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. 1989 Nov 25;17(22):9173–9184. doi: 10.1093/nar/17.22.9173

Identification of multiple cis-elements and trans-acting factors involved in the induced expression of human IL-2 gene.

H Shibuya 1, T Taniguchi 1
PMCID: PMC335122  PMID: 2555786

Abstract

Regulated expression of interleukin-2 (IL-2) gene constitutes an essential part in the clonal proliferation of activated T lymphocytes (T-cells). In order to gain insight on the mechanism(s) of the IL-2 gene induction, deletions were introduced in the human IL-2 gene 5'-flanking region and the mitogen inducibility of each deletion mutant was examined in cultured T cell lines. At least four functional regions were identified, they contain potential binding sites for several transcription factors including one NF-kappa B and two octamer binding factor sites. Whereas each of the functional regions (or elements) is required for the maximal induction of the IL-2 gene by mitogen, one such region was found to be dispensable for activation by the HTLV-1-encoded trans-activator, tax-1. Furthermore, the potent immunosuppressive agent, cyclosporin A was found to inhibit the gene induction by mitogen, but not by tax-1.

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Selected References

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

  1. Bickel M., Tsuda H., Amstad P., Evequoz V., Mergenhagen S. E., Wahl S. M., Pluznik D. H. Differential regulation of colony-stimulating factors and interleukin 2 production by cyclosporin A. Proc Natl Acad Sci U S A. 1987 May;84(10):3274–3277. doi: 10.1073/pnas.84.10.3274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Böhnlein E., Lowenthal J. W., Siekevitz M., Ballard D. W., Franza B. R., Greene W. C. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell. 1988 Jun 3;53(5):827–836. doi: 10.1016/0092-8674(88)90099-2. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Doi T., Hatakeyama M., Itoh S., Taniguchi T. Transient induction of IL-2 receptor in cultured T cell lines by HTLV-1 LTR-linked tax-1 gene. EMBO J. 1989 Jul;8(7):1953–1958. doi: 10.1002/j.1460-2075.1989.tb03600.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Durand D. B., Bush M. R., Morgan J. G., Weiss A., Crabtree G. R. A 275 basepair fragment at the 5' end of the interleukin 2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor. J Exp Med. 1987 Feb 1;165(2):395–407. doi: 10.1084/jem.165.2.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Durand D. B., Shaw J. P., Bush M. R., Replogle R. E., Belagaje R., Crabtree G. R. Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol. 1988 Apr;8(4):1715–1724. doi: 10.1128/mcb.8.4.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Elliott J. F., Lin Y., Mizel S. B., Bleackley R. C., Harnish D. G., Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984 Dec 21;226(4681):1439–1441. doi: 10.1126/science.6334364. [DOI] [PubMed] [Google Scholar]
  8. Fujita T., Miyamoto M., Kimura Y., Hammer J., Taniguchi T. Involvement of a cis-element that binds an H2TF-1/NF kappa B like factor(s) in the virus-induced interferon-beta gene expression. Nucleic Acids Res. 1989 May 11;17(9):3335–3346. doi: 10.1093/nar/17.9.3335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fujita T., Sakakibara J., Sudo Y., Miyamoto M., Kimura Y., Taniguchi T. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J. 1988 Nov;7(11):3397–3405. doi: 10.1002/j.1460-2075.1988.tb03213.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fujita T., Shibuya H., Hotta H., Yamanishi K., Taniguchi T. Interferon-beta gene regulation: tandemly repeated sequences of a synthetic 6 bp oligomer function as a virus-inducible enhancer. Cell. 1987 May 8;49(3):357–367. doi: 10.1016/0092-8674(87)90288-1. [DOI] [PubMed] [Google Scholar]
  11. Fujita T., Shibuya H., Ohashi T., Yamanishi K., Taniguchi T. Regulation of human interleukin-2 gene: functional DNA sequences in the 5' flanking region for the gene expression in activated T lymphocytes. Cell. 1986 Aug 1;46(3):401–405. doi: 10.1016/0092-8674(86)90660-4. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Granelli-Piperno A., Inaba K., Steinman R. M. Stimulation of lymphokine release from T lymphoblasts. Requirement for mRNA synthesis and inhibition by cyclosporin A. J Exp Med. 1984 Dec 1;160(6):1792–1802. doi: 10.1084/jem.160.6.1792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Greene W. C., Böhnlein E., Ballard D. W. HIV-1, HTLV-1 and normal T-cell growth: transcriptional strategies and surprises. Immunol Today. 1989 Aug;10(8):272–278. doi: 10.1016/0167-5699(89)90141-2. [DOI] [PubMed] [Google Scholar]
  15. Greene W. C., Leonard W. J. The human interleukin-2 receptor. Annu Rev Immunol. 1986;4:69–95. doi: 10.1146/annurev.iy.04.040186.000441. [DOI] [PubMed] [Google Scholar]
  16. Hatakeyama M., Tsudo M., Minamoto S., Kono T., Doi T., Miyata T., Miyasaka M., Taniguchi T. Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. Science. 1989 May 5;244(4904):551–556. doi: 10.1126/science.2785715. [DOI] [PubMed] [Google Scholar]
  17. Hoyos B., Ballard D. W., Böhnlein E., Siekevitz M., Greene W. C. Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression. Science. 1989 Apr 28;244(4903):457–460. doi: 10.1126/science.2497518. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Krönke M., Leonard W. J., Depper J. M., Arya S. K., Wong-Staal F., Gallo R. C., Waldmann T. A., Greene W. C. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214–5218. doi: 10.1073/pnas.81.16.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Müller M. M., Ruppert S., Schaffner W., Matthias P. A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature. 1988 Dec 8;336(6199):544–551. doi: 10.1038/336544a0. [DOI] [PubMed] [Google Scholar]
  23. Nabel G. J., Gorka C., Baltimore D. T-cell-specific expression of interleukin 2: evidence for a negative regulatory site. Proc Natl Acad Sci U S A. 1988 May;85(9):2934–2938. doi: 10.1073/pnas.85.9.2934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Robertson M. Homoeo boxes, POU proteins and the limits to promiscuity. Nature. 1988 Dec 8;336(6199):522–524. doi: 10.1038/336522a0. [DOI] [PubMed] [Google Scholar]
  25. Serfling E., Barthelmäs R., Pfeuffer I., Schenk B., Zarius S., Swoboda R., Mercurio F., Karin M. Ubiquitous and lymphocyte-specific factors are involved in the induction of the mouse interleukin 2 gene in T lymphocytes. EMBO J. 1989 Feb;8(2):465–473. doi: 10.1002/j.1460-2075.1989.tb03399.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Shevach E. M. The effects of cyclosporin A on the immune system. Annu Rev Immunol. 1985;3:397–423. doi: 10.1146/annurev.iy.03.040185.002145. [DOI] [PubMed] [Google Scholar]
  27. Shibuya H., Yoneyama M., Taniguchi T. Involvement of a common transcription factor in the regulated expression of IL-2 and IL-2 receptor genes. Int Immunol. 1989;1(1):43–49. doi: 10.1093/intimm/1.1.43. [DOI] [PubMed] [Google Scholar]
  28. Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  29. Taniguchi T. Regulation of cytokine gene expression. Annu Rev Immunol. 1988;6:439–464. doi: 10.1146/annurev.iy.06.040188.002255. [DOI] [PubMed] [Google Scholar]
  30. Yoshida M., Seiki M. Recent advances in the molecular biology of HTLV-1: trans-activation of viral and cellular genes. Annu Rev Immunol. 1987;5:541–559. doi: 10.1146/annurev.iy.05.040187.002545. [DOI] [PubMed] [Google Scholar]

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