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. 1992 Mar 1;89(5):1740–1744. doi: 10.1073/pnas.89.5.1740

The c-rel protooncogene product c-Rel but not NF-kappa B binds to the intronic region of the human interferon-gamma gene at a site related to an interferon-stimulable response element.

A Sica 1, T H Tan 1, N Rice 1, M Kretzschmar 1, P Ghosh 1, H A Young 1
PMCID: PMC48528  PMID: 1542667

Abstract

Interferon-gamma (IFN-gamma) is an important immunoregulatory protein that is expressed usually only in large granular lymphocytes and T cells. The gene encoding IFN-gamma was previously found to contain an intronic enhancer element that was not tissue-specific in its activity, despite the restricted expression of the intact IFN-gamma-encoding gene. Using nuclear extracts from the human T-cell line Jurkat, we have now identified two protein-binding regions in this intronic enhancer element. One of the protected regions has strong partial identify to the NF-kappa B site present in the promoter region of the human interleukin 2-encoding gene. Based on this observation and recent reports of the interaction of the c-rel protooncogene product (c-Rel) with NF-kappa B sites, we determined whether c-Rel could interact with the intronic enhancer element in the human IFN-gamma genomic DNA. Most surprisingly, gel-shift analysis, using c-Rel expressed in Escherichia coli established that c-Rel binds specifically to the IFN-gamma intronic DNA but not to the interleukin 2-like NF-kappa B site. Additional studies with antibodies prepared against c-Rel peptides verified specificity of the interaction of c-Rel with this binding site. In addition, using an affinity-purified p50 subunit of the NF-kappa B complex, we observed that the p50 protein did not bind to this additional c-Rel-binding site. Furthermore, nucleotide sequence analysis of this DNA region revealed a strong similarity of the additional c-Rel-binding site to a previously identified IFN-stimulable response element. These data show that c-Rel can interact with DNA regions distinct from that recognized by NF-kappa B and may, in fact, be involved in transcriptional regulation of the IFN-stimulable genes via the IFN-stimulable response element.

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Selected References

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

  1. Ackrill A. M., Reid L. E., Gilbert C. S., Gewert D. R., Porter A. C., Lewin A. R., Stark G. R., Kerr I. M. Differential response of the human 6-16 and 9-27 genes to alpha and gamma interferons. Nucleic Acids Res. 1991 Feb 11;19(3):591–598. doi: 10.1093/nar/19.3.591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
  3. Baeuerle P. A. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta. 1991 Apr 16;1072(1):63–80. doi: 10.1016/0304-419x(91)90007-8. [DOI] [PubMed] [Google Scholar]
  4. Ballard D. W., Walker W. H., Doerre S., Sista P., Molitor J. A., Dixon E. P., Peffer N. J., Hannink M., Greene W. C. The v-rel oncogene encodes a kappa B enhancer binding protein that inhibits NF-kappa B function. Cell. 1990 Nov 16;63(4):803–814. doi: 10.1016/0092-8674(90)90146-6. [DOI] [PubMed] [Google Scholar]
  5. Brown D. A., Nelson F. B., Reinherz E. L., Diamond D. J. The human interferon-gamma gene contains an inducible promoter that can be transactivated by tax I and II. Eur J Immunol. 1991 Aug;21(8):1879–1885. doi: 10.1002/eji.1830210815. [DOI] [PubMed] [Google Scholar]
  6. Brownell E., Mittereder N., Rice N. R. A human rel proto-oncogene cDNA containing an Alu fragment as a potential coding exon. Oncogene. 1989 Jul;4(7):935–942. [PubMed] [Google Scholar]
  7. Bull P., Hunter T., Verma I. M. Transcriptional induction of the murine c-rel gene with serum and phorbol-12-myristate-13-acetate in fibroblasts. Mol Cell Biol. 1989 Nov;9(11):5239–5243. doi: 10.1128/mcb.9.11.5239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bull P., Morley K. L., Hoekstra M. F., Hunter T., Verma I. M. The mouse c-rel protein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain. Mol Cell Biol. 1990 Oct;10(10):5473–5485. doi: 10.1128/mcb.10.10.5473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chrivia J. C., Wedrychowicz T., Young H. A., Hardy K. J. A model of human cytokine regulation based on transfection of gamma interferon gene fragments directly into isolated peripheral blood T lymphocytes. J Exp Med. 1990 Aug 1;172(2):661–664. doi: 10.1084/jem.172.2.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ciccarone V. C., Chrivia J., Hardy K. J., Young H. A. Identification of enhancer-like elements in human IFN-gamma genomic DNA. J Immunol. 1990 Jan 15;144(2):725–730. [PubMed] [Google Scholar]
  11. Collart M. A., Belin D., Vassalli J. D., de Kossodo S., Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986 Dec 1;164(6):2113–2118. doi: 10.1084/jem.164.6.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dorn P., DaSilva L., Martarano L., Derse D. Equine infectious anemia virus tat: insights into the structure, function, and evolution of lentivirus trans-activator proteins. J Virol. 1990 Apr;64(4):1616–1624. doi: 10.1128/jvi.64.4.1616-1624.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fox H. S., Bond B. L., Parslow T. G. Estrogen regulates the IFN-gamma promoter. J Immunol. 1991 Jun 15;146(12):4362–4367. [PubMed] [Google Scholar]
  14. Ghosh S., Gifford A. M., Riviere L. R., Tempst P., Nolan G. P., Baltimore D. Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell. 1990 Sep 7;62(5):1019–1029. doi: 10.1016/0092-8674(90)90276-k. [DOI] [PubMed] [Google Scholar]
  15. Grumont R. J., Gerondakis S. Murine c-rel transcription is rapidly induced in T-cells and fibroblasts by mitogenic agents and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Cell Growth Differ. 1990 Aug;1(8):345–350. [PubMed] [Google Scholar]
  16. Grumont R. J., Gerondakis S. The murine c-rel proto-oncogene encodes two mRNAs the expression of which is modulated by lymphoid stimuli. Oncogene Res. 1990;5(4):245–254. [PubMed] [Google Scholar]
  17. Gupta S. L. Regulation of cellular gene expression by interferon-gamma: involvement of multiple pathways. Int J Cell Cloning. 1990 Jan;8 (Suppl 1):92–102. doi: 10.1002/stem.5530080709. [DOI] [PubMed] [Google Scholar]
  18. Gélinas C., Temin H. M. The v-rel oncogene encodes a cell-specific transcriptional activator of certain promoters. Oncogene. 1988 Oct;3(4):349–355. [PubMed] [Google Scholar]
  19. Hannink M., Temin H. M. Transactivation of gene expression by nuclear and cytoplasmic rel proteins. Mol Cell Biol. 1989 Oct;9(10):4323–4336. doi: 10.1128/mcb.9.10.4323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hardy K. J., Manger B., Newton M., Stobo J. D. Molecular events involved in regulating human interferon-gamma gene expression during T cell activation. J Immunol. 1987 Apr 1;138(7):2353–2358. [PubMed] [Google Scholar]
  21. Hardy K. J., Peterlin B. M., Atchison R. E., Stobo J. D. Regulation of expression of the human interferon gamma gene. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8173–8177. doi: 10.1073/pnas.82.23.8173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Inoue J., Kerr L. D., Ransone L. J., Bengal E., Hunter T., Verma I. M. c-rel activates but v-rel suppresses transcription from kappa B sites. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3715–3719. doi: 10.1073/pnas.88.9.3715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kadonaga J. T., Carner K. R., Masiarz F. R., Tjian R. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell. 1987 Dec 24;51(6):1079–1090. doi: 10.1016/0092-8674(87)90594-0. [DOI] [PubMed] [Google Scholar]
  25. Kasahara T., Hooks J. J., Dougherty S. F., Oppenheim J. J. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 1983 Apr;130(4):1784–1789. [PubMed] [Google Scholar]
  26. Kerr I. M., Stark G. R. The control of interferon-inducible gene expression. FEBS Lett. 1991 Jul 22;285(2):194–198. doi: 10.1016/0014-5793(91)80802-a. [DOI] [PubMed] [Google Scholar]
  27. Kieran M., Blank V., Logeat F., Vandekerckhove J., Lottspeich F., Le Bail O., Urban M. B., Kourilsky P., Baeuerle P. A., Israël A. The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell. 1990 Sep 7;62(5):1007–1018. doi: 10.1016/0092-8674(90)90275-j. [DOI] [PubMed] [Google Scholar]
  28. Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nolan G. P., Ghosh S., Liou H. C., Tempst P., Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell. 1991 Mar 8;64(5):961–969. doi: 10.1016/0092-8674(91)90320-x. [DOI] [PubMed] [Google Scholar]
  30. Rice N. R., Copeland T. D., Simek S., Oroszlan S., Gilden R. V. Detection and characterization of the protein encoded by the v-rel oncogene. Virology. 1986 Mar;149(2):217–229. doi: 10.1016/0042-6822(86)90123-6. [DOI] [PubMed] [Google Scholar]
  31. Richardson P. M., Gilmore T. D. vRel is an inactive member of the Rel family of transcriptional activating proteins. J Virol. 1991 Jun;65(6):3122–3130. doi: 10.1128/jvi.65.6.3122-3130.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Sen R., Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986 Aug 29;46(5):705–716. doi: 10.1016/0092-8674(86)90346-6. [DOI] [PubMed] [Google Scholar]
  34. Tan T. H., Horikoshi M., Roeder R. G. Purification and characterization of multiple nuclear factors that bind to the TAX-inducible enhancer within the human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1989 Apr;9(4):1733–1745. doi: 10.1128/mcb.9.4.1733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Urban M. B., Schreck R., Baeuerle P. A. NF-kappa B contacts DNA by a heterodimer of the p50 and p65 subunit. EMBO J. 1991 Jul;10(7):1817–1825. doi: 10.1002/j.1460-2075.1991.tb07707.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Young H. A., Hardy K. J. Interferon-gamma: producer cells, activation stimuli, and molecular genetic regulation. Pharmacol Ther. 1990;45(1):137–151. doi: 10.1016/0163-7258(90)90012-q. [DOI] [PubMed] [Google Scholar]
  37. Young H. A., Ortaldo J. R. One-signal requirement for interferon-gamma production by human large granular lymphocytes. J Immunol. 1987 Aug 1;139(3):724–727. [PubMed] [Google Scholar]

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