Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1989 Dec;9(12):5404–5411. doi: 10.1128/mcb.9.12.5404

Alpha interferon and gamma interferon stimulate transcription of a single gene through different signal transduction pathways.

D J Lew 1, T Decker 1, J E Darnell Jr 1
PMCID: PMC363708  PMID: 2555698

Abstract

Interferons (IFNs) play a key role in the defense against virus infection and the regulation of cell growth and differentiation, in part through changes in specific gene transcription in target cells. We describe several differences between the signal transduction events that result in transcriptional activation of the human gene coding for a guanylate-binding protein (GBP) by alpha interferon (IFN-alpha) and gamma interferon (IFN-gamma). Activation by IFN-alpha was rapid, transient, and cycloheximide resistant. Activation by IFN-gamma was slower, sustained, and delayed by cycloheximide. IFN-gamma led to the formation of a stable intracellular signal which led to continued GBP transcription even if the ligand was withdrawn, whereas IFN-alpha-induced GBP transcription decayed rapidly if IFN-alpha was withdrawn. Perturbations of signaling pathways involving classical second messengers (cyclic AMP, Ca2+, protein kinase C) did not induce GBP transcription. However, various kinase inhibitors blocked the transcriptional response to IFN-gamma but not IFN-alpha, suggesting that a specific and possibly novel kinase is involved in gene activation by IFN-gamma.

Full text

PDF
5404

Images in this article

5405Image
on p.5405
5405Image
on p.5405
5406Image
on p.5406
5407Image
on p.5407
5408Image
on p.5408
5408Image
on p.5408

Selected References

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

  1. Aguet M., Dembić Z., Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell. 1988 Oct 21;55(2):273–280. doi: 10.1016/0092-8674(88)90050-5. [DOI] [PubMed] [Google Scholar]
  2. Almendral J. M., Sommer D., Macdonald-Bravo H., Burckhardt J., Perera J., Bravo R. Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol. 1988 May;8(5):2140–2148. doi: 10.1128/mcb.8.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Amaldi I., Reith W., Berte C., Mach B. Induction of HLA class II genes by IFN-gamma is transcriptional and requires a trans-acting protein. J Immunol. 1989 Feb 1;142(3):999–1004. [PubMed] [Google Scholar]
  4. Blanar M. A., Boettger E. C., Flavell R. A. Transcriptional activation of HLA-DR alpha by interferon gamma requires a trans-acting protein. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4672–4676. doi: 10.1073/pnas.85.13.4672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brenner D. A., O'Hara M., Angel P., Chojkier M., Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. doi: 10.1038/337661a0. [DOI] [PubMed] [Google Scholar]
  6. Caplen H. S., Gupta S. L. Differential regulation of a cellular gene by human interferon-gamma and interferon-alpha. J Biol Chem. 1988 Jan 5;263(1):332–339. [PubMed] [Google Scholar]
  7. Cheng Y. S., Becker-Manley M. F., Chow T. P., Horan D. C. Affinity purification of an interferon-induced human guanylate-binding protein and its characterization. J Biol Chem. 1985 Dec 15;260(29):15834–15839. [PubMed] [Google Scholar]
  8. Cheng Y. S., Becker-Manley M. F., Nguyen T. D., DeGrado W. F., Jonak G. J. Nonidentical induction of the guanylate binding protein and the 56K protein by type I and type II interferons. J Interferon Res. 1986 Aug;6(4):417–427. doi: 10.1089/jir.1986.6.417. [DOI] [PubMed] [Google Scholar]
  9. Cheng Y. S., Colonno R. J., Yin F. H. Interferon induction of fibroblast proteins with guanylate binding activity. J Biol Chem. 1983 Jun 25;258(12):7746–7750. [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. Cleveland D. W., Lopata M. A., MacDonald R. J., Cowan N. J., Rutter W. J., Kirschner M. W. Number and evolutionary conservation of alpha- and beta-tubulin and cytoplasmic beta- and gamma-actin genes using specific cloned cDNA probes. Cell. 1980 May;20(1):95–105. doi: 10.1016/0092-8674(80)90238-x. [DOI] [PubMed] [Google Scholar]
  12. Cochran B. H., Reffel A. C., Stiles C. D. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell. 1983 Jul;33(3):939–947. doi: 10.1016/0092-8674(83)90037-5. [DOI] [PubMed] [Google Scholar]
  13. Costa R. H., Lai E., Grayson D. R., Darnell J. E., Jr The cell-specific enhancer of the mouse transthyretin (prealbumin) gene binds a common factor at one site and a liver-specific factor(s) at two other sites. Mol Cell Biol. 1988 Jan;8(1):81–90. doi: 10.1128/mcb.8.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dale T. C., Rosen J. M., Guille M. J., Lewin A. R., Porter A. G., Kerr I. M., Stark G. R. Overlapping sites for constitutive and induced DNA binding factors involved in interferon-stimulated transcription. EMBO J. 1989 Mar;8(3):831–839. doi: 10.1002/j.1460-2075.1989.tb03444.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Decker T., Lew D. J., Cheng Y. S., Levy D. E., Darnell J. E., Jr Interactions of alpha- and gamma-interferon in the transcriptional regulation of the gene encoding a guanylate-binding protein. EMBO J. 1989 Jul;8(7):2009–2014. doi: 10.1002/j.1460-2075.1989.tb03608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Elder P. K., Schmidt L. J., Ono T., Getz M. J. Specific stimulation of actin gene transcription by epidermal growth factor and cycloheximide. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7476–7480. doi: 10.1073/pnas.81.23.7476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Enoch T., Zinn K., Maniatis T. Activation of the human beta-interferon gene requires an interferon-inducible factor. Mol Cell Biol. 1986 Mar;6(3):801–810. doi: 10.1128/mcb.6.3.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fan C. M., Maniatis T. Two different virus-inducible elements are required for human beta-interferon gene regulation. EMBO J. 1989 Jan;8(1):101–110. doi: 10.1002/j.1460-2075.1989.tb03353.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fan X. D., Goldberg M., Bloom B. R. Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5122–5125. doi: 10.1073/pnas.85.14.5122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fan X. D., Stark G. R., Bloom B. R. Molecular cloning of a gene selectively induced by gamma interferon from human macrophage cell line U937. Mol Cell Biol. 1989 May;9(5):1922–1928. doi: 10.1128/mcb.9.5.1922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Farrell P. J., Balkow K., Hunt T., Jackson R. J., Trachsel H. Phosphorylation of initiation factor elF-2 and the control of reticulocyte protein synthesis. Cell. 1977 May;11(1):187–200. doi: 10.1016/0092-8674(77)90330-0. [DOI] [PubMed] [Google Scholar]
  22. Fisch T. M., Prywes R., Roeder R. G. c-fos sequence necessary for basal expression and induction by epidermal growth factor, 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore. Mol Cell Biol. 1987 Oct;7(10):3490–3502. doi: 10.1128/mcb.7.10.3490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Friedman R. L., Manly S. P., McMahon M., Kerr I. M., Stark G. R. Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell. 1984 Oct;38(3):745–755. doi: 10.1016/0092-8674(84)90270-8. [DOI] [PubMed] [Google Scholar]
  24. Greenberg M. E., Greene L. A., Ziff E. B. Nerve growth factor and epidermal growth factor induce rapid transient changes in proto-oncogene transcription in PC12 cells. J Biol Chem. 1985 Nov 15;260(26):14101–14110. [PubMed] [Google Scholar]
  25. Greenberg M. E., Ziff E. B., Greene L. A. Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science. 1986 Oct 3;234(4772):80–83. doi: 10.1126/science.3749894. [DOI] [PubMed] [Google Scholar]
  26. Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
  27. Hamilton T. A., Becton D. L., Somers S. D., Gray P. W., Adams D. O. Interferon-gamma modulates protein kinase C activity in murine peritoneal macrophages. J Biol Chem. 1985 Feb 10;260(3):1378–1381. [PubMed] [Google Scholar]
  28. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  29. Hofer E., Darnell J. E., Jr The primary transcription unit of the mouse beta-major globin gene. Cell. 1981 Feb;23(2):585–593. doi: 10.1016/0092-8674(81)90154-9. [DOI] [PubMed] [Google Scholar]
  30. Hug H., Costas M., Staeheli P., Aebi M., Weissmann C. Organization of the murine Mx gene and characterization of its interferon- and virus-inducible promoter. Mol Cell Biol. 1988 Aug;8(8):3065–3079. doi: 10.1128/mcb.8.8.3065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kaibuchi K., Tsuda T., Kikuchi A., Tanimoto T., Yamashita T., Takai Y. Possible involvement of protein kinase C and calcium ion in growth factor-induced expression of c-myc oncogene in Swiss 3T3 fibroblasts. J Biol Chem. 1986 Jan 25;261(3):1187–1192. [PubMed] [Google Scholar]
  32. Kessler D. S., Levy D. E., Darnell J. E., Jr Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8521–8525. doi: 10.1073/pnas.85.22.8521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kessler D. S., Pine R., Pfeffer L. M., Levy D. E., Darnell J. E., Jr Cells resistant to interferon are defective in activation of a promoter-binding factor. EMBO J. 1988 Dec 1;7(12):3779–3783. doi: 10.1002/j.1460-2075.1988.tb03262.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Larner A. C., Chaudhuri A., Darnell J. E., Jr Transcriptional induction by interferon. New protein(s) determine the extent and length of the induction. J Biol Chem. 1986 Jan 5;261(1):453–459. [PubMed] [Google Scholar]
  35. Larner A. C., Jonak G., Cheng Y. S., Korant B., Knight E., Darnell J. E., Jr Transcriptional induction of two genes in human cells by beta interferon. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6733–6737. doi: 10.1073/pnas.81.21.6733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lau L. F., Nathans D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1182–1186. doi: 10.1073/pnas.84.5.1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Lau L. F., Nathans D. Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO J. 1985 Dec 1;4(12):3145–3151. doi: 10.1002/j.1460-2075.1985.tb04057.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Levy D. E., Kessler D. S., Pine R., Reich N., Darnell J. E., Jr Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988 Apr;2(4):383–393. doi: 10.1101/gad.2.4.383. [DOI] [PubMed] [Google Scholar]
  39. Levy D., Larner A., Chaudhuri A., Babiss L. E., Darnell J. E., Jr Interferon-stimulated transcription: isolation of an inducible gene and identification of its regulatory region. Proc Natl Acad Sci U S A. 1986 Dec;83(23):8929–8933. doi: 10.1073/pnas.83.23.8929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Luster A. D., Unkeless J. C., Ravetch J. V. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985 Jun 20;315(6021):672–676. doi: 10.1038/315672a0. [DOI] [PubMed] [Google Scholar]
  41. Marcus P. I., Sekellick M. J. Interferon induction by viruses. XVI. 2-Aminopurine blocks selectively and reversibly an early stage in interferon induction. J Gen Virol. 1988 Jul;69(Pt 7):1637–1645. doi: 10.1099/0022-1317-69-7-1637. [DOI] [PubMed] [Google Scholar]
  42. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Murdoch G. H., Franco R., Evans R. M., Rosenfeld M. G. Polypeptide hormone regulation of gene expression. Thyrotropin-releasing hormone rapidly stimulates both transcription of the prolactin gene and the phosphorylation of a specific nuclear protein. J Biol Chem. 1983 Dec 25;258(24):15329–15335. [PubMed] [Google Scholar]
  44. Müller R., Bravo R., Burckhardt J., Curran T. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature. 1984 Dec 20;312(5996):716–720. doi: 10.1038/312716a0. [DOI] [PubMed] [Google Scholar]
  45. Nagata Y., Rosen O. M., Makman M. H., Bloom B. R. Biochemical analysis of mutants of a macrophage cell line resistant to the growth-inhibitory activity of interferon. J Cell Biol. 1984 Apr;98(4):1342–1347. doi: 10.1083/jcb.98.4.1342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ostrowski J., Meier K. E., Stanton T. H., Smith L. L., Bomsztyk K. Interferon-gamma and interleukin-1 alpha induce transient translocation of protein kinase C activity to membranes in a B lymphoid cell line. Evidence for a protein kinase C-independent pathway in lymphokine-induced cytoplasmic alkalinization. J Biol Chem. 1988 Sep 25;263(27):13786–13790. [PubMed] [Google Scholar]
  47. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. doi: 10.1146/annurev.bi.56.070187.003455. [DOI] [PubMed] [Google Scholar]
  48. Porter A. C., Chernajovsky Y., Dale T. C., Gilbert C. S., Stark G. R., Kerr I. M. Interferon response element of the human gene 6-16. EMBO J. 1988 Jan;7(1):85–92. doi: 10.1002/j.1460-2075.1988.tb02786.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Prowse K. R., Baumann H. Hepatocyte-stimulating factor, beta 2 interferon, and interleukin-1 enhance expression of the rat alpha 1-acid glycoprotein gene via a distal upstream regulatory region. Mol Cell Biol. 1988 Jan;8(1):42–51. doi: 10.1128/mcb.8.1.42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Prywes R., Roeder R. G. Inducible binding of a factor to the c-fos enhancer. Cell. 1986 Dec 5;47(5):777–784. doi: 10.1016/0092-8674(86)90520-9. [DOI] [PubMed] [Google Scholar]
  51. Ray A., Tatter S. B., May L. T., Sehgal P. B. Activation of the human "beta 2-interferon/hepatocyte-stimulating factor/interleukin 6" promoter by cytokines, viruses, and second messenger agonists. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6701–6705. doi: 10.1073/pnas.85.18.6701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Reich N., Evans B., Levy D., Fahey D., Knight E., Jr, Darnell J. E., Jr Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6394–6398. doi: 10.1073/pnas.84.18.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Reid L. E., Brasnett A. H., Gilbert C. S., Porter A. C., Gewert D. R., Stark G. R., Kerr I. M. A single DNA response element can confer inducibility by both alpha- and gamma-interferons. Proc Natl Acad Sci U S A. 1989 Feb;86(3):840–844. doi: 10.1073/pnas.86.3.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Riabowol K. T., Fink J. S., Gilman M. Z., Walsh D. A., Goodman R. H., Feramisco J. R. The catalytic subunit of cAMP-dependent protein kinase induces expression of genes containing cAMP-responsive enhancer elements. Nature. 1988 Nov 3;336(6194):83–86. doi: 10.1038/336083a0. [DOI] [PubMed] [Google Scholar]
  55. Roesler W. J., Vandenbark G. R., Hanson R. W. Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem. 1988 Jul 5;263(19):9063–9066. [PubMed] [Google Scholar]
  56. Rozengurt E. Early signals in the mitogenic response. Science. 1986 Oct 10;234(4773):161–166. doi: 10.1126/science.3018928. [DOI] [PubMed] [Google Scholar]
  57. Rubinstein M., Novick D., Fischer D. G. The human interferon-gamma receptor system. Immunol Rev. 1987 Jun;97:29–50. doi: 10.1111/j.1600-065x.1987.tb00515.x. [DOI] [PubMed] [Google Scholar]
  58. Schneck J., Rager-Zisman B., Rosen O. M., Bloom B. R. Genetic analysis of the role of cAMP in mediating effects of interferon. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1879–1883. doi: 10.1073/pnas.79.6.1879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tamm I., Lin S. L., Pfeffer L. M., Sehgal P. B. Interferons alpha and beta as cellular regulatory molecules. Interferon. 1987;9:13–74. [PubMed] [Google Scholar]
  60. Tiwari R. K., Kusari J., Kumar R., Sen G. C. Gene induction by interferons and double-stranded RNA: selective inhibition by 2-aminopurine. Mol Cell Biol. 1988 Oct;8(10):4289–4294. doi: 10.1128/mcb.8.10.4289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Wathelet M. G., Clauss I. M., Content J., Huez G. A. Regulation of two interferon-inducible human genes by interferon, poly(rI).poly(rC) and viruses. Eur J Biochem. 1988 Jun 1;174(2):323–329. doi: 10.1111/j.1432-1033.1988.tb14101.x. [DOI] [PubMed] [Google Scholar]
  62. Wathelet M. G., Clauss I. M., Nols C. B., Content J., Huez G. A. New inducers revealed by the promoter sequence analysis of two interferon-activated human genes. Eur J Biochem. 1987 Dec 1;169(2):313–321. doi: 10.1111/j.1432-1033.1987.tb13614.x. [DOI] [PubMed] [Google Scholar]
  63. Wilde C. D., Crowther C. E., Cripe T. P., Gwo-Shu Lee M., Cowan N. J. Evidence that a human beta-tubulin pseudogene is derived from its corresponding mRNA. Nature. 1982 May 6;297(5861):83–84. doi: 10.1038/297083a0. [DOI] [PubMed] [Google Scholar]
  64. Yan C., Sehgal P. B., Tamm I. Signal transduction pathways in the induction of 2',5'-oligoadenylate synthetase gene expression by interferon alpha/beta. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2243–2247. doi: 10.1073/pnas.86.7.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Yap W. H., Teo T. S., McCoy E., Tan Y. H. Rapid and transient rise in diacylglycerol concentration in Daudi cells exposed to interferon. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7765–7769. doi: 10.1073/pnas.83.20.7765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Yap W. H., Teo T. S., Tan Y. H. An early event in the interferon-induced transmembrane signaling process. Science. 1986 Oct 17;234(4774):355–358. doi: 10.1126/science.2429366. [DOI] [PubMed] [Google Scholar]
  67. Zinn K., Keller A., Whittemore L. A., Maniatis T. 2-Aminopurine selectively inhibits the induction of beta-interferon, c-fos, and c-myc gene expression. Science. 1988 Apr 8;240(4849):210–213. doi: 10.1126/science.3281258. [DOI] [PubMed] [Google Scholar]

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

RESOURCES