Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1989 Nov;9(11):4731–4737. doi: 10.1128/mcb.9.11.4731

trans activation of granulocyte-macrophage colony-stimulating factor and the interleukin-2 receptor in transgenic mice carrying the human T-lymphotropic virus type 1 tax gene.

J E Green 1, C G Begley 1, D K Wagner 1, T A Waldmann 1, G Jay 1
PMCID: PMC363620  PMID: 2689863

Abstract

Three lines of transgenic mice carrying the human T-cell lymphotropic virus type 1 tax gene have previously been reported to develop neurofibromas composed of perineural fibroblasts (S. H. Hinrichs, M. Nerenberg, R. K. Reynolds, G. Khoury, and G. Jay, Science 237:1340-1343, 1987; M. Nerenberg, S. H. Hinrichs, R. K. Reynolds, G. Khoury, and G. Jay, Science 237:1324-1329, 1987). Tumors from these mice and tumor cell lines derived from them expressed high levels of tax RNA and protein. They also expressed high levels of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene as measured by proliferative responses of FD-CP1 target cells using conditioned media from tumor cells and by Northern (RNA) blot analysis of RNA from tumors and tumor cell lines. Although other tissues, such as salivary glands and muscles, in the transgenic mice also expressed high levels of tax, they did not express the gene for GM-CSF. This indicates that tissue-specific cellular factors, in addition to tax, are required for GM-CSF gene expression. Systemic effects of excessive GM-CSF production were demonstrated by infiltration of polymorphonuclear leukocytes into tumor tissues which are not necrotic, by peripheral granulocytosis, and by splenomegaly resulting from myeloid hyperplasia. The interleukin-2 (IL-2) receptor was also found to be expressed by the tumors and tumor cell lines as measured by IL-2-binding and cross-linking studies. This is the first demonstration that the IL-2 receptor can be activated by tax in a nonlymphoid cell type. These in vivo findings are consistent with other reports which have demonstrated in vitro cis-regulatory elements within the 5'-flanking regions of the genes for GM-CSF and the IL-2 receptor which are responsive to trans activation by the tax gene.

Full text

PDF
4736

Images in this article

4733Image
on p.4733
4734Image
on p.4734
4735Image
on p.4735

Selected References

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

  1. 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]
  2. Barlow D. P., Bućan M., Lehrach H., Hogan B. L., Gough N. M. Close genetic and physical linkage between the murine haemopoietic growth factor genes GM-CSF and Multi-CSF (IL3). EMBO J. 1987 Mar;6(3):617–623. doi: 10.1002/j.1460-2075.1987.tb04799.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Begley C. G., Lopez A. F., Nicola N. A., Warren D. J., Vadas M. A., Sanderson C. J., Metcalf D. Purified colony-stimulating factors enhance the survival of human neutrophils and eosinophils in vitro: a rapid and sensitive microassay for colony-stimulating factors. Blood. 1986 Jul;68(1):162–166. [PubMed] [Google Scholar]
  4. Cannistra S. A., Griffin J. D. Regulation of the production and function of granulocytes and monocytes. Semin Hematol. 1988 Jul;25(3):173–188. [PubMed] [Google Scholar]
  5. Chan J. Y., Slamon D. J., Nimer S. D., Golde D. W., Gasson J. C. Regulation of expression of human granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8669–8673. doi: 10.1073/pnas.83.22.8669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clark S. C., Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987 Jun 5;236(4806):1229–1237. doi: 10.1126/science.3296190. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Cross S. L., Halden N. F., Lenardo M. J., Leonard W. J. Functionally distinct NF-kappa B binding sites in the immunoglobulin kappa and IL-2 receptor alpha chain genes. Science. 1989 Apr 28;244(4903):466–469. doi: 10.1126/science.2497520. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. Gazzolo L., Duc Dodon M. Direct activation of resting T lymphocytes by human T-lymphotropic virus type I. Nature. 1987 Apr 16;326(6114):714–717. doi: 10.1038/326714a0. [DOI] [PubMed] [Google Scholar]
  13. Gough N. M., Metcalf D., Gough J., Grail D., Dunn A. R. Structure and expression of the mRNA for murine granulocyte-macrophage colony stimulating factor. EMBO J. 1985 Mar;4(3):645–653. doi: 10.1002/j.1460-2075.1985.tb03678.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Herrmann T., Diamantstein T. The mouse high affinity IL 2 receptor complex. I. Evidence for a third molecule, the putative gamma-chain, associated with the alpha- and/or beta-chain of the receptor. Immunobiology. 1987 Sep;175(3):145–158. doi: 10.1016/s0171-2985(87)80024-4. [DOI] [PubMed] [Google Scholar]
  15. Hinrichs S. H., Nerenberg M., Reynolds R. K., Khoury G., Jay G. A transgenic mouse model for human neurofibromatosis. Science. 1987 Sep 11;237(4820):1340–1343. doi: 10.1126/science.2888191. [DOI] [PubMed] [Google Scholar]
  16. 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]
  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. 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]
  20. Jacobson S., Raine C. S., Mingioli E. S., McFarlin D. E. Isolation of an HTLV-1-like retrovirus from patients with tropical spastic paraparesis. Nature. 1988 Feb 11;331(6156):540–543. doi: 10.1038/331540a0. [DOI] [PubMed] [Google Scholar]
  21. Leonard W. J., Depper J. M., Kanehisa M., Krönke M., Peffer N. J., Svetlik P. B., Sullivan M., Greene W. C. Structure of the human interleukin-2 receptor gene. Science. 1985 Nov 8;230(4726):633–639. doi: 10.1126/science.2996141. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Metcalf D., Begley C. G., Nicola N. A., Johnson G. R. Quantitative responsiveness of murine hemopoietic populations in vitro and in vivo to recombinant multi-CSF (IL-3). Exp Hematol. 1987 Mar;15(3):288–295. [PubMed] [Google Scholar]
  24. Metcalf D., Begley C. G., Williamson D. J., Nice E. C., De Lamarter J., Mermod J. J., Thatcher D., Schmidt A. Hemopoietic responses in mice injected with purified recombinant murine GM-CSF. Exp Hematol. 1987 Jan;15(1):1–9. [PubMed] [Google Scholar]
  25. Metcalf D. The granulocyte-macrophage colony stimulating factors. Cell. 1985 Nov;43(1):5–6. doi: 10.1016/0092-8674(85)90004-2. [DOI] [PubMed] [Google Scholar]
  26. Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood. 1986 Feb;67(2):257–267. [PubMed] [Google Scholar]
  27. 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]
  28. Morstyn G., Burgess A. W. Hemopoietic growth factors: a review. Cancer Res. 1988 Oct 15;48(20):5624–5637. [PubMed] [Google Scholar]
  29. 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]
  30. Nicola N. A., Begley C. G., Metcalf D. Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells. Nature. 1985 Apr 18;314(6012):625–628. doi: 10.1038/314625a0. [DOI] [PubMed] [Google Scholar]
  31. Nimer S. D., Morita E. A., Martis M. J., Wachsman W., Gasson J. C. Characterization of the human granulocyte-macrophage colony-stimulating factor promoter region by genetic analysis: correlation with DNase I footprinting. Mol Cell Biol. 1988 May;8(5):1979–1984. doi: 10.1128/mcb.8.5.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Robb R. J., Greene W. C., Rusk C. M. Low and high affinity cellular receptors for interleukin 2. Implications for the level of Tac antigen. J Exp Med. 1984 Oct 1;160(4):1126–1146. doi: 10.1084/jem.160.4.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Robert-Guroff M., Nakao Y., Notake K., Ito Y., Sliski A., Gallo R. C. Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T cell leukemia. Science. 1982 Feb 19;215(4535):975–978. doi: 10.1126/science.6760397. [DOI] [PubMed] [Google Scholar]
  36. Rodgers-Johnson P., Gajdusek D. C., Morgan O. S., Zaninovic V., Sarin P. S., Graham D. S. HTLV-I and HTLV-III antibodies and tropical spastic paraparesis. Lancet. 1985 Nov 30;2(8466):1247–1248. doi: 10.1016/s0140-6736(85)90778-0. [DOI] [PubMed] [Google Scholar]
  37. Ruben S., Poteat H., Tan T. H., Kawakami K., Roeder R., Haseltine W., Rosen C. A. Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product. Science. 1988 Jul 1;241(4861):89–92. doi: 10.1126/science.2838905. [DOI] [PubMed] [Google Scholar]
  38. Saragovi H., Malek T. R. The murine interleukin 2 receptor. Irreversible cross-linking of radiolabeled interleukin 2 to high affinity interleukin 2 receptors reveals a noncovalently associated subunit. J Immunol. 1987 Sep 15;139(6):1918–1926. [PubMed] [Google Scholar]
  39. 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]
  40. Shannon M. F., Gamble J. R., Vadas M. A. Nuclear proteins interacting with the promoter region of the human granulocyte/macrophage colony-stimulating factor gene. Proc Natl Acad Sci U S A. 1988 Feb;85(3):674–678. doi: 10.1073/pnas.85.3.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. 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]
  42. 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]
  43. Tsudo M., Kozak R. W., Goldman C. K., Waldmann T. A. Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9694–9698. doi: 10.1073/pnas.83.24.9694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wagner D. K., York-Jolley J., Malek T. R., Berzofsky J. A., Nelson D. L. Antigen-specific murine T cell clones produce soluble interleukin 2 receptor on stimulation with specific antigens. J Immunol. 1986 Jul 15;137(2):592–596. [PubMed] [Google Scholar]
  45. Yoshida M., Miyoshi I., Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Proc Natl Acad Sci U S A. 1982 Mar;79(6):2031–2035. doi: 10.1073/pnas.79.6.2031. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES