Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1992 Aug;12(8):3325–3336. doi: 10.1128/mcb.12.8.3325

Inducible processing of interferon regulatory factor-2.

V J Palombella 1, T Maniatis 1
PMCID: PMC364579  PMID: 1630448

Abstract

PRDI-BFc and PRDI-BFi are proteins that bind specifically to a regulatory element required for virus induction of the human beta interferon (IFN-beta). PRDI-BFc is a constitutive binding activity, while the PRDI-BFi binding activity is observed only after cells are treated with inducers such as virus or poly(I).poly(C) plus cycloheximide or in some cells by cycloheximide alone. In this paper we report that PRDI-BFc is interferon regulatory factor-2 (IRF-2), a known transcriptional repressor. In addition, we find that PRDI-BFi is a truncated form of IRF-2, lacking approximately 185 C-terminal amino acids. Thus, PRDI-BFi appears to be generated by inducible proteolysis. Although the affinity of PRDI-BFc/IRF-2 for the IFN-beta promoter does not appear to be affected by the removal of C-terminal amino acids, the ability of PRDI-BFi to function as a repressor in cotransfection experiments is significantly less than that of intact IRF-2. Studies have shown that IRF-2 can block the activity of the transcriptional activator IRF-1, which also binds specifically to the IFN-beta gene promoter. Thus, the inducible proteolysis of IRF-2 may be involved in the regulation of the IFN-beta gene or of other genes in which the ratio of IRF-1 to IRF-2 can affect the level of transcription.

Full text

PDF
3325

Images in this article

3328Image
on p.3328
3329Image
on p.3329
3330Image
on p.3330
3330Image
on p.3330
3331Image
on p.3331
3331Image
on p.3331
3333Image
on p.3333

Selected References

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

  1. Baeuerle P. A., Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell. 1988 Apr 22;53(2):211–217. doi: 10.1016/0092-8674(88)90382-0. [DOI] [PubMed] [Google Scholar]
  2. Brand A. H., Breeden L., Abraham J., Sternglanz R., Nasmyth K. Characterization of a "silencer" in yeast: a DNA sequence with properties opposite to those of a transcriptional enhancer. Cell. 1985 May;41(1):41–48. doi: 10.1016/0092-8674(85)90059-5. [DOI] [PubMed] [Google Scholar]
  3. Chen C. A., Okayama H. Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA. Biotechniques. 1988 Jul-Aug;6(7):632–638. [PubMed] [Google Scholar]
  4. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Du W., Maniatis T. An ATF/CREB binding site is required for virus induction of the human interferon beta gene [corrected]. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2150–2154. doi: 10.1073/pnas.89.6.2150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Fan C. M., Maniatis T. Generation of p50 subunit of NF-kappa B by processing of p105 through an ATP-dependent pathway. Nature. 1991 Dec 5;354(6352):395–398. doi: 10.1038/354395a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Fried M., Crothers D. M. Equilibria and kinetics of lac repressor-operator interactions by polyacrylamide gel electrophoresis. Nucleic Acids Res. 1981 Dec 11;9(23):6505–6525. doi: 10.1093/nar/9.23.6505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fujita T., Kimura Y., Miyamoto M., Barsoumian E. L., Taniguchi T. Induction of endogenous IFN-alpha and IFN-beta genes by a regulatory transcription factor, IRF-1. Nature. 1989 Jan 19;337(6204):270–272. doi: 10.1038/337270a0. [DOI] [PubMed] [Google Scholar]
  11. Fujita T., Miyamoto M., Kimura Y., Hammer J., Taniguchi T. Involvement of a cis-element that binds an H2TF-1/NF kappa B like factor(s) in the virus-induced interferon-beta gene expression. Nucleic Acids Res. 1989 May 11;17(9):3335–3346. doi: 10.1093/nar/17.9.3335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fujita T., Ohno S., Yasumitsu H., Taniguchi T. Delimitation and properties of DNA sequences required for the regulated expression of human interferon-beta gene. Cell. 1985 Jun;41(2):489–496. doi: 10.1016/s0092-8674(85)80022-2. [DOI] [PubMed] [Google Scholar]
  13. Fujita T., Reis L. F., Watanabe N., Kimura Y., Taniguchi T., Vilcek J. Induction of the transcription factor IRF-1 and interferon-beta mRNAs by cytokines and activators of second-messenger pathways. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9936–9940. doi: 10.1073/pnas.86.24.9936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fujita T., Sakakibara J., Sudo Y., Miyamoto M., Kimura Y., Taniguchi T. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J. 1988 Nov;7(11):3397–3405. doi: 10.1002/j.1460-2075.1988.tb03213.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fujita T., Shibuya H., Hotta H., Yamanishi K., Taniguchi T. Interferon-beta gene regulation: tandemly repeated sequences of a synthetic 6 bp oligomer function as a virus-inducible enhancer. Cell. 1987 May 8;49(3):357–367. doi: 10.1016/0092-8674(87)90288-1. [DOI] [PubMed] [Google Scholar]
  16. Goodbourn S., Maniatis T. Overlapping positive and negative regulatory domains of the human beta-interferon gene. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1447–1451. doi: 10.1073/pnas.85.5.1447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Harada H., Fujita T., Miyamoto M., Kimura Y., Maruyama M., Furia A., Miyata T., Taniguchi T. Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell. 1989 Aug 25;58(4):729–739. doi: 10.1016/0092-8674(89)90107-4. [DOI] [PubMed] [Google Scholar]
  20. Hiscott J., Alper D., Cohen L., Leblanc J. F., Sportza L., Wong A., Xanthoudakis S. Induction of human interferon gene expression is associated with a nuclear factor that interacts with the NF-kappa B site of the human immunodeficiency virus enhancer. J Virol. 1989 Jun;63(6):2557–2566. doi: 10.1128/jvi.63.6.2557-2566.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Itoh S., Harada H., Fujita T., Mimura T., Taniguchi T. Sequence of a cDNA coding for human IRF-2. Nucleic Acids Res. 1989 Oct 25;17(20):8372–8372. doi: 10.1093/nar/17.20.8372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kadonaga J. T., Tjian R. Affinity purification of sequence-specific DNA binding proteins. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5889–5893. doi: 10.1073/pnas.83.16.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Keller A. D., Maniatis T. Identification and characterization of a novel repressor of beta-interferon gene expression. Genes Dev. 1991 May;5(5):868–879. doi: 10.1101/gad.5.5.868. [DOI] [PubMed] [Google Scholar]
  24. Keller A. D., Maniatis T. Identification of an inducible factor that binds to a positive regulatory element of the human beta-interferon gene. Proc Natl Acad Sci U S A. 1988 May;85(10):3309–3313. doi: 10.1073/pnas.85.10.3309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kuhl D., de la Fuente J., Chaturvedi M., Parimoo S., Ryals J., Meyer F., Weissmann C. Reversible silencing of enhancers by sequences derived from the human IFN-alpha promoter. Cell. 1987 Sep 25;50(7):1057–1069. doi: 10.1016/0092-8674(87)90172-3. [DOI] [PubMed] [Google Scholar]
  26. Leblanc J. F., Cohen L., Rodrigues M., Hiscott J. Synergism between distinct enhanson domains in viral induction of the human beta interferon gene. Mol Cell Biol. 1990 Aug;10(8):3987–3993. doi: 10.1128/mcb.10.8.3987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lenardo M. J., Fan C. M., Maniatis T., Baltimore D. The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell. 1989 Apr 21;57(2):287–294. doi: 10.1016/0092-8674(89)90966-5. [DOI] [PubMed] [Google Scholar]
  28. Levine M., Manley J. L. Transcriptional repression of eukaryotic promoters. Cell. 1989 Nov 3;59(3):405–408. doi: 10.1016/0092-8674(89)90024-x. [DOI] [PubMed] [Google Scholar]
  29. MacDonald N. J., Kuhl D., Maguire D., Näf D., Gallant P., Goswamy A., Hug H., Büeler H., Chaturvedi M., de la Fuente J. Different pathways mediate virus inducibility of the human IFN-alpha 1 and IFN-beta genes. Cell. 1990 Mar 9;60(5):767–779. doi: 10.1016/0092-8674(90)90091-r. [DOI] [PubMed] [Google Scholar]
  30. MacGregor G. R., Caskey C. T. Construction of plasmids that express E. coli beta-galactosidase in mammalian cells. Nucleic Acids Res. 1989 Mar 25;17(6):2365–2365. doi: 10.1093/nar/17.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Maroteaux L., Chen L., Mitrani-Rosenbaum S., Howley P. M., Revel M. Cycloheximide induces expression of the human interferon beta 1 gene in mouse cells transformed by bovine papillomavirus-interferon beta 1 recombinants. J Virol. 1983 Jul;47(1):89–95. doi: 10.1128/jvi.47.1.89-95.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miyamoto M., Fujita T., Kimura Y., Maruyama M., Harada H., Sudo Y., Miyata T., Taniguchi T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell. 1988 Sep 9;54(6):903–913. doi: 10.1016/s0092-8674(88)91307-4. [DOI] [PubMed] [Google Scholar]
  33. Munro S., Pelham H. R. A C-terminal signal prevents secretion of luminal ER proteins. Cell. 1987 Mar 13;48(5):899–907. doi: 10.1016/0092-8674(87)90086-9. [DOI] [PubMed] [Google Scholar]
  34. Näf D., Hardin S. E., Weissmann C. Multimerization of AAGTGA and GAAAGT generates sequences that mediate virus inducibility by mimicking an interferon promoter element. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1369–1373. doi: 10.1073/pnas.88.4.1369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ogawa H., Ogawa T. Regulation in repressor inactivation by RecA protein. Adv Biophys. 1990;26:33–49. doi: 10.1016/0065-227x(90)90006-f. [DOI] [PubMed] [Google Scholar]
  36. Pine R., Decker T., Kessler D. S., Levy D. E., Darnell J. E., Jr Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Mol Cell Biol. 1990 Jun;10(6):2448–2457. doi: 10.1128/mcb.10.6.2448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Raj N. B., Engelhardt J., Au W. C., Levy D. E., Pitha P. M. Virus infection and interferon can activate gene expression through a single synthetic element, but endogenous genes show distinct regulation. J Biol Chem. 1989 Oct 5;264(28):16658–16666. [PubMed] [Google Scholar]
  38. Raj N. B., Pitha P. M. Two levels of regulation of beta-interferon gene expression in human cells. Proc Natl Acad Sci U S A. 1983 Jul;80(13):3923–3927. doi: 10.1073/pnas.80.13.3923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Reis L. F., Harada H., Wolchok J. D., Taniguchi T., Vilcek J. Critical role of a common transcription factor, IRF-1, in the regulation of IFN-beta and IFN-inducible genes. EMBO J. 1992 Jan;11(1):185–193. doi: 10.1002/j.1460-2075.1992.tb05041.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Renkawitz R. Transcriptional repression in eukaryotes. Trends Genet. 1990 Jun;6(6):192–197. doi: 10.1016/0168-9525(90)90176-7. [DOI] [PubMed] [Google Scholar]
  41. Rivière Y., Blank V., Kourilsky P., Israël A. Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection. Nature. 1991 Apr 18;350(6319):625–626. doi: 10.1038/350625a0. [DOI] [PubMed] [Google Scholar]
  42. Sehgal P. B., Dobberstein B., Tamm I. Interferon messenger RNA content of human fibroblasts during induction, shutoff, and superinduction of interferon production. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3409–3413. doi: 10.1073/pnas.74.8.3409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sehgal P. B., Tamm I. Two mechanisms contribute to the superinduction of poly(I).poly(C)-induced human fibroblast interferon production. Virology. 1979 Jan 15;92(1):240–244. doi: 10.1016/0042-6822(79)90230-7. [DOI] [PubMed] [Google Scholar]
  44. Sen R., Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26;47(6):921–928. doi: 10.1016/0092-8674(86)90807-x. [DOI] [PubMed] [Google Scholar]
  45. Visvanathan K. V., Goodbourn S. Double-stranded RNA activates binding of NF-kappa B to an inducible element in the human beta-interferon promoter. EMBO J. 1989 Apr;8(4):1129–1138. doi: 10.1002/j.1460-2075.1989.tb03483.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Watanabe N., Sakakibara J., Hovanessian A. G., Taniguchi T., Fujita T. Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF-1 synthesis. Nucleic Acids Res. 1991 Aug 25;19(16):4421–4428. doi: 10.1093/nar/19.16.4421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Weinstock G. M., McEntee K. RecA protein-dependent proteolysis of bacteriophage lambda repressor Characterization of the reaction and stimulation by DNA-binding proteins. J Biol Chem. 1981 Nov 10;256(21):10883–10888. [PubMed] [Google Scholar]
  48. Whiteside S. T., Visvanathan K. V., Goodbourn S. Identification of novel factors that bind to the PRD I region of the human beta-interferon promoter. Nucleic Acids Res. 1992 Apr 11;20(7):1531–1538. doi: 10.1093/nar/20.7.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Whittemore L. A., Maniatis T. Postinduction repression of the beta-interferon gene is mediated through two positive regulatory domains. Proc Natl Acad Sci U S A. 1990 Oct;87(20):7799–7803. doi: 10.1073/pnas.87.20.7799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Whittemore L. A., Maniatis T. Postinduction turnoff of beta-interferon gene expression. Mol Cell Biol. 1990 Apr;10(4):1329–1337. doi: 10.1128/mcb.10.4.1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Xanthoudakis S., Cohen L., Hiscott J. Multiple protein-DNA interactions within the human interferon-beta regulatory element. J Biol Chem. 1989 Jan 15;264(2):1139–1145. [PubMed] [Google Scholar]
  52. Yang Y. C., Ciarletta A. B., Temple P. A., Chung M. P., Kovacic S., Witek-Giannotti J. S., Leary A. C., Kriz R., Donahue R. E., Wong G. G. Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell. 1986 Oct 10;47(1):3–10. doi: 10.1016/0092-8674(86)90360-0. [DOI] [PubMed] [Google Scholar]
  53. Zinn K., DiMaio D., Maniatis T. Identification of two distinct regulatory regions adjacent to the human beta-interferon gene. Cell. 1983 Oct;34(3):865–879. doi: 10.1016/0092-8674(83)90544-5. [DOI] [PubMed] [Google Scholar]

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

RESOURCES