Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1989 Jun;63(6):2616–2622. doi: 10.1128/jvi.63.6.2616-2622.1989

Regulation of the interferon-inducible IFI-78K gene, the human equivalent of the murine Mx gene, by interferons, double-stranded RNA, certain cytokines, and viruses.

J F Goetschy 1, H Zeller 1, J Content 1, M A Horisberger 1
PMCID: PMC250741  PMID: 2542574

Abstract

The interferon-inducible gene (IFI-78K gene) that codes for a human protein, p78, of 78,000 Mr is the equivalent of the mouse Mx gene encoding Mx protein. The IFI-78K gene is located on chromosome 21 together with the alpha/beta interferon (IFN-alpha/beta) receptor. The p78 protein is important since it may be involved in resistance to influenza viruses. The regulation of the IFI-78K gene was studied in human diploid cells by using a cDNA probe to p78 mRNA and specific monoclonal antibodies to p78 protein. The IFI-78K gene, a normally quiescent gene, is transcriptionally regulated by IFN-alpha, and its induction does not require protein synthesis. The rate of transcription measured in a run-on assay increased rapidly but transiently. The level of p78 mRNA increased up to 8 h, declining slowly afterwards. The p78 protein, undetectable in untreated cells, accumulated up to 16 h, and its amount remained stable for at least 36 h after the addition of IFN-alpha. Cytokines such as tumor necrosis factor, interleukin-1 alpha, and interleukin-1 beta activated the IFI-78K gene at concentrations comparable to that of IFN-alpha. However, gene activation by these cytokines required protein synthesis. Poly(rI)-poly(rC) induced the IFI-78K gene directly at the transcriptional level without requirement for protein synthesis. Newcastle disease virus, influenza virus, and to a lesser extent vesicular stomatitis virus also induced the IFI-78K gene in the absence of any protein synthesis. Induction of transcription by viruses was markedly enhanced by pretreatment of cells with IFN-gamma (which by itself is a poor inducer of the IFI-78K gene), resulting in accumulation of p78 protein during the course of infection; this suggests that IFN-gamma programs cells to full antiviral activity upon virus infection.

Full text

PDF
2616

Images in this article

2618Image
on p.2618
2619Image
on p.2619
2619Image
on p.2619

Selected References

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

  1. Aguet M., Mogensen K. E. Interferon receptors. Interferon. 1983;5:1–22. [PubMed] [Google Scholar]
  2. Beresini M. H., Lempert M. J., Epstein L. B. Overlapping polypeptide induction in human fibroblasts in response to treatment with interferon-alpha, interferon-gamma, interleukin 1 alpha, interleukin 1 beta, and tumor necrosis factor. J Immunol. 1988 Jan 15;140(2):485–493. [PubMed] [Google Scholar]
  3. Chebath J., Merlin G., Metz R., Benech P., Revel M. Interferon-induced 56,000 Mr protein and its mRNA in human cells: molecular cloning and partial sequence of the cDNA. Nucleic Acids Res. 1983 Mar 11;11(5):1213–1226. doi: 10.1093/nar/11.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Content J., De Wit L., Poupart P., Opdenakker G., Van Damme J., Billiau A. Induction of a 26-kDa-protein mRNA in human cells treated with an interleukin-1-related, leukocyte-derived factor. Eur J Biochem. 1985 Oct 15;152(2):253–257. doi: 10.1111/j.1432-1033.1985.tb09191.x. [DOI] [PubMed] [Google Scholar]
  5. Czarniecki C. W., Fennie C. W., Powers D. B., Estell D. A. Synergistic antiviral and antiproliferative activities of Escherichia coli-derived human alpha, beta, and gamma interferons. J Virol. 1984 Feb;49(2):490–496. doi: 10.1128/jvi.49.2.490-496.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fleischmann W. R., Jr, Georgiades J. A., Osborne L. C., Johnson H. M. Potentiation of interferon activity by mixed preparations of fibroblast and immune interferon. Infect Immun. 1979 Oct;26(1):248–253. doi: 10.1128/iai.26.1.248-253.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fleischmann W. R., Jr Potentiation of the direct anticellular activity of mouse interferons: mutual synergism and interferon concentration dependence. Cancer Res. 1982 Mar;42(3):869–875. [PubMed] [Google Scholar]
  8. 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]
  9. Goodbourn S., Zinn K., Maniatis T. Human beta-interferon gene expression is regulated by an inducible enhancer element. Cell. 1985 Jun;41(2):509–520. doi: 10.1016/s0092-8674(85)80024-6. [DOI] [PubMed] [Google Scholar]
  10. Horisberger M. A., Hochkeppel H. K. IFN-alpha induced human 78 kD protein: purification and homologies with the mouse Mx protein, production of monoclonal antibodies, and potentiation effect of IFN-gamma. J Interferon Res. 1987 Aug;7(4):331–343. doi: 10.1089/jir.1987.7.331. [DOI] [PubMed] [Google Scholar]
  11. Horisberger M. A., Staeheli P., Haller O. Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1910–1914. doi: 10.1073/pnas.80.7.1910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Horisberger M. A., Wathelet M., Szpirer J., Szpirer C., Islam Q., Levan G., Huez G., Content J. cDNA cloning and assignment to chromosome 21 of IFI-78K gene, the human equivalent of murine Mx gene. Somat Cell Mol Genet. 1988 Mar;14(2):123–131. doi: 10.1007/BF01534397. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Kohase M., Henriksen-DeStefano D., May L. T., Vilcek J., Sehgal P. B. Induction of beta 2-interferon by tumor necrosis factor: a homeostatic mechanism in the control of cell proliferation. Cell. 1986 Jun 6;45(5):659–666. doi: 10.1016/0092-8674(86)90780-4. [DOI] [PubMed] [Google Scholar]
  15. Kohase M., May L. T., Tamm I., Vilcek J., Sehgal P. B. A cytokine network in human diploid fibroblasts: interactions of beta-interferons, tumor necrosis factor, platelet-derived growth factor, and interleukin-1. Mol Cell Biol. 1987 Jan;7(1):273–280. doi: 10.1128/mcb.7.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kusari J., Sen G. C. Transcriptional analyses of interferon-inducible mRNAs. Mol Cell Biol. 1987 Jan;7(1):528–531. doi: 10.1128/mcb.7.1.528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kyhse-Andersen J. Electroblotting of multiple gels: a simple apparatus without buffer tank for rapid transfer of proteins from polyacrylamide to nitrocellulose. J Biochem Biophys Methods. 1984 Dec;10(3-4):203–209. doi: 10.1016/0165-022x(84)90040-x. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. Lengyel P. Biochemistry of interferons and their actions. Annu Rev Biochem. 1982;51:251–282. doi: 10.1146/annurev.bi.51.070182.001343. [DOI] [PubMed] [Google Scholar]
  21. Manuelidis E. E., de Figueiredo J. M., Kim J. H., Fritch W. W., Manuelidis L. Transmission studies from blood of Alzheimer disease patients and healthy relatives. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4898–4901. doi: 10.1073/pnas.85.13.4898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mestan J., Digel W., Mittnacht S., Hillen H., Blohm D., Möller A., Jacobsen H., Kirchner H. Antiviral effects of recombinant tumour necrosis factor in vitro. 1986 Oct 30-Nov 5Nature. 323(6091):816–819. doi: 10.1038/323816a0. [DOI] [PubMed] [Google Scholar]
  23. Meyer T., Horisberger M. A. Combined action of mouse alpha and beta interferons in influenza virus-infected macrophages carrying the resistance gene Mx. J Virol. 1984 Mar;49(3):709–716. doi: 10.1128/jvi.49.3.709-716.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nielsen P. J., McMaster G. K., Trachsel H. Cloning of eukaryotic protein synthesis initiation factor genes: isolation and characterization of cDNA clones encoding factor eIF-4A. Nucleic Acids Res. 1985 Oct 11;13(19):6867–6880. doi: 10.1093/nar/13.19.6867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ogata K., Arakawa M., Kasahara T., Shioiri-Nakano K., Hiraoka K. Detection of toxoplasma membrane antigens transferred from SDS-polyacrylamide gel to nitrocellulose with monoclonal antibody and avidin-biotin, peroxidase anti-peroxidase and immunoperoxidase methods. J Immunol Methods. 1983 Dec 16;65(1-2):75–82. doi: 10.1016/0022-1759(83)90305-8. [DOI] [PubMed] [Google Scholar]
  26. Raziuddin A., Sarkar F. H., Dutkowski R., Shulman L., Ruddle F. H., Gupta S. L. Receptors for human alpha and beta interferon but not for gamma interferon are specified by human chromosome 21. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5504–5508. doi: 10.1073/pnas.81.17.5504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Reis L. F., Le J. M., Hirano T., Kishimoto T., Vilcek J. Antiviral action of tumor necrosis factor in human fibroblasts is not mediated by B cell stimulatory factor 2/IFN-beta 2, and is inhibited by specific antibodies to IFN-beta. J Immunol. 1988 Mar 1;140(5):1566–1570. [PubMed] [Google Scholar]
  28. Staeheli P., Danielson P., Haller O., Sutcliffe J. G. Transcriptional activation of the mouse Mx gene by type I interferon. Mol Cell Biol. 1986 Dec;6(12):4770–4774. doi: 10.1128/mcb.6.12.4770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Staeheli P., Haller O., Boll W., Lindenmann J., Weissmann C. Mx protein: constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus. Cell. 1986 Jan 17;44(1):147–158. doi: 10.1016/0092-8674(86)90493-9. [DOI] [PubMed] [Google Scholar]
  30. Tiwari R. K., Kusari J., Sen G. C. Functional equivalents of interferon-mediated signals needed for induction of an mRNA can be generated by double-stranded RNA and growth factors. EMBO J. 1987 Nov;6(11):3373–3378. doi: 10.1002/j.1460-2075.1987.tb02659.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Van Damme J., De Ley M., Van Snick J., Dinarello C. A., Billiau A. The role of interferon-beta 1 and the 26-kDa protein (interferon-beta 2) as mediators of the antiviral effect of interleukin 1 and tumor necrosis factor. J Immunol. 1987 Sep 15;139(6):1867–1872. [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. White B. A., Bancroft F. C. Cytoplasmic dot hybridization. Simple analysis of relative mRNA levels in multiple small cell or tissue samples. J Biol Chem. 1982 Aug 10;257(15):8569–8572. [PubMed] [Google Scholar]
  35. Wong G. H., Goeddel D. V. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. 1986 Oct 30-Nov 5Nature. 323(6091):819–822. doi: 10.1038/323819a0. [DOI] [PubMed] [Google Scholar]
  36. Zerial A., Hovanessian A. G., Stefanos S., Huygen K., Werner G. H., Falcoff E. Synergistic activities of type I (alpha, beta) and type II (gamma) murine interferons. Antiviral Res. 1982 Sep;2(4):227–239. doi: 10.1016/0166-3542(82)90045-6. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Zullo J. N., Cochran B. H., Huang A. S., Stiles C. D. Platelet-derived growth factor and double-stranded ribonucleic acids stimulate expression of the same genes in 3T3 cells. Cell. 1985 Dec;43(3 Pt 2):793–800. doi: 10.1016/0092-8674(85)90252-1. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES