 to a responsive element in the viral long terminal repeat. Mol Cell Biol. 1989 Oct;9(10):4152–4160. doi: 10.1128/mcb.9.10.4152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Marriott S. J., Lindholm P. F., Brown K. M., Gitlin S. D., Duvall J. F., Radonovich M. F., Brady J. N. A 36-kilodalton cellular transcription factor mediates an indirect interaction of human T-cell leukemia/lymphoma virus type I TAX1 with a responsive element in the viral long terminal repeat. Mol Cell Biol. 1990 Aug;10(8):4192–4201. doi: 10.1128/mcb.10.8.4192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Metz T., Graf T. Fusion of the nuclear oncoproteins v-Myb and v-Ets is required for the leukemogenicity of E26 virus. Cell. 1991 Jul 12;66(1):95–105. doi: 10.1016/0092-8674(91)90142-l. [DOI] [PubMed] [Google Scholar]
  33. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  34. Niki M., Ohtani K., Nakamura M., Sugamura K. Multistep regulation of enhancer activity of the 21-base-pair element of human T-cell leukemia virus type I. J Virol. 1992 Jul;66(7):4348–4357. doi: 10.1128/jvi.66.7.4348-4357.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Numata N., Ohtani K., Niki M., Nakamura M., Sugamura K. Synergism between two distinct elements of the HTLV-I enhancer during activation by the trans-activator of HTLV-I. New Biol. 1991 Sep;3(9):896–906. [PubMed] [Google Scholar]
  36. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  37. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Poiesz B. J., Ruscetti F. W., Reitz M. S., Kalyanaraman V. S., Gallo R. C. Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sézary T-cell leukaemia. Nature. 1981 Nov 19;294(5838):268–271. doi: 10.1038/294268a0. [DOI] [PubMed] [Google Scholar]
  39. Poteat H. T., Chen F. Y., Kadison P., Sodroski J. G., Haseltine W. A. Protein kinase A-dependent binding of a nuclear factor to the 21-base-pair repeat of the human T-cell leukemia virus type I long terminal repeat. J Virol. 1990 Mar;64(3):1264–1270. doi: 10.1128/jvi.64.3.1264-1270.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Poteat H. T., Kadison P., McGuire K., Park L., Park R. E., Sodroski J. G., Haseltine W. A. Response of the human T-cell leukemia virus type 1 long terminal repeat to cyclic AMP. J Virol. 1989 Apr;63(4):1604–1611. doi: 10.1128/jvi.63.4.1604-1611.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Prosser H. M., Wotton D., Gegonne A., Ghysdael J., Wang S., Speck N. A., Owen M. J. A phorbol ester response element within the human T-cell receptor beta-chain enhancer. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9934–9938. doi: 10.1073/pnas.89.20.9934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Queen C., Baltimore D. Immunoglobulin gene transcription is activated by downstream sequence elements. Cell. 1983 Jul;33(3):741–748. doi: 10.1016/0092-8674(83)90016-8. [DOI] [PubMed] [Google Scholar]
  43. Ravel-Chapuis P., Leprince D., Pain B., Li R., Domenget C., Stehelin D., Samarut J., Jurdic P. v-myb and v-ets cooperate for the mitogenic stimulation of primary fibroblasts by avian E26 retrovirus. J Virol. 1991 Jul;65(7):3928–3931. doi: 10.1128/jvi.65.7.3928-3931.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Redondo J. M., Pfohl J. L., Hernandez-Munain C., Wang S., Speck N. A., Krangel M. S. Indistinguishable nuclear factor binding to functional core sites of the T-cell receptor delta and murine leukemia virus enhancers. Mol Cell Biol. 1992 Nov;12(11):4817–4823. doi: 10.1128/mcb.12.11.4817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Richardson J. H., Edwards A. J., Cruickshank J. K., Rudge P., Dalgleish A. G. In vivo cellular tropism of human T-cell leukemia virus type 1. J Virol. 1990 Nov;64(11):5682–5687. doi: 10.1128/jvi.64.11.5682-5687.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rosenblatt J. D., Chen I. S., Wachsman W. Infection with HTLV-I and HTLV-II: evolving concepts. Semin Hematol. 1988 Jul;25(3):230–246. [PubMed] [Google Scholar]
  47. Seiki M., Hattori S., Hirayama Y., Yoshida M. Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618–3622. doi: 10.1073/pnas.80.12.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Shaw J. P., Utz P. J., Durand D. B., Toole J. J., Emmel E. A., Crabtree G. R. Identification of a putative regulator of early T cell activation genes. Science. 1988 Jul 8;241(4862):202–205. doi: 10.1126/science.3260404. [DOI] [PubMed] [Google Scholar]
  49. Singh H., Sen R., Baltimore D., Sharp P. A. A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature. 1986 Jan 9;319(6049):154–158. doi: 10.1038/319154a0. [DOI] [PubMed] [Google Scholar]
  50. Smith M. R., Greene W. C. Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. J Clin Invest. 1991 Mar;87(3):761–766. doi: 10.1172/JCI115078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Sodroski J. G., Rosen C. A., Haseltine W. A. Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. Science. 1984 Jul 27;225(4660):381–385. doi: 10.1126/science.6330891. [DOI] [PubMed] [Google Scholar]
  52. Speck N. A., Renjifo B., Hopkins N. Point mutations in the Moloney murine leukemia virus enhancer identify a lymphoid-specific viral core motif and 1,3-phorbol myristate acetate-inducible element. J Virol. 1990 Feb;64(2):543–550. doi: 10.1128/jvi.64.2.543-550.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Thompson C. B., Wang C. Y., Ho I. C., Bohjanen P. R., Petryniak B., June C. H., Miesfeldt S., Zhang L., Nabel G. J., Karpinski B. cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Mol Cell Biol. 1992 Mar;12(3):1043–1053. doi: 10.1128/mcb.12.3.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Thompson C. C., Brown T. A., McKnight S. L. Convergence of Ets- and notch-related structural motifs in a heteromeric DNA binding complex. Science. 1991 Aug 16;253(5021):762–768. doi: 10.1126/science.1876833. [DOI] [PubMed] [Google Scholar]
  55. Uchiyama T., Yodoi J., Sagawa K., Takatsuki K., Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977 Sep;50(3):481–492. [PubMed] [Google Scholar]
  56. Wang C. Y., Petryniak B., Ho I. C., Thompson C. B., Leiden J. M. Evolutionarily conserved Ets family members display distinct DNA binding specificities. J Exp Med. 1992 May 1;175(5):1391–1399. doi: 10.1084/jem.175.5.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Wang S. W., Speck N. A. Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers. Mol Cell Biol. 1992 Jan;12(1):89–102. doi: 10.1128/mcb.12.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wano Y., Feinberg M., Hosking J. B., Bogerd H., Greene W. C. Stable expression of the tax gene of type I human T-cell leukemia virus in human T cells activates specific cellular genes involved in growth. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9733–9737. doi: 10.1073/pnas.85.24.9733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wasylyk B., Wasylyk C., Flores P., Begue A., Leprince D., Stehelin D. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature. 1990 Jul 12;346(6280):191–193. doi: 10.1038/346191a0. [DOI] [PubMed] [Google Scholar]
  60. Yoshida M., Miyoshi I., Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031–2035. doi: 10.1073/pnas.79.6.2031. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES