Logo of molcellbPermissionsJournals.ASM.orgJournalMCB ArticleJournal InfoAuthorsReviewers
Mol Cell Biol. Jun 1993; 13(6): 3756–3764.
PMCID: PMC359855

Double-stranded RNA activates novel factors that bind to the interferon-stimulated response element.

Abstract

Infection of cells with adenovirus or transfection of cells with double-stranded RNA (dsRNA) activates transcription of the alpha/beta interferon-stimulated genes (ISGs). Induction of ISG expression by adenovirus appears to be mediated through the same DNA target that is responsive to alpha/beta interferons, the interferon-stimulated response element (ISRE). Transcriptional induction by alpha/beta interferons has been shown previously to be mediated by the activation of a latent cytoplasmic transcription factor, ISGF3, that translocates to the nucleus and binds to the ISRE. However, ISG expression induced by adenovirus or dsRNA appears to be mediated by unique dsRNA-activated factors (DRAFs) that bind to the ISRE. The activation of these preexisting factors by dsRNA does not require new protein synthesis. Two DRAFs, DRAF1 and DRAF2, have been identified in our studies as ISRE-binding complexes in gel mobility shift assays. The ISRE-binding specificity of DRAF1 is similar to that of ISGF3; however, the ISRE-binding specificity of DRAF2 is distinct. Activation of DRAF1 and DRAF2 is independent of interferon action since it occurs in cells that are nonresponsive to interferon and in cells that lack the alpha/beta interferon locus. The activation pathway of DRAF1 and DRAF2 is blocked by the protein kinase inhibitors staurosporine and genistein. This is analogous to the interferon signal transduction pathway and suggests that phosphorylation, possibly tyrosine phosphorylation, is involved in activation of these factors.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ackrill AM, Foster GR, Laxton CD, Flavell DM, Stark GR, Kerr IM. Inhibition of the cellular response to interferons by products of the adenovirus type 5 E1A oncogene. Nucleic Acids Res. 1991 Aug 25;19(16):4387–4393. [PMC free article] [PubMed]
  • Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987 Apr 25;262(12):5592–5595. [PubMed]
  • Bazzigher L, Pavlovic J, Haller O, Staeheli P. Mx genes show weaker primary response to virus than other interferon-regulated genes. Virology. 1992 Jan;186(1):154–160. [PubMed]
  • Cohen B, Peretz D, Vaiman D, Benech P, Chebath J. Enhancer-like interferon responsive sequences of the human and murine (2'-5') oligoadenylate synthetase gene promoters. EMBO J. 1988 May;7(5):1411–1419. [PMC free article] [PubMed]
  • Dale TC, Imam AM, Kerr IM, Stark GR. Rapid activation by interferon alpha of a latent DNA-binding protein present in the cytoplasm of untreated cells. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1203–1207. [PMC free article] [PubMed]
  • Decker T. Double-stranded RNA and interferon-alpha induce transcription through different molecular mechanisms. J Interferon Res. 1992 Dec;12(6):445–448. [PubMed]
  • Diaz MO, Ziemin S, Le Beau MM, Pitha P, Smith SD, Chilcote RR, Rowley JD. Homozygous deletion of the alpha- and beta 1-interferon genes in human leukemia and derived cell lines. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5259–5263. [PMC free article] [PubMed]
  • Dignam JD, Lebovitz RM, Roeder RG. 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. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Foster GR, Ackrill AM, Goldin RD, Kerr IM, Thomas HC, Stark GR. Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2888–2892. [PMC free article] [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]
  • Fu XY, Kessler DS, Veals SA, Levy DE, Darnell JE., Jr ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8555–8559. [PMC free article] [PubMed]
  • Fu XY, Schindler C, Improta T, Aebersold R, Darnell JE., Jr The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7840–7843. [PMC free article] [PubMed]
  • Fuse A, Ashino-Fuse H, Kuwata T. Binding of 125I-labeled human interferon to cell lines with low sensitivity to interferon. Gan. 1984 Apr;75(4):379–384. [PubMed]
  • Gutch MJ, Daly C, Reich NC. Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11411–11415. [PMC free article] [PubMed]
  • Gutch MJ, Reich NC. Repression of the interferon signal transduction pathway by the adenovirus E1A oncogene. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):7913–7917. [PMC free article] [PubMed]
  • Hofer E, Darnell JE., Jr The primary transcription unit of the mouse beta-major globin gene. Cell. 1981 Feb;23(2):585–593. [PubMed]
  • John J, McKendry R, Pellegrini S, Flavell D, Kerr IM, Stark GR. Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons. Mol Cell Biol. 1991 Aug;11(8):4189–4195. [PMC free article] [PubMed]
  • Kalvakolanu DV, Bandyopadhyay SK, Harter ML, Sen GC. Inhibition of interferon-inducible gene expression by adenovirus E1A proteins: block in transcriptional complex formation. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7459–7463. [PMC free article] [PubMed]
  • Katze MG. The war against the interferon-induced dsRNA-activated protein kinase: can viruses win? J Interferon Res. 1992 Aug;12(4):241–248. [PubMed]
  • Kerr IM, Stark GR. The control of interferon-inducible gene expression. FEBS Lett. 1991 Jul 22;285(2):194–198. [PubMed]
  • Kessler DS, Veals SA, Fu XY, Levy DE. Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator. Genes Dev. 1990 Oct;4(10):1753–1765. [PubMed]
  • Larner AC, Chaudhuri A, Darnell JE., 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]
  • Levy D, Larner A, Chaudhuri A, Babiss LE, Darnell JE., 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. [PMC free article] [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]
  • 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, Lew DJ, Decker T, Kessler DS, Darnell JE., Jr Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3. EMBO J. 1990 Apr;9(4):1105–1111. [PMC free article] [PubMed]
  • Lopata MA, Cleveland DW, Sollner-Webb B. High level transient expression of a chloramphenicol acetyl transferase gene by DEAE-dextran mediated DNA transfection coupled with a dimethyl sulfoxide or glycerol shock treatment. Nucleic Acids Res. 1984 Jul 25;12(14):5707–5717. [PMC free article] [PubMed]
  • Mathews MB, Shenk T. Adenovirus virus-associated RNA and translation control. J Virol. 1991 Nov;65(11):5657–5662. [PMC free article] [PubMed]
  • Meurs E, Chong K, Galabru J, Thomas NS, Kerr IM, Williams BR, Hovanessian AG. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell. 1990 Jul 27;62(2):379–390. [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]
  • Nevins JR. Definition and mapping of adenovirus 2 nuclear transcription. Methods Enzymol. 1980;65(1):768–785. [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]
  • Platanias LC, Colamonici OR. Interferon alpha induces rapid tyrosine phosphorylation of the alpha subunit of its receptor. J Biol Chem. 1992 Nov 25;267(33):24053–24057. [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]
  • 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 N, Pine R, Levy D, Darnell JE., Jr Transcription of interferon-stimulated genes is induced by adenovirus particles but is suppressed by E1A gene products. J Virol. 1988 Jan;62(1):114–119. [PMC free article] [PubMed]
  • Reich NC, Darnell JE., Jr Differential binding of interferon-induced factors to an oligonucleotide that mediates transcriptional activation. Nucleic Acids Res. 1989 May 11;17(9):3415–3424. [PMC free article] [PubMed]
  • Reich NC, Pfeffer LM. Evidence for involvement of protein kinase C in the cellular response to interferon alpha. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8761–8765. [PMC free article] [PubMed]
  • Rutherford MN, Hannigan GE, Williams BR. Interferon-induced binding of nuclear factors to promoter elements of the 2-5A synthetase gene. EMBO J. 1988 Mar;7(3):751–759. [PMC free article] [PubMed]
  • Schindler C, Fu XY, Improta T, Aebersold R, Darnell JE., Jr Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84-kDa ISGF-3 proteins that are activated by interferon alpha. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836–7839. [PMC free article] [PubMed]
  • Schindler C, Shuai K, Prezioso VR, Darnell JE., Jr Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992 Aug 7;257(5071):809–813. [PubMed]
  • Sen GC, Lengyel P. The interferon system. A bird's eye view of its biochemistry. J Biol Chem. 1992 Mar 15;267(8):5017–5020. [PubMed]
  • Staeheli P. Interferon-induced proteins and the antiviral state. Adv Virus Res. 1990;38:147–200. [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]
  • Tiwari RK, Kusari J, Kumar R, Sen GC. Gene induction by interferons and double-stranded RNA: selective inhibition by 2-aminopurine. Mol Cell Biol. 1988 Oct;8(10):4289–4294. [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]
  • Velazquez L, Fellous M, Stark GR, Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. [PubMed]
  • Verhaegen M, Divizia M, Vandenbussche P, Kuwata T, Content J. Abnormal behavior of interferon-induced enzymatic activities in an interferon-resistant cell line. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4479–4483. [PMC free article] [PubMed]
  • Wathelet MG, Berr PM, Huez GA. Regulation of gene expression by cytokines and virus in human cells lacking the type-I interferon locus. Eur J Biochem. 1992 Jun 15;206(3):901–910. [PubMed]
  • Wathelet MG, Clauss IM, Content J, Huez GA. 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. [PubMed]
  • Wathelet MG, Clauss IM, Paillard FC, Huez GA. 2-Aminopurine selectively blocks the transcriptional activation of cellular genes by virus, double-stranded RNA and interferons in human cells. Eur J Biochem. 1989 Oct 1;184(3):503–509. [PubMed]

Articles from Molecular and Cellular Biology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...