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Mol Cell Biol. Aug 1993; 13(8): 4531–4538.
PMCID: PMC360068

Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system.

Abstract

Interferon (IFN) regulatory factor 1 (IRF-1) and IRF-2 were originally identified as transcription factors involved in the regulation of the IFN system. IRF-1 functions as a transcriptional activator, while IRF-2 represses IRF-1 function. More recently, evidence has been provided that IRF-1 and IRF-2 manifest antioncogenic and oncogenic properties, respectively, and that loss of one or both of the IRF-1 alleles may be critical for the development of human hematopoietic neoplasms. Both factors show a high degree of structural similarity in their N-terminal DNA-binding domains, and previous studies suggested that IRF-1 and IRF-2 bind to similar or identical cis elements within type I IFN (IFN-alpha and -beta) and IFN-inducible genes. However, the exact recognition sequences of these two factors have not yet been determined; hence, the spectrum of the IRF-responsive genes remains unclear. In this study, we determined the DNA sequences recognized by IRF-1 and IRF-2, using a polymerase chain reaction-assisted DNA-binding site selection method. We report that sequences selected by this method and the affinities for each sequence were virtually indistinguishable between IRF-1 and IRF-2. We confirm the presence of two contiguous IRF recognition sequences within the promoter region of the IFN-beta gene and of at least one such sequence in all of the IFN-inducible genes examined. Furthermore, we report the presence of potential IRF sequences in the upstream region of several genes involved in cell growth control.

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  • Abdollahi A, Lord KA, Hoffman-Liebermann B, Liebermann DA. Interferon regulatory factor 1 is a myeloid differentiation primary response gene induced by interleukin 6 and leukemia inhibitory factor: role in growth inhibition. Cell Growth Differ. 1991 Aug;2(8):401–407. [PubMed]
  • Behrens J, Löwrick O, Klein-Hitpass L, Birchmeier W. The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11495–11499. [PMC free article] [PubMed]
  • Benech P, Vigneron M, Peretz D, Revel M, Chebath J. Interferon-responsive regulatory elements in the promoter of the human 2',5'-oligo(A) synthetase gene. Mol Cell Biol. 1987 Dec;7(12):4498–4504. [PMC free article] [PubMed]
  • Clemens MJ, McNurlan MA. Regulation of cell proliferation and differentiation by interferons. Biochem J. 1985 Mar 1;226(2):345–360. [PMC free article] [PubMed]
  • Dalton S, Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. [PubMed]
  • Driggers PH, Ennist DL, Gleason SL, Mak WH, Marks MS, Levi BZ, Flanagan JR, Appella E, Ozato K. An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc Natl Acad Sci U S A. 1990 May;87(10):3743–3747. [PMC free article] [PubMed]
  • Eder A, Krafft-Czepa H, Krammer PH. The 5' region of the human interleukin 4 gene: structure and potential regulatory elements. Nucleic Acids Res. 1988 Jan 25;16(2):772–772. [PMC free article] [PubMed]
  • Friedman RL, Stark GR. alpha-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences. Nature. 1985 Apr 18;314(6012):637–639. [PubMed]
  • Fu XY. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24;70(2):323–335. [PubMed]
  • Fujita T, Kimura Y, Miyamoto M, Barsoumian EL, 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. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Fujita T, Reis LF, 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. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, Ishihara M, Taniguchi T. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science. 1993 Feb 12;259(5097):971–974. [PubMed]
  • Harada H, Willison K, Sakakibara J, Miyamoto M, Fujita T, Taniguchi T. Absence of the type I IFN system in EC cells: transcriptional activator (IRF-1) and repressor (IRF-2) genes are developmentally regulated. Cell. 1990 Oct 19;63(2):303–312. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Imam AM, Ackrill AM, Dale TC, Kerr IM, Stark GR. Transcription factors induced by interferons alpha and gamma. Nucleic Acids Res. 1990 Nov 25;18(22):6573–6580. [PMC free article] [PubMed]
  • Israel A, Kimura A, Fournier A, Fellous M, Kourilsky P. Interferon response sequence potentiates activity of an enhancer in the promoter region of a mouse H-2 gene. Nature. 1986 Aug 21;322(6081):743–746. [PubMed]
  • Israël A, Kimura A, Kieran M, Yano O, Kanellopoulos J, Le Bail O, Kourilsky P. A common positive trans-acting factor binds to enhancer sequences in the promoters of mouse H-2 and beta 2-microglobulin genes. Proc Natl Acad Sci U S A. 1987 May;84(9):2653–2657. [PMC free article] [PubMed]
  • Jacobsen H, Krause D, Friedman RM, Silverman RH. Induction of ppp(A2'p)nA-dependent RNase in murine JLS-V9R cells during growth inhibition. Proc Natl Acad Sci U S A. 1983 Aug;80(16):4954–4958. [PMC free article] [PubMed]
  • Jackson RJ, Hunt T. Preparation and use of nuclease-treated rabbit reticulocyte lysates for the translation of eukaryotic messenger RNA. Methods Enzymol. 1983;96:50–74. [PubMed]
  • Johnson PF, McKnight SL. Eukaryotic transcriptional regulatory proteins. Annu Rev Biochem. 1989;58:799–839. [PubMed]
  • Kessler DS, Levy DE, Darnell JE., 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. [PMC free article] [PubMed]
  • Kohase M, May LT, Tamm I, Vilcek J, Sehgal PB. 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. [PMC free article] [PubMed]
  • Koromilas AE, Roy S, Barber GN, Katze MG, Sonenberg N. Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science. 1992 Sep 18;257(5077):1685–1689. [PubMed]
  • Leid M, Kastner P, Lyons R, Nakshatri H, Saunders M, Zacharewski T, Chen JY, Staub A, Garnier JM, Mader S, et al. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377–395. [PubMed]
  • Lengyel P. Biochemistry of interferons and their actions. Annu Rev Biochem. 1982;51:251–282. [PubMed]
  • Levy DE, Kessler DS, Pine R, Reich N, Darnell JE., 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. [PubMed]
  • Levy DE, Kessler DS, Pine R, Darnell JE., Jr Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev. 1989 Sep;3(9):1362–1371. [PubMed]
  • Lew DJ, Decker T, Strehlow I, Darnell JE. Overlapping elements in the guanylate-binding protein gene promoter mediate transcriptional induction by alpha and gamma interferons. Mol Cell Biol. 1991 Jan;11(1):182–191. [PMC free article] [PubMed]
  • Li R, Knight JD, Jackson SP, Tjian R, Botchan MR. Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription. Cell. 1991 May 3;65(3):493–505. [PubMed]
  • Luster AD, Ravetch JV. Genomic characterization of a gamma-interferon-inducible gene (IP-10) and identification of an interferon-inducible hypersensitive site. Mol Cell Biol. 1987 Oct;7(10):3723–3731. [PMC free article] [PubMed]
  • MacDonald NJ, Kuhl D, Maguire D, Näf D, Gallant P, Goswamy A, Hug H, Büeler H, Chaturvedi M, de la Fuente J, et al. Different pathways mediate virus inducibility of the human IFN-alpha 1 and IFN-beta genes. Cell. 1990 Mar 9;60(5):767–779. [PubMed]
  • 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. [PubMed]
  • Moore RN, Larsen HS, Horohov DW, Rouse BT. Endogenous regulation of macrophage proliferative expansion by colony-stimulating factor-induced interferon. Science. 1984 Jan 13;223(4632):178–181. [PubMed]
  • Ohno S, Taniguchi T. The 5'-flanking sequence of human interferon-beta 1 gene is responsible for viral induction of transcription. Nucleic Acids Res. 1983 Aug 25;11(16):5403–5412. [PMC free article] [PubMed]
  • Onozaki K, Urawa H, Tamatani T, Iwamura Y, Hashimoto T, Baba T, Suzuki H, Yamada M, Yamamoto S, Oppenheim JJ, et al. Synergistic interactions of interleukin 1, interferon-beta, and tumor necrosis factor in terminally differentiating a mouse myeloid leukemic cell line (M1). Evidence that interferon-beta is an autocrine differentiating factor. J Immunol. 1988 Jan 1;140(1):112–119. [PubMed]
  • Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. [PubMed]
  • Pine R, Decker T, Kessler DS, Levy DE, Darnell JE., 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. [PMC free article] [PubMed]
  • Pleiman CM, Gimpel SD, Park LS, Harada H, Taniguchi T, Ziegler SF. Organization of the murine and human interleukin-7 receptor genes: two mRNAs generated by differential splicing and presence of a type I-interferon-inducible promoter. Mol Cell Biol. 1991 Jun;11(6):3052–3059. [PMC free article] [PubMed]
  • Pollock R, Treisman R. A sensitive method for the determination of protein-DNA binding specificities. Nucleic Acids Res. 1990 Nov 11;18(21):6197–6204. [PMC free article] [PubMed]
  • Porter AC, Chernajovsky Y, Dale TC, Gilbert CS, Stark GR, Kerr IM. Interferon response element of the human gene 6-16. EMBO J. 1988 Jan;7(1):85–92. [PMC free article] [PubMed]
  • Ragg H, Weissmann C. Not more than 117 base pairs of 5'-flanking sequence are required for inducible expression of a human IFN-alpha gene. Nature. 1983 Jun 2;303(5916):439–442. [PubMed]
  • Reich N, Evans B, Levy D, Fahey D, Knight E, Jr, Darnell JE., 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. [PMC free article] [PubMed]
  • Reich NC, Levine AJ. Growth regulation of a cellular tumour antigen, p53, in nontransformed cells. Nature. 1984 Mar 8;308(5955):199–201. [PubMed]
  • Reis LF, Harada H, Wolchok JD, 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. [PMC free article] [PubMed]
  • Stark GR, Kerr IM. Interferon-dependent signaling pathways: DNA elements, transcription factors, mutations, and effects of viral proteins. J Interferon Res. 1992 Jun;12(3):147–151. [PubMed]
  • Tamm I, Lin SL, Pfeffer LM, Sehgal PB. Interferons alpha and beta as cellular regulatory molecules. Interferon. 1987;9:13–74. [PubMed]
  • Tanabe T, Konishi M, Mizuta T, Noma T, Honjo T. Molecular cloning and structure of the human interleukin-5 gene. J Biol Chem. 1987 Dec 5;262(34):16580–16584. [PubMed]
  • Tanaka N, Taniguchi T. Cytokine gene regulation: regulatory cis-elements and DNA binding factors involved in the interferon system. Adv Immunol. 1992;52:263–281. [PubMed]
  • Tuck SP, Crawford L. Characterization of the human p53 gene promoter. Mol Cell Biol. 1989 May;9(5):2163–2172. [PMC free article] [PubMed]
  • Uegaki K, Shirakawa M, Fujita T, Taniguchi T, Kyogoku Y. Characterization of the DNA binding domain of the mouse IRF-2 protein. Protein Eng. 1993 Feb;6(2):195–200. [PubMed]
  • Van Damme J, De Ley M, Van Snick J, Dinarello CA, 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]
  • Veals SA, Santa Maria T, Levy DE. Two domains of ISGF3 gamma that mediate protein-DNA and protein-protein interactions during transcription factor assembly contribute to DNA-binding specificity. Mol Cell Biol. 1993 Jan;13(1):196–206. [PMC free article] [PubMed]
  • Veals SA, Schindler C, Leonard D, Fu XY, Aebersold R, Darnell JE, Jr, Levy DE. Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Mol Cell Biol. 1992 Aug;12(8):3315–3324. [PMC free article] [PubMed]
  • Vleminckx K, Vakaet L, Jr, Mareel M, Fiers W, van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991 Jul 12;66(1):107–119. [PubMed]
  • Vogelstein B, Kinzler KW. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. [PubMed]
  • Watanabe N, Sakakibara J, Hovanessian AG, 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. [PMC free article] [PubMed]
  • Wathelet MG, Clauss IM, Nols CB, Content J, Huez GA. New inducers revealed by the promoter sequence analysis of two interferon-activated human genes. Eur J Biochem. 1987 Dec 1;169(2):313–321. [PubMed]
  • Willman CL, Sever CE, Pallavicini MG, Harada H, Tanaka N, Slovak ML, Yamamoto H, Harada K, Meeker TC, List AF, et al. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science. 1993 Feb 12;259(5097):968–971. [PubMed]
  • Wu LC, Morley BJ, Campbell RD. Cell-specific expression of the human complement protein factor B gene: evidence for the role of two distinct 5'-flanking elements. Cell. 1987 Jan 30;48(2):331–342. [PubMed]
  • Yamada G, Ogawa M, Akagi K, Miyamoto H, Nakano N, Itoh S, Miyazaki J, Nishikawa S, Yamamura K, Taniguchi T. Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):532–536. [PMC free article] [PubMed]

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