Abstract
The proto-oncogene c-myb encodes a nuclear transcription factor that binds to DNA in a sequence-specific manner and activates transcription of several viral and cellular genes. Expression of the c-myb gene is induced in mitogen- and/or antigen-stimulated T lymphocytes, which are also the preferential target cells of human T-lymphotropic virus type I (HTLV-I) in vivo and in vitro. We report here that Myb binds to the HTLV-I long terminal repeat (LTR) in four different regions in a sequence-specific manner. Electrophoretic mobility shift assay using labeled LTR fragments as well as labeled double-stranded oligonucleotides show that there are two high-affinity and two low-affinity Myb-binding sites present in the HTLV-I LTR. DNase I footprinting analysis and oligonucleotide competition experiments indicate that this binding is sequence specific. Cotransfection experiments in HeLa cells, using a Myb expression vector and chloramphenicol acetyltransferase reporter gene linked to the HTLV-I LTR, show that Myb activates HTLV-I LTR-mediated transcription by a factor of four-to sixfold. Thus, in HTLV-I-infected T cells, Myb protein binding to the HTLV-I LTR may constitute one of the signal that regulate HTLV-I transcription in vivo.
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- Biedenkapp H., Borgmeyer U., Sippel A. E., Klempnauer K. H. Viral myb oncogene encodes a sequence-specific DNA-binding activity. Nature. 1988 Oct 27;335(6193):835–837. doi: 10.1038/335835a0. [DOI] [PubMed] [Google Scholar]
- Bonnerot C., Rocancourt D., Briand P., Grimber G., Nicolas J. F. A beta-galactosidase hybrid protein targeted to nuclei as a marker for developmental studies. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6795–6799. doi: 10.1073/pnas.84.19.6795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Brenowitz M., Senear D. F., Shea M. A., Ackers G. K. Quantitative DNase footprint titration: a method for studying protein-DNA interactions. Methods Enzymol. 1986;130:132–181. doi: 10.1016/0076-6879(86)30011-9. [DOI] [PubMed] [Google Scholar]
- Churilla A. M., Braciale T. J., Braciale V. L. Regulation of T lymphocyte proliferation. Interleukin 2-mediated induction of c-myb gene expression is dependent on T lymphocyte activation state. J Exp Med. 1989 Jul 1;170(1):105–121. doi: 10.1084/jem.170.1.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cullen B. R. Trans-activation of human immunodeficiency virus occurs via a bimodal mechanism. Cell. 1986 Sep 26;46(7):973–982. doi: 10.1016/0092-8674(86)90696-3. [DOI] [PubMed] [Google Scholar]
- Dasgupta P., Saikumar P., Reddy C. D., Reddy E. P. Myb protein binds to human immunodeficiency virus 1 long terminal repeat (LTR) sequences and transactivates LTR-mediated transcription. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8090–8094. doi: 10.1073/pnas.87.20.8090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Evans J. L., Moore T. L., Kuehl W. M., Bender T., Ting J. P. Functional analysis of c-Myb protein in T-lymphocytic cell lines shows that it trans-activates the c-myc promoter. Mol Cell Biol. 1990 Nov;10(11):5747–5752. doi: 10.1128/mcb.10.11.5747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gessain A., Saal F., Giron M. L., Lasneret J., Lagaye S., Gout O., De Thé G., Sigaux F., Peries J. Cell surface phenotype and human T lymphotropic virus type 1 antigen expression in 12 T cell lines derived from peripheral blood and cerebrospinal fluid of West Indian, Guyanese and African patients with tropical spastic paraparesis. J Gen Virol. 1990 Feb;71(Pt 2):333–341. doi: 10.1099/0022-1317-71-2-333. [DOI] [PubMed] [Google Scholar]
- 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]
- Hattori T., Uchiyama T., Toibana T., Takatsuki K., Uchino H. Surface phenotype of Japanese adult T-cell leukemia cells characterized by monoclonal antibodies. Blood. 1981 Sep;58(3):645–647. [PubMed] [Google Scholar]
- Hidaka M., Inoue J., Yoshida M., Seiki M. Post-transcriptional regulator (rex) of HTLV-1 initiates expression of viral structural proteins but suppresses expression of regulatory proteins. EMBO J. 1988 Feb;7(2):519–523. doi: 10.1002/j.1460-2075.1988.tb02840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Inoue J., Yoshida M., Seiki M. Transcriptional (p40x) and post-transcriptional (p27x-III) regulators are required for the expression and replication of human T-cell leukemia virus type I genes. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3653–3657. doi: 10.1073/pnas.84.11.3653. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Klempnauer K. H., Arnold H., Biedenkapp H. Activation of transcription by v-myb: evidence for two different mechanisms. Genes Dev. 1989 Oct;3(10):1582–1589. doi: 10.1101/gad.3.10.1582. [DOI] [PubMed] [Google Scholar]
- Majors J. The structure and function of retroviral long terminal repeats. Curr Top Microbiol Immunol. 1990;157:49–92. doi: 10.1007/978-3-642-75218-6_3. [DOI] [PubMed] [Google Scholar]
- 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]
- Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
- McFarlin D. E., Koprowski H. Neurological disorders associated with HTLV-1. Curr Top Microbiol Immunol. 1990;160:100–119. [PubMed] [Google Scholar]
- Mitchell P. J., Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. doi: 10.1126/science.2667136. [DOI] [PubMed] [Google Scholar]
- Montagne J., Béraud C., Crenon I., Lombard-Platet G., Gazzolo L., Sergeant A., Jalinot P. Tax1 induction of the HTLV-I 21 bp enhancer requires cooperation between two cellular DNA-binding proteins. EMBO J. 1990 Mar;9(3):957–964. doi: 10.1002/j.1460-2075.1990.tb08194.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakagoshi H., Nagase T., Kanei-Ishii C., Ueno Y., Ishii S. Binding of the c-myb proto-oncogene product to the simian virus 40 enhancer stimulates transcription. J Biol Chem. 1990 Feb 25;265(6):3479–3483. [PubMed] [Google Scholar]
- Ness S. A., Marknell A., Graf T. The v-myb oncogene product binds to and activates the promyelocyte-specific mim-1 gene. Cell. 1989 Dec 22;59(6):1115–1125. doi: 10.1016/0092-8674(89)90767-8. [DOI] [PubMed] [Google Scholar]
- Nyborg J. K., Dynan W. S., Chen I. S., Wachsman W. Binding of host-cell factors to DNA sequences in the long terminal repeat of human T-cell leukemia virus type I: implications for viral gene expression. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1457–1461. doi: 10.1073/pnas.85.5.1457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nyborg J. K., Matthews M. A., Yucel J., Walls L., Golde W. T., Dynan W. S., Wachsman W. Interaction of host cell proteins with the human T-cell leukemia virus type I transcriptional control region. II. A comprehensive map of protein-binding sites facilitates construction of a simple chimeric promoter responsive to the viral tax2 gene product. J Biol Chem. 1990 May 15;265(14):8237–8242. [PubMed] [Google Scholar]
- 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]
- Reddy E. P., Mettus R. V., DeFreitas E., Wroblewska Z., Cisco M., Koprowski H. Molecular cloning of human T-cell lymphotrophic virus type I-like proviral genome from the peripheral lymphocyte DNA of a patient with chronic neurologic disorders. Proc Natl Acad Sci U S A. 1988 May;85(10):3599–3603. doi: 10.1073/pnas.85.10.3599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Román G. C., Osame M. Identity of HTLV-I-associated tropical spastic paraparesis and HTLV-I-associated myelopathy. Lancet. 1988 Mar 19;1(8586):651–651. doi: 10.1016/s0140-6736(88)91452-3. [DOI] [PubMed] [Google Scholar]
- Sakura H., Kanei-Ishii C., Nagase T., Nakagoshi H., Gonda T. J., Ishii S. Delineation of three functional domains of the transcriptional activator encoded by the c-myb protooncogene. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5758–5762. doi: 10.1073/pnas.86.15.5758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Seth A., Lapis P., Vande Woude G. F., Papas T. High-level expression vectors to synthesize unfused proteins in Escherichia coli. Gene. 1986;42(1):49–57. doi: 10.1016/0378-1119(86)90149-6. [DOI] [PubMed] [Google Scholar]
- 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]
- Tan T. H., Horikoshi M., Roeder R. G. Purification and characterization of multiple nuclear factors that bind to the TAX-inducible enhancer within the human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1989 Apr;9(4):1733–1745. doi: 10.1128/mcb.9.4.1733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tan T. H., Jia R., Roeder R. G. Utilization of signal transduction pathway by the human T-cell leukemia virus type I transcriptional activator tax. J Virol. 1989 Sep;63(9):3761–3768. doi: 10.1128/jvi.63.9.3761-3768.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Torelli G., Selleri L., Donelli A., Ferrari S., Emilia G., Venturelli D., Moretti L., Torelli U. Activation of c-myb expression by phytohemagglutinin stimulation in normal human T lymphocytes. Mol Cell Biol. 1985 Oct;5(10):2874–2877. doi: 10.1128/mcb.5.10.2874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsujimoto A., Nyunoya H., Morita T., Sato T., Shimotohno K. Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I. J Virol. 1991 Mar;65(3):1420–1426. doi: 10.1128/jvi.65.3.1420-1426.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weston K., Bishop J. M. Transcriptional activation by the v-myb oncogene and its cellular progenitor, c-myb. Cell. 1989 Jul 14;58(1):85–93. doi: 10.1016/0092-8674(89)90405-4. [DOI] [PubMed] [Google Scholar]
- Wong-Staal F., Gallo R. C. Human T-lymphotropic retroviruses. Nature. 1985 Oct 3;317(6036):395–403. doi: 10.1038/317395a0. [DOI] [PubMed] [Google Scholar]
- Xu Y. L., Adya N., Siores E., Gao Q. S., Giam C. Z. Cellular factors involved in transcription and Tax-mediated trans-activation directed by the TGACGT motifs in human T-cell leukemia virus type I promoter. J Biol Chem. 1990 Nov 25;265(33):20285–20292. [PubMed] [Google Scholar]
- Yoshimura T., Fujisawa J., Yoshida M. Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid domain. EMBO J. 1990 Aug;9(8):2537–2542. doi: 10.1002/j.1460-2075.1990.tb07434.x. [DOI] [PMC free article] [PubMed] [Google Scholar]