Abstract
Transcriptional activation of the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) by viral protein p40x requires a 21-base-pair (bp) sequence which is repeated three times within the LTR. This sequence contains a core octanucleotide (TGACGTCT) which has been attributed to be a cyclic-AMP (cAMP)-responsive element. We demonstrate here that the HTLV-I LTR can be specifically stimulated by cAMP regulators and have identified four proteins in HeLa cells that bind to the HTLV-I 21-bp sequence. We correlated the in vitro binding and transcriptional activity of one of these cellular factors (Mr, 180,000) to the trans-activation of the HTLV-I LTR by p40x. Point mutations were generated within the cAMP octanucleotide of the HTLV-I 21-bp sequence that simultaneously abolished biological responsiveness to trans-activation by p40x and to stimulation by cAMP. We found that these mutations also eliminated the binding of the 180-kilodalton HeLa factor to the HTLV-I 21-bp element. In the absence of a demonstrable DNA-binding property for p40x, we hypothesize that cellular proteins are involved, possibly through signal transduction pathways, in its trans-activation of responsive promoters.
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Selected References
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- Altman R., Harrich D., Garcia J. A., Gaynor R. B. Human T-cell leukemia virus types I and II exhibit different DNase I protection patterns. J Virol. 1988 Apr;62(4):1339–1346. doi: 10.1128/jvi.62.4.1339-1346.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
- Berk A. J., Lee F., Harrison T., Williams J., Sharp P. A. Pre-early adenovirus 5 gene product regulates synthesis of early viral messenger RNAs. Cell. 1979 Aug;17(4):935–944. doi: 10.1016/0092-8674(79)90333-7. [DOI] [PubMed] [Google Scholar]
- Brady J., Jeang K. T., Duvall J., Khoury G. Identification of p40x-responsive regulatory sequences within the human T-cell leukemia virus type I long terminal repeat. J Virol. 1987 Jul;61(7):2175–2181. doi: 10.1128/jvi.61.7.2175-2181.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chodosh L. A., Carthew R. W., Sharp P. A. A single polypeptide possesses the binding and transcription activities of the adenovirus major late transcription factor. Mol Cell Biol. 1986 Dec;6(12):4723–4733. doi: 10.1128/mcb.6.12.4723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Comb M., Birnberg N. C., Seasholtz A., Herbert E., Goodman H. M. A cyclic AMP- and phorbol ester-inducible DNA element. 1986 Sep 25-Oct 1Nature. 323(6086):353–356. doi: 10.1038/323353a0. [DOI] [PubMed] [Google Scholar]
- Cross S. L., Feinberg M. B., Wolf J. B., Holbrook N. J., Wong-Staal F., Leonard W. J. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. doi: 10.1016/0092-8674(87)90754-9. [DOI] [PubMed] [Google Scholar]
- Derse D. Bovine leukemia virus transcription is controlled by a virus-encoded trans-acting factor and by cis-acting response elements. J Virol. 1987 Aug;61(8):2462–2471. doi: 10.1128/jvi.61.8.2462-2471.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DesGroseillers L., Rassart E., Jolicoeur P. Thymotropism of murine leukemia virus is conferred by its long terminal repeat. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4203–4207. doi: 10.1073/pnas.80.14.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DesGroseillers L., Rassart E., Jolicoeur P. Thymotropism of murine leukemia virus is conferred by its long terminal repeat. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4203–4207. doi: 10.1073/pnas.80.14.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Dynan W. S., Tjian R. Isolation of transcription factors that discriminate between different promoters recognized by RNA polymerase II. Cell. 1983 Mar;32(3):669–680. doi: 10.1016/0092-8674(83)90053-3. [DOI] [PubMed] [Google Scholar]
- Felber B. K., Paskalis H., Kleinman-Ewing C., Wong-Staal F., Pavlakis G. N. The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science. 1985 Aug 16;229(4714):675–679. doi: 10.1126/science.2992082. [DOI] [PubMed] [Google Scholar]
- Franza B. R., Jr, Josephs S. F., Gilman M. Z., Ryan W., Clarkson B. Characterization of cellular proteins recognizing the HIV enhancer using a microscale DNA-affinity precipitation assay. 1987 Nov 26-Dec 2Nature. 330(6146):391–395. doi: 10.1038/330391a0. [DOI] [PubMed] [Google Scholar]
- Fried M., Crothers D. M. Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis. Nucleic Acids Res. 1981 Dec 11;9(23):6505–6525. doi: 10.1093/nar/9.23.6505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fujisawa J., Seiki M., Sato M., Yoshida M. A transcriptional enhancer sequence of HTLV-I is responsible for trans-activation mediated by p40 chi HTLV-I. EMBO J. 1986 Apr;5(4):713–718. doi: 10.1002/j.1460-2075.1986.tb04272.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Galas D. J., Schmitz A. DNAse footprinting: a simple method for the detection of protein-DNA binding specificity. Nucleic Acids Res. 1978 Sep;5(9):3157–3170. doi: 10.1093/nar/5.9.3157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gallo R. C. The first human retrovirus. Sci Am. 1986 Dec;255(6):88–98. doi: 10.1038/scientificamerican1286-88. [DOI] [PubMed] [Google Scholar]
- Garner M. M., Revzin A. A gel electrophoresis method for quantifying the binding of proteins to specific DNA regions: application to components of the Escherichia coli lactose operon regulatory system. Nucleic Acids Res. 1981 Jul 10;9(13):3047–3060. doi: 10.1093/nar/9.13.3047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gaynor R. B., Hillman D., Berk A. J. Adenovirus early region 1A protein activates transcription of a nonviral gene introduced into mammalian cells by infection or transfection. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1193–1197. doi: 10.1073/pnas.81.4.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gendelman H. E., Phelps W., Feigenbaum L., Ostrove J. M., Adachi A., Howley P. M., Khoury G., Ginsberg H. S., Martin M. A. Trans-activation of the human immunodeficiency virus long terminal repeat sequence by DNA viruses. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9759–9763. doi: 10.1073/pnas.83.24.9759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Giam C. Z., Nerenberg M., Khoury G., Jay G. Expression of the complete human T-cell leukemia virus type I pX coding sequence as a functional protein in Escherichia coli. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7192–7196. doi: 10.1073/pnas.83.19.7192. [DOI] [PMC free article] [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]
- Gottesman M. M. Genetic approaches to cyclic AMP effects in cultured mammalian cells. Cell. 1980 Nov;22(2 Pt 2):329–330. doi: 10.1016/0092-8674(80)90342-6. [DOI] [PubMed] [Google Scholar]
- Hardy S., Shenk T. Adenoviral control regions activated by E1A and the cAMP response element bind to the same factor. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4171–4175. doi: 10.1073/pnas.85.12.4171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haseltine W. A., Sodroski J., Patarca R., Briggs D., Perkins D., Wong-Staal F. Structure of 3' terminal region of type II human T lymphotropic virus: evidence for new coding region. Science. 1984 Jul 27;225(4660):419–421. doi: 10.1126/science.6330894. [DOI] [PubMed] [Google Scholar]
- Holbrook N. J., Luethy J. D., Kin J. Transient expression of foreign genes in lymphoid cells is enhanced by phorbol ester. Mol Cell Biol. 1987 Jul;7(7):2610–2613. doi: 10.1128/mcb.7.7.2610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Inoue J., Seiki M., Taniguchi T., Tsuru S., Yoshida M. Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 1986 Nov;5(11):2883–2888. doi: 10.1002/j.1460-2075.1986.tb04583.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jeang K. T., Giam C. Z., Nerenberg M., Khoury G. Abundant synthesis of functional human T-cell leukemia virus type I p40x protein in eucaryotic cells by using a baculovirus expression vector. J Virol. 1987 Mar;61(3):708–713. doi: 10.1128/jvi.61.3.708-713.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones N., Shenk T. An adenovirus type 5 early gene function regulates expression of other early viral genes. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3665–3669. doi: 10.1073/pnas.76.8.3665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Josephs S. F., Wong-Staal F., Manzari V., Gallo R. C., Sodroski J. G., Trus M. D., Perkins D., Patarca R., Haseltine W. A. Long terminal repeat structure of an American isolate of type I human T-cell leukemia virus. Virology. 1984 Dec;139(2):340–345. doi: 10.1016/0042-6822(84)90379-9. [DOI] [PubMed] [Google Scholar]
- Kingston R. E., Baldwin A. S., Sharp P. A. Transcription control by oncogenes. Cell. 1985 May;41(1):3–5. doi: 10.1016/0092-8674(85)90049-2. [DOI] [PubMed] [Google Scholar]
- Kiyokawa T., Seiki M., Iwashita S., Imagawa K., Shimizu F., Yoshida M. p27x-III and p21x-III, proteins encoded by the pX sequence of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8359–8363. doi: 10.1073/pnas.82.24.8359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Laimins L. A., Gruss P., Pozzatti R., Khoury G. Characterization of enhancer elements in the long terminal repeat of Moloney murine sarcoma virus. J Virol. 1984 Jan;49(1):183–189. doi: 10.1128/jvi.49.1.183-189.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Laimins L., Holmgren-König M., Khoury G. Transcriptional "silencer" element in rat repetitive sequences associated with the rat insulin 1 gene locus. Proc Natl Acad Sci U S A. 1986 May;83(10):3151–3155. doi: 10.1073/pnas.83.10.3151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee T. H., Coligan J. E., Sodroski J. G., Haseltine W. A., Salahuddin S. Z., Wong-Staal F., Gallo R. C., Essex M. Antigens encoded by the 3'-terminal region of human T-cell leukemia virus: evidence for a functional gene. Science. 1984 Oct 5;226(4670):57–61. doi: 10.1126/science.6089350. [DOI] [PubMed] [Google Scholar]
- Lee W., Mitchell P., Tjian R. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell. 1987 Jun 19;49(6):741–752. doi: 10.1016/0092-8674(87)90612-x. [DOI] [PubMed] [Google Scholar]
- Lenz J., Celander D., Crowther R. L., Patarca R., Perkins D. W., Haseltine W. A. Determination of the leukaemogenicity of a murine retrovirus by sequences within the long terminal repeat. 1984 Mar 29-Apr 4Nature. 308(5958):467–470. doi: 10.1038/308467a0. [DOI] [PubMed] [Google Scholar]
- Leza M. A., Hearing P. Cellular transcription factor binds to adenovirus early region promoters and to a cyclic AMP response element. J Virol. 1988 Aug;62(8):3003–3013. doi: 10.1128/jvi.62.8.3003-3013.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin Y. S., Green M. R. Interaction of a common cellular transcription factor, ATF, with regulatory elements in both E1a- and cyclic AMP-inducible promoters. Proc Natl Acad Sci U S A. 1988 May;85(10):3396–3400. doi: 10.1073/pnas.85.10.3396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mamoun R. Z., Astier-Gin T., Kettmann R., Deschamps J., Rebeyrotte N., Guillemain B. J. The pX region of the bovine leukemia virus is transcribed as a 2.1-kilobase mRNA. J Virol. 1985 May;54(2):625–629. doi: 10.1128/jvi.54.2.625-629.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Manley J. L., Fire A., Cano A., Sharp P. A., Gefter M. L. DNA-dependent transcription of adenovirus genes in a soluble whole-cell extract. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3855–3859. doi: 10.1073/pnas.77.7.3855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Montminy M. R., Bilezikjian L. M. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987 Jul 9;328(6126):175–178. doi: 10.1038/328175a0. [DOI] [PubMed] [Google Scholar]
- Montminy M. R., Sevarino K. A., Wagner J. A., Mandel G., Goodman R. H. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6682–6686. doi: 10.1073/pnas.83.18.6682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nagashima K., Yoshida M., Seiki M. A single species of pX mRNA of human T-cell leukemia virus type I encodes trans-activator p40x and two other phosphoproteins. J Virol. 1986 Nov;60(2):394–399. doi: 10.1128/jvi.60.2.394-399.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nerenberg M., Hinrichs S. H., Reynolds R. K., Khoury G., Jay G. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science. 1987 Sep 11;237(4820):1324–1329. doi: 10.1126/science.2888190. [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]
- Paskalis H., Felber B. K., Pavlakis G. N. Cis-acting sequences responsible for the transcriptional activation of human T-cell leukemia virus type I constitute a conditional enhancer. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6558–6562. doi: 10.1073/pnas.83.17.6558. [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]
- Seiki M., Hattori S., Yoshida M. Human adult T-cell leukemia virus: molecular cloning of the provirus DNA and the unique terminal structure. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6899–6902. doi: 10.1073/pnas.79.22.6899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seiki M., Inoue J., Takeda T., Yoshida M. Direct evidence that p40x of human T-cell leukemia virus type I is a trans-acting transcriptional activator. EMBO J. 1986 Mar;5(3):561–565. doi: 10.1002/j.1460-2075.1986.tb04247.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shimotohno K., Takano M., Teruuchi T., Miwa M. Requirement of multiple copies of a 21-nucleotide sequence in the U3 regions of human T-cell leukemia virus type I and type II long terminal repeats for trans-acting activation of transcription. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8112–8116. doi: 10.1073/pnas.83.21.8112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shimotohno K., Wachsman W., Takahashi Y., Golde D. W., Miwa M., Sugimura T., Chen I. S. Nucleotide sequence of the 3' region of an infectious human T-cell leukemia virus type II genome. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6657–6661. doi: 10.1073/pnas.81.21.6657. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Short N. J. Regulation of transcription. Flexible interpretation. Nature. 1988 Jul 21;334(6179):192–193. doi: 10.1038/334192a0. [DOI] [PubMed] [Google Scholar]
- Simons A., Tils D., von Wilcken-Bergmann B., Müller-Hill B. Possible ideal lac operator: Escherichia coli lac operator-like sequences from eukaryotic genomes lack the central G X C pair. Proc Natl Acad Sci U S A. 1984 Mar;81(6):1624–1628. doi: 10.1073/pnas.81.6.1624. [DOI] [PMC free article] [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]
- Spalholz B. A., Lambert P. F., Yee C. L., Howley P. M. Bovine papillomavirus transcriptional regulation: localization of the E2-responsive elements of the long control region. J Virol. 1987 Jul;61(7):2128–2137. doi: 10.1128/jvi.61.7.2128-2137.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Svensson C., Akusjärvi G. Adenovirus 2 early region 1A stimulates expression of both viral and cellular genes. EMBO J. 1984 Apr;3(4):789–794. doi: 10.1002/j.1460-2075.1984.tb01886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Treisman R., Green M. R., Maniatis T. cis and trans activation of globin gene transcription in transient assays. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7428–7432. doi: 10.1073/pnas.80.24.7428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsukada T., Fink J. S., Mandel G., Goodman R. H. Identification of a region in the human vasoactive intestinal polypeptide gene responsible for regulation by cyclic AMP. J Biol Chem. 1987 Jun 25;262(18):8743–8747. [PubMed] [Google Scholar]
- Weber I. T., Takio K., Titani K., Steitz T. A. The cAMP-binding domains of the regulatory subunit of cAMP-dependent protein kinase and the catabolite gene activator protein are homologous. Proc Natl Acad Sci U S A. 1982 Dec;79(24):7679–7683. doi: 10.1073/pnas.79.24.7679. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wildeman A. G., Sassone-Corsi P., Grundström T., Zenke M., Chambon P. Stimulation of in vitro transcription from the SV40 early promoter by the enhancer involves a specific trans-acting factor. EMBO J. 1984 Dec 20;3(13):3129–3133. doi: 10.1002/j.1460-2075.1984.tb02269.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu C., Wilson S., Walker B., Dawid I., Paisley T., Zimarino V., Ueda H. Purification and properties of Drosophila heat shock activator protein. Science. 1987 Nov 27;238(4831):1247–1253. doi: 10.1126/science.3685975. [DOI] [PubMed] [Google Scholar]