Abstract
Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) have two nonstructural trans-acting regulatory genes, tax and rex, located in the 3' region of the viral genome. The tax gene product (HTLV-I p40tax and HTLV-II p37tax) is the transcriptional activator of the viral long terminal repeat. The rex gene encodes two protein products, p27rex/p21rex and p26rex/p24rex in HTLV-I and HTLV-II, respectively. Rex acts posttranscriptionally to facilitate accumulation of full-length gag/pol and singly spliced env mRNA in the cytoplasm of HTLV-infected cells. Previous studies showed that the first ATG of the rex gene is critical for Rex production and function. The importance of the internal ATGs to Rex function is not known. However, in vitro mutagenesis of the HTLV-I rex gene has provided indirect evidence which suggests that p21rex, and by analogy HTLV-II p24rex, results from initiation at an internal AUG of the tax/rex mRNA. By using an infectious molecular clone of HTLV-II, we investigated the importance of the internal ATGs of the rex gene on Rex protein production and function. Our results indicate that p24rex of HTLV-II is not initiated at an internal AUG and that the internal methionine codons are not crucial to the function of the rex gene and, ultimately, the transforming properties of the virus.
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- Ballard D. W., Böhnlein E., Lowenthal J. W., Wano Y., Franza B. R., Greene W. C. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science. 1988 Sep 23;241(4873):1652–1655. doi: 10.1126/science.241.4873.1652. [DOI] [PubMed] [Google Scholar]
- Berk A. J., Sharp P. A. Sizing and mapping of early adenovirus mRNAs by gel electrophoresis of S1 endonuclease-digested hybrids. Cell. 1977 Nov;12(3):721–732. doi: 10.1016/0092-8674(77)90272-0. [DOI] [PubMed] [Google Scholar]
- Cann A. J., Rosenblatt J. D., Wachsman W., Shah N. P., Chen I. S. Identification of the gene responsible for human T-cell leukaemia virus transcriptional regulation. Nature. 1985 Dec 12;318(6046):571–574. doi: 10.1038/318571a0. [DOI] [PubMed] [Google Scholar]
- Chen I. S., Cann A. J., Shah N. P., Gaynor R. B. Functional relation between HTLV-II x and adenovirus E1A proteins in transcriptional activation. Science. 1985 Nov 1;230(4725):570–573. doi: 10.1126/science.2996140. [DOI] [PubMed] [Google Scholar]
- Chen I. S., McLaughlin J., Gasson J. C., Clark S. C., Golde D. W. Molecular characterization of genome of a novel human T-cell leukaemia virus. Nature. 1983 Oct 6;305(5934):502–505. doi: 10.1038/305502a0. [DOI] [PubMed] [Google Scholar]
- Chen I. S., Quan S. G., Golde D. W. Human T-cell leukemia virus type II transforms normal human lymphocytes. Proc Natl Acad Sci U S A. 1983 Nov;80(22):7006–7009. doi: 10.1073/pnas.80.22.7006. [DOI] [PMC free article] [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]
- 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]
- Fujisawa J., Seiki M., Kiyokawa T., Yoshida M. Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2277–2281. doi: 10.1073/pnas.82.8.2277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Goh W. C., Sodroski J., Rosen C., Essex M., Haseltine W. A. Subcellular localization of the product of the long open reading frame of human T-cell leukemia virus type I. Science. 1985 Mar 8;227(4691):1227–1228. doi: 10.1126/science.2983419. [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]
- Grassmann R., Dengler C., Müller-Fleckenstein I., Fleckenstein B., McGuire K., Dokhelar M. C., Sodroski J. G., Haseltine W. A. Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci U S A. 1989 May;86(9):3351–3355. doi: 10.1073/pnas.86.9.3351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Green P. L., Kaehler D. A., Bennett L. M., Risser R. Multiple steps are required for the induction of tumors by Abelson murine leukemia virus. J Virol. 1989 May;63(5):1989–1994. doi: 10.1128/jvi.63.5.1989-1994.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hanly S. M., Rimsky L. T., Malim M. H., Kim J. H., Hauber J., Duc Dodon M., Le S. Y., Maizel J. V., Cullen B. R., Greene W. C. Comparative analysis of the HTLV-I Rex and HIV-1 Rev trans-regulatory proteins and their RNA response elements. Genes Dev. 1989 Oct;3(10):1534–1544. doi: 10.1101/gad.3.10.1534. [DOI] [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]
- Hinuma Y., Nagata K., Hanaoka M., Nakai M., Matsumoto T., Kinoshita K. I., Shirakawa S., Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6476–6480. doi: 10.1073/pnas.78.10.6476. [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]
- Inoue J., Seiki M., Yoshida M. The second pX product p27 chi-III of HTLV-1 is required for gag gene expression. FEBS Lett. 1986 Dec 15;209(2):187–190. doi: 10.1016/0014-5793(86)81108-5. [DOI] [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]
- Kalyanaraman V. S., Sarngadharan M. G., Robert-Guroff M., Miyoshi I., Golde D., Gallo R. C. A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science. 1982 Nov 5;218(4572):571–573. doi: 10.1126/science.6981847. [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]
- Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee H., Swanson P., Shorty V. S., Zack J. A., Rosenblatt J. D., Chen I. S. High rate of HTLV-II infection in seropositive i.v. drug abusers in New Orleans. Science. 1989 Apr 28;244(4903):471–475. doi: 10.1126/science.2655084. [DOI] [PubMed] [Google Scholar]
- Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
- Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miwa M., Shimotohno K., Hoshino H., Fujino M., Sugimura T. Detection of pX proteins in human T-cell leukemia virus (HTLV)-infected cells by using antibody against peptide deduced from sequences of X-IV DNA of HTLV-I and Xc DNA of HTLV-II proviruses. Gan. 1984 Sep;75(9):752–755. [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]
- Nimer S. D., Gasson J. C., Hu K., Smalberg I., Williams J. L., Chen I. S., Rosenblatt J. D. Activation of the GM-CSF promoter by HTLV-I and -II tax proteins. Oncogene. 1989 Jun;4(6):671–676. [PubMed] [Google Scholar]
- Poiesz B. J., Ruscetti F. W., Mier J. W., Woods A. M., Gallo R. C. T-cell lines established from human T-lymphocytic neoplasias by direct response to T-cell growth factor. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6815–6819. doi: 10.1073/pnas.77.11.6815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Popovic M., Lange-Wantzin G., Sarin P. S., Mann D., Gallo R. C. Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5402–5406. doi: 10.1073/pnas.80.17.5402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rice N. R., Stephens R. M., Couez D., Deschamps J., Kettmann R., Burny A., Gilden R. V. The nucleotide sequence of the env gene and post-env region of bovine leukemia virus. Virology. 1984 Oct 15;138(1):82–93. doi: 10.1016/0042-6822(84)90149-1. [DOI] [PubMed] [Google Scholar]
- Robert-Guroff M., Weiss S. H., Giron J. A., Jennings A. M., Ginzburg H. M., Margolis I. B., Blattner W. A., Gallo R. C. Prevalence of antibodies to HTLV-I, -II, and -III in intravenous drug abusers from an AIDS endemic region. JAMA. 1986 Jun 13;255(22):3133–3137. [PubMed] [Google Scholar]
- Rosenblatt J. D., Cann A. J., Slamon D. J., Smalberg I. S., Shah N. P., Fujii J., Wachsman W., Chen I. S. HTLV-II transactivation is regulated by the overlapping tax/rex nonstructural genes. Science. 1988 May 13;240(4854):916–919. doi: 10.1126/science.2834826. [DOI] [PubMed] [Google Scholar]
- Rosenblatt J. D., Golde D. W., Wachsman W., Giorgi J. V., Jacobs A., Schmidt G. M., Quan S., Gasson J. C., Chen I. S. A second isolate of HTLV-II associated with atypical hairy-cell leukemia. N Engl J Med. 1986 Aug 7;315(6):372–377. doi: 10.1056/NEJM198608073150606. [DOI] [PubMed] [Google Scholar]
- Sanger F., Coulson A. R., Barrell B. G., Smith A. J., Roe B. A. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. doi: 10.1016/0022-2836(80)90196-5. [DOI] [PubMed] [Google Scholar]
- Saxon A., Stevens R. H., Golde D. W. T-lymphocyte variant of hairy-cell leukemia. Ann Intern Med. 1978 Mar;88(3):323–326. doi: 10.7326/0003-4819-88-3-323. [DOI] [PubMed] [Google Scholar]
- Seiki M., Eddy R., Shows T. B., Yoshida M. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells. Nature. 1984 Jun 14;309(5969):640–642. doi: 10.1038/309640a0. [DOI] [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]
- Shima H., Takano M., Shimotohno K., Miwa M. Identification of p26Xb and p24Xb of human T-cell leukemia virus type II. FEBS Lett. 1986 Dec 15;209(2):289–294. doi: 10.1016/0014-5793(86)81129-2. [DOI] [PubMed] [Google Scholar]
- Shimotohno K., Takahashi Y., Shimizu N., Gojobori T., Golde D. W., Chen I. S., Miwa M., Sugimura T. Complete nucleotide sequence of an infectious clone of human T-cell leukemia virus type II: an open reading frame for the protease gene. Proc Natl Acad Sci U S A. 1985 May;82(10):3101–3105. doi: 10.1073/pnas.82.10.3101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Slamon D. J., Press M. F., Souza L. M., Murdock D. C., Cline M. J., Golde D. W., Gasson J. C., Chen I. S. Studies of the putative transforming protein of the type I human T-cell leukemia virus. Science. 1985 Jun 21;228(4706):1427–1430. doi: 10.1126/science.2990027. [DOI] [PubMed] [Google Scholar]
- 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]
- Tanaka A., Takahashi C., Yamaoka S., Nosaka T., Maki M., Hatanaka M. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1071–1075. doi: 10.1073/pnas.87.3.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tedder R. S., Shanson D. C., Jeffries D. J., Cheingsong-Popov R., Clapham P., Dalgleish A., Nagy K., Weiss R. A. Low prevalence in the UK of HTLV-I and HTLV-II infection in subjects with AIDS, with extended lymphadenopathy, and at risk of AIDS. Lancet. 1984 Jul 21;2(8395):125–128. doi: 10.1016/s0140-6736(84)91046-8. [DOI] [PubMed] [Google Scholar]
- 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]
- Yamamoto N., Okada M., Koyanagi Y., Kannagi M., Hinuma Y. Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line. Science. 1982 Aug 20;217(4561):737–739. doi: 10.1126/science.6980467. [DOI] [PubMed] [Google Scholar]





