Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Jul 1;172(1):121–129. doi: 10.1084/jem.172.1.121

Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia

PMCID: PMC2188182  PMID: 2358774

Abstract

We examined the effect of the human T lymphotropic virus type 1 (HTLV- I) Tax gene product on the human transforming growth factor beta 1 (TGF- beta 1) promoter. Transfection of deleted constructs of the TGF-beta 1 promoter revealed regions homologous with AP-1 binding sites that were required for Tax-induced transactivation of the TGF-beta 1 promoter. In addition, we examined the expression and secretion of TGF-beta in fresh leukemic cells isolated from patients with adult T cell leukemia (ATL) and in HTLV-1-infected T cell lines. We report that fresh leukemic cells from ATL patients constitutively produce high levels of TGF-beta 1 mRNA and secrete TGF-beta 1 but not TGF-beta 2 into the culture medium. In addition, long-term ATL cell lines expressed significant amounts of TGF-beta 1 mRNA as well as detectable levels of TGF-beta 1 protein. These results suggest a role for Tax in the upregulation of TGF-beta 1 in HTLV-I-infected cells.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Akhurst R. J., Fee F., Balmain A. Localized production of TGF-beta mRNA in tumour promoter-stimulated mouse epidermis. Nature. 1988 Jan 28;331(6154):363–365. doi: 10.1038/331363a0. [DOI] [PubMed] [Google Scholar]
  2. Angel P., Baumann I., Stein B., Delius H., Rahmsdorf H. J., Herrlich P. 12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5'-flanking region. Mol Cell Biol. 1987 Jun;7(6):2256–2266. doi: 10.1128/mcb.7.6.2256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anzano M. A., Roberts A. B., Smith J. M., Sporn M. B., De Larco J. E. Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type alpha and type beta transforming growth factors. Proc Natl Acad Sci U S A. 1983 Oct;80(20):6264–6268. doi: 10.1073/pnas.80.20.6264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Brigham B. A., Bunn P. A., Jr, Horton J. E., Schechter G. P., Wahl L. M., Bradley E. C., Dunnick N. R., Matthews M. J. Skeletal manifestations in cutaneous T-cell lymphomas. Arch Dermatol. 1982 Jul;118(7):461–467. [PubMed] [Google Scholar]
  6. Broder S., Bunn P. A., Jr, Jaffe E. S., Blattner W., Gallo R. C., Wong-Staal F., Waldmann T. A., DeVita V. T., Jr NIH conference. T-cell lymphoproliferative syndrome associated with human T-cell leukemia/lymphoma virus. Ann Intern Med. 1984 Apr;100(4):543–557. doi: 10.7326/0003-4819-100-4-543. [DOI] [PubMed] [Google Scholar]
  7. Bunn P. A., Jr, Schechter G. P., Jaffe E., Blayney D., Young R. C., Matthews M. J., Blattner W., Broder S., Robert-Guroff M., Gallo R. C. Clinical course of retrovirus-associated adult T-cell lymphoma in the United States. N Engl J Med. 1983 Aug 4;309(5):257–264. doi: 10.1056/NEJM198308043090501. [DOI] [PubMed] [Google Scholar]
  8. Cappell M. S., Chow J. HTLV-I-associated lymphoma involving the entire alimentary tract and presenting with an acquired immune deficiency. Am J Med. 1987 Mar 23;82(3 Spec No):649–654. doi: 10.1016/0002-9343(87)90117-3. [DOI] [PubMed] [Google Scholar]
  9. Catovsky D., Greaves M. F., Rose M., Galton D. A., Goolden A. W., McCluskey D. R., White J. M., Lampert I., Bourikas G., Ireland R. Adult T-cell lymphoma-leukaemia in Blacks from the West Indies. Lancet. 1982 Mar 20;1(8273):639–643. doi: 10.1016/s0140-6736(82)92200-0. [DOI] [PubMed] [Google Scholar]
  10. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  11. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Coffey R. J., Jr, Kost L. J., Lyons R. M., Moses H. L., LaRusso N. F. Hepatic processing of transforming growth factor beta in the rat. Uptake, metabolism, and biliary excretion. J Clin Invest. 1987 Sep;80(3):750–757. doi: 10.1172/JCI113130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Danielpour D., Dart L. L., Flanders K. C., Roberts A. B., Sporn M. B. Immunodetection and quantitation of the two forms of transforming growth factor-beta (TGF-beta 1 and TGF-beta 2) secreted by cells in culture. J Cell Physiol. 1989 Jan;138(1):79–86. doi: 10.1002/jcp.1041380112. [DOI] [PubMed] [Google Scholar]
  14. Espevik T., Figari I. S., Shalaby M. R., Lackides G. A., Lewis G. D., Shepard H. M., Palladino M. A., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. doi: 10.1084/jem.166.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Franchini G., Wong-Staal F., Gallo R. C. Human T-cell leukemia virus (HTLV-I) transcripts in fresh and cultured cells of patients with adult T-cell leukemia. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6207–6211. doi: 10.1073/pnas.81.19.6207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fujihira T., Eto S., Sato K., Zeki K., Oda S., Chiba S., Suzuki H. Evidence of bone resorption-stimulating factor in adult T-cell leukemia. Jpn J Clin Oncol. 1985 Jun;15(2):385–391. [PubMed] [Google Scholar]
  18. Fujii M., Sassone-Corsi P., Verma I. M. c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8526–8530. doi: 10.1073/pnas.85.22.8526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Grossman B., Schechter G. P., Horton J. E., Pierce L., Jaffe E., Wahl L. Hypercalcemia associated with T-cell lymphoma-leukemia. Am J Clin Pathol. 1981 Feb;75(2):149–155. doi: 10.1093/ajcp/75.2.149. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Karin M., Richards R. I. Human metallothionein genes--primary structure of the metallothionein-II gene and a related processed gene. Nature. 1982 Oct 28;299(5886):797–802. doi: 10.1038/299797a0. [DOI] [PubMed] [Google Scholar]
  25. Kehrl J. H., Roberts A. B., Wakefield L. M., Jakowlew S., Sporn M. B., Fauci A. S. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986 Dec 15;137(12):3855–3860. [PubMed] [Google Scholar]
  26. Kehrl J. H., Wakefield L. M., Roberts A. B., Jakowlew S., Alvarez-Mon M., Derynck R., Sporn M. B., Fauci A. S. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986 May 1;163(5):1037–1050. doi: 10.1084/jem.163.5.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kim S. J., Angel P., Lafyatis R., Hattori K., Kim K. Y., Sporn M. B., Karin M., Roberts A. B. Autoinduction of transforming growth factor beta 1 is mediated by the AP-1 complex. Mol Cell Biol. 1990 Apr;10(4):1492–1497. doi: 10.1128/mcb.10.4.1492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kim S. J., Glick A., Sporn M. B., Roberts A. B. Characterization of the promoter region of the human transforming growth factor-beta 1 gene. J Biol Chem. 1989 Jan 5;264(1):402–408. [PubMed] [Google Scholar]
  29. Kim S. J., Jeang K. T., Glick A. B., Sporn M. B., Roberts A. B. Promoter sequences of the human transforming growth factor-beta 1 gene responsive to transforming growth factor-beta 1 autoinduction. J Biol Chem. 1989 Apr 25;264(12):7041–7045. [PubMed] [Google Scholar]
  30. Kuefler P. R., Bunn P. A., Jr Adult T cell leukaemia/lymphoma. Clin Haematol. 1986 Aug;15(3):695–726. [PubMed] [Google Scholar]
  31. Lee G., Ellingsworth L. R., Gillis S., Wall R., Kincade P. W. Beta transforming growth factors are potential regulators of B lymphopoiesis. J Exp Med. 1987 Nov 1;166(5):1290–1299. doi: 10.1084/jem.166.5.1290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Luse D. S., Roeder R. G. Accurate transcription initiation on a purified mouse beta-globin DNA fragment in a cell-free system. Cell. 1980 Jul;20(3):691–699. doi: 10.1016/0092-8674(80)90315-3. [DOI] [PubMed] [Google Scholar]
  33. Maeda M., Shimizu A., Ikuta K., Okamoto H., Kashihara M., Uchiyama T., Honjo T., Yodoi J. Origin of human T-lymphotrophic virus I-positive T cell lines in adult T cell leukemia. Analysis of T cell receptor gene rearrangement. J Exp Med. 1985 Dec 1;162(6):2169–2174. doi: 10.1084/jem.162.6.2169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Miyatake S., Seiki M., Malefijt R. D., Heike T., Fujisawa J., Takebe Y., Nishida J., Shlomai J., Yokota T., Yoshida M. Activation of T cell-derived lymphokine genes in T cells and fibroblasts: effects of human T cell leukemia virus type I p40x protein and bovine papilloma virus encoded E2 protein. Nucleic Acids Res. 1988 Jul 25;16(14A):6547–6566. doi: 10.1093/nar/16.14.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Miyatake S., Seiki M., Yoshida M., Arai K. T-cell activation signals and human T-cell leukemia virus type I-encoded p40x protein activate the mouse granulocyte-macrophage colony-stimulating factor gene through a common DNA element. Mol Cell Biol. 1988 Dec;8(12):5581–5587. doi: 10.1128/mcb.8.12.5581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miyazono K., Hellman U., Wernstedt C., Heldin C. H. Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J Biol Chem. 1988 May 5;263(13):6407–6415. [PubMed] [Google Scholar]
  38. Morimoto C., Matsuyama T., Oshige C., Tanaka H., Hercend T., Reinherz E. L., Schlossman S. F. Functional and phenotypic studies of Japanese adult T cell leukemia cells. J Clin Invest. 1985 Mar;75(3):836–843. doi: 10.1172/JCI111780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mulé J. J., Schwarz S. L., Roberts A. B., Sporn M. B., Rosenberg S. A. Transforming growth factor-beta inhibits the in vitro generation of lymphokine-activated killer cells and cytotoxic T cells. Cancer Immunol Immunother. 1988;26(2):95–100. doi: 10.1007/BF00205600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Niitsu Y., Urushizaki Y., Koshida Y., Terui K., Mahara K., Kohgo Y., Urushizaki I. Expression of TGF-beta gene in adult T cell leukemia. Blood. 1988 Jan;71(1):263–266. [PubMed] [Google Scholar]
  41. Ondek B., Shepard A., Herr W. Discrete elements within the SV40 enhancer region display different cell-specific enhancer activities. EMBO J. 1987 Apr;6(4):1017–1025. doi: 10.1002/j.1460-2075.1987.tb04854.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Petkovich P. M., Wrana J. L., Grigoriadis A. E., Heersche J. N., Sodek J. 1,25-Dihydroxyvitamin D3 increases epidermal growth factor receptors and transforming growth factor beta-like activity in a bone-derived cell line. J Biol Chem. 1987 Oct 5;262(28):13424–13428. [PubMed] [Google Scholar]
  43. Pfeilschifter J., Mundy G. R. Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A. 1987 Apr;84(7):2024–2028. doi: 10.1073/pnas.84.7.2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. 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]
  45. Radonovich M., Jeang K. T. Activation of the human T-cell leukemia virus type I long terminal repeat by 12-O-tetradecanoylphorbol-13-acetate and by tax (p40x) occurs through similar but functionally distinct target sequences. J Virol. 1989 Jul;63(7):2987–2994. doi: 10.1128/jvi.63.7.2987-2994.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ranges G. E., Figari I. S., Espevik T., Palladino M. A., Jr Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987 Oct 1;166(4):991–998. doi: 10.1084/jem.166.4.991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Roberts A. B., Frolik C. A., Anzano M. A., Sporn M. B. Transforming growth factors from neoplastic and nonneoplastic tissues. Fed Proc. 1983 Jun;42(9):2621–2626. [PubMed] [Google Scholar]
  48. Rook A. H., Kehrl J. H., Wakefield L. M., Roberts A. B., Sporn M. B., Burlington D. B., Lane H. C., Fauci A. S. Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol. 1986 May 15;136(10):3916–3920. [PubMed] [Google Scholar]
  49. Shaw G. M., Broder S., Essex M., Gallo R. C. Human T-cell leukemia virus: its discovery and role in leukemogenesis and immunosuppression. Adv Intern Med. 1984;30:1–27. [PubMed] [Google Scholar]
  50. Shirakawa F., Tanaka Y., Oda S., Chiba S., Suzuki H., Eto S., Yamashita U. Immunosuppressive factors from adult T-cell leukemia cells. Cancer Res. 1986 Sep;46(9):4458–4462. [PubMed] [Google Scholar]
  51. Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sodroski J., Rosen C., Goh W. C., Haseltine W. A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science. 1985 Jun 21;228(4706):1430–1434. doi: 10.1126/science.2990028. [DOI] [PubMed] [Google Scholar]
  53. Tagawa S., Sawada M., Tokumine Y., Ueda E., Machii T., Hayashi S., Kurata Y., Kitani T. Serum immunosuppressive acidic protein in adult T-cell leukaemia (ATL). Scand J Haematol. 1985 May;34(5):360–369. doi: 10.1111/j.1600-0609.1985.tb00763.x. [DOI] [PubMed] [Google Scholar]
  54. Tschachler E., Robert-Guroff M., Gallo R. C., Reitz M. S., Jr Human T-lymphotropic virus I-infected T cells constitutively express lymphotoxin in vitro. Blood. 1989 Jan;73(1):194–201. [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. Van Obberghen-Schilling E., Kondaiah P., Ludwig R. L., Sporn M. B., Baker C. C. Complementary deoxyribonucleic acid cloning of bovine transforming growth factor-beta 1. Mol Endocrinol. 1987 Oct;1(10):693–698. doi: 10.1210/mend-1-10-693. [DOI] [PubMed] [Google Scholar]
  57. Wakefield L. M., Smith D. M., Flanders K. C., Sporn M. B. Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences. J Biol Chem. 1988 Jun 5;263(16):7646–7654. [PubMed] [Google Scholar]
  58. Waldmann T. A., Greene W. C., Sarin P. S., Saxinger C., Blayney D. W., Blattner W. A., Goldman C. K., Bongiovanni K., Sharrow S., Depper J. M. Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. J Clin Invest. 1984 Jun;73(6):1711–1718. doi: 10.1172/JCI111379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wano Y., Hattori T., Matsuoka M., Takatsuki K., Chua A. O., Gubler U., Greene W. C. Interleukin 1 gene expression in adult T cell leukemia. J Clin Invest. 1987 Sep;80(3):911–916. doi: 10.1172/JCI113152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wrann M., Bodmer S., de Martin R., Siepl C., Hofer-Warbinek R., Frei K., Hofer E., Fontana A. T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. EMBO J. 1987 Jun;6(6):1633–1636. doi: 10.1002/j.1460-2075.1987.tb02411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Yamashita U., Shirakawa F., Nakamura H. Production of interleukin 1 by adult T cell leukemia (ATL) cell lines. J Immunol. 1987 May 15;138(10):3284–3289. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES