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Gene Review

IRF9  -  interferon regulatory factor 9

Homo sapiens

Synonyms: IFN-alpha-responsive transcription factor subunit, IRF-9, ISGF-3 gamma, ISGF3, ISGF3 p48 subunit, ...
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Disease relevance of ISGF3G


High impact information on ISGF3G

  • These observations indicate that interferon alpha-induced direct tyrosine phosphorylation of ISGF3 alpha proteins is necessary for activation of the transcription factor ISGF3 [5].
  • A specific interferon alpha-induced cytoplasmic protein tyrosine kinase(s) can form a transient complex with ISGF3 alpha proteins [5].
  • The double-stranded (ds) RNA-dependent protein kinase is a 100,000-110,000 Mr complex of two interferon-induced subunits each having ATP binding sites: a 48,000 Mr protein (p48) which appears to be responsible for the phosphorylation of a 68,000 Mr protein (p68) in the presence of dsRNA [6].
  • The growth suppression function of the retinoblastoma protein (Rb) is though to be mediated by Rb binding to cellular proteins. p48 is one of the major proteins that binds to a putative functional domain at the carboxy terminus of the Rb protein [7].
  • A system was developed in which IFN-alpha activated ISGF3 in homogenates of HeLa cells [8].

Biological context of ISGF3G


Anatomical context of ISGF3G

  • Two other genes of relevance to the immune system were located close to those for PA28 at 14q11.2 including ISGF3G, a protein involved in transcription after IFNalpha signalling [11].
  • We show that p48 plays an essential role in both type I and type II IFN responses; activation of IFN-inducible genes and establishment of the antiviral state by IFN-alpha or -gamma are both severely impaired, and ISRE-binding activities induced by both IFNs are absent in the p48-negative embryonic fibroblasts (EFs) [12].
  • However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells, apparently correlating to an enhanced responsiveness of these cells to IFNs [2].
  • These data indicate that a specific IFN signaling pathway is inactive in JEG-3 trophoblast cells because of altered activity of p48/ISGF3gamma, and they suggest IFN insensitivity as a mechanism that may help promote feto-placental survival [13].
  • Cell lines vary in their constitutive levels of the inducible component of ISGF3 and in the ability of IFNs to increase its synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)[14]

Associations of ISGF3G with chemical compounds

  • We show that in undifferentiated NB4 cells, 2',5'-oligoadenylate synthetase and MxB gene expression is not activated by IFN-alpha, possibly due to a relative lack of signaling molecules, especially p48 protein [2].
  • Alpha interferon (IFN-alpha)-induced transcriptional activation requires the induction of a complex of DNA-binding proteins, including tyrosine-phosphorylated Stat1 and Stat2, and of p48, a protein which is not phosphorylated on tyrosine and which comes from a separate family of DNA-binding proteins [15].
  • By using gel shift assays, it was shown that the activation of ISGF3 by alpha interferon treatment of HeLaM cells had characteristics identical to those of induced transcription: inhibition by 2-aminopurine and the need for ongoing protein synthesis which was obviated by pretreating the cells with gamma interferon [16].
  • Upon mixing in vitro the cytoplasmic fraction of gamma interferon-treated HeLaM cells with that of cells treated with alpha interferon and cycloheximide, active ISGF3 was reconstituted, presumably through complementation of two components, ISGF3 gamma and ISGF3 alpha, present in the two respective fractions [16].
  • The PKC-specific inhibitor calphostin C did not perturb activation or nuclear accumulation of ISGF3 [17].

Physical interactions of ISGF3G

  • Analysis of the transcriptional competence, affinity, and specificity of Stat2-p48 complexes compared with other Stat protein-containing transcription factor complexes suggests distinct roles for each component [18].
  • Stat1 homodimers formed in response to IFN-gamma treatment can also interact with p48 and function as transcriptional activators [18].
  • We now show that Stat2 is capable of forming a stable homodimer that interacts with p48, can be recruited to DNA, and can activate transcription, raising a question of why Stat1 is required [18].
  • The other IRF family proteins bind DNA with a specificity related to but distinct from that of ISGF3 gamma [19].
  • ISGF3 gamma DNA-binding activity was identified as a 48-kDa polypeptide, and partial amino acid sequence has allowed isolation of cDNA clones [19].

Enzymatic interactions of ISGF3G


Regulatory relationships of ISGF3G

  • Retention by STAT2 may serve to regulate the activity of free p48 and/or guarantee that cytoplasmic pools of preassociated STAT2:p48 are available for rapid activation of the IFN response [21].
  • Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression [22].
  • Collectively, results indicate that IFNtau effect on IRF-1 expression is primarily regulated by tyrosine-phosphorylated Stat1alpha or Stat1beta dimers, whereas the decline of IRF-1 after 6 h of IFNtau treatment is regulated by IRF-9 [23].
  • Examination of the ISRE binding factors strongly suggested that signal transducer and activator of transcription (Stat)-2 and p48/IFN-stimulated gene factor 3gamma (ISGF3gamma) are not required for the induction of RANTES by type I IFNs [24].
  • IFN-gamma pretreatment enhanced the upregulation of p48 levels by IFN-alpha [25].

Other interactions of ISGF3G

  • Coimmunoprecipitation assays demonstrate p48 association with STAT2 but not STAT1 [26].
  • Lack of p48 expression could be one of the mechanisms of promyelocytic leukemia cell escape from growth-inhibitory effects of IFN-alpha [2].
  • In IRF-9-deficient cells stimulated with IFNtau, IRF-1 increased from 0 to 6 h but did not exhibit the sharp decline from 6 to 12 h observed in other cells [23].
  • Interestingly, ectopic expression of IRF9 reverses the inhibitory actions of TSA, suggesting that IRF9 functions to recruit RNA polymerase II to the promoter of interferon-stimulated genes [27].
  • Interferon (IFN) beta acts downstream of IFN-gamma-induced class II transactivator messenger RNA accumulation to block major histocompatibility complex class II gene expression and requires the 48-kD DNA-binding protein, ISGF3-gamma [28].

Analytical, diagnostic and therapeutic context of ISGF3G


  1. A hybrid IRF9-STAT2 protein recapitulates interferon-stimulated gene expression and antiviral response. Kraus, T.A., Lau, J.F., Parisien, J.P., Horvath, C.M. J. Biol. Chem. (2003) [Pubmed]
  2. Retinoic acid induces signal transducer and activator of transcription (STAT) 1, STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons. Matikainen, S., Ronni, T., Lehtonen, A., Sareneva, T., Melén, K., Nordling, S., Levy, D.E., Julkunen, I. Cell Growth Differ. (1997) [Pubmed]
  3. Overexpression of IRF9 confers resistance to antimicrotubule agents in breast cancer cells. Luker, K.E., Pica, C.M., Schreiber, R.D., Piwnica-Worms, D. Cancer Res. (2001) [Pubmed]
  4. Type I interferon induces inhibitory 16-kD CCAAT/ enhancer binding protein (C/EBP)beta, repressing the HIV-1 long terminal repeat in macrophages: pulmonary tuberculosis alters C/EBP expression, enhancing HIV-1 replication. Honda, Y., Rogers, L., Nakata, K., Zhao, B.Y., Pine, R., Nakai, Y., Kurosu, K., Rom, W.N., Weiden, M. J. Exp. Med. (1998) [Pubmed]
  5. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Fu, X.Y. Cell (1992) [Pubmed]
  6. Two interferon-induced proteins are involved in the protein kinase complex dependent on double-stranded RNA. Galabru, J., Hovanessian, A.G. Cell (1985) [Pubmed]
  7. A retinoblastoma-binding protein related to a negative regulator of Ras in yeast. Qian, Y.W., Wang, Y.C., Hollingsworth, R.E., Jones, D., Ling, N., Lee, E.Y. Nature (1993) [Pubmed]
  8. Activation of transcription factors by interferon-alpha in a cell-free system. David, M., Larner, A.C. Science (1992) [Pubmed]
  9. Role of metazoan mediator proteins in interferon-responsive transcription. Lau, J.F., Nusinzon, I., Burakov, D., Freedman, L.P., Horvath, C.M. Mol. Cell. Biol. (2003) [Pubmed]
  10. Functional relevance of the conserved DNA-binding domain of STAT2. Brierley, M.M., Fish, E.N. J. Biol. Chem. (2005) [Pubmed]
  11. Organization of the genes encoding the human proteasome activators PA28alpha and beta. McCusker, D., Wilson, M., Trowsdale, J. Immunogenetics (1999) [Pubmed]
  12. Essential and non-redundant roles of p48 (ISGF3 gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies. Kimura, T., Kadokawa, Y., Harada, H., Matsumoto, M., Sato, M., Kashiwazaki, Y., Tarutani, M., Tan, R.S., Takasugi, T., Matsuyama, T., Mak, T.W., Noguchi, S., Taniguchi, T. Genes Cells (1996) [Pubmed]
  13. Defective induction of the transcription factor interferon-stimulated gene factor-3 and interferon alpha insensitivity in human trophoblast cells. Cross, J.C., Lam, S., Yagel, S., Werb, Z. Biol. Reprod. (1999) [Pubmed]
  14. Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3. Levy, D.E., Lew, D.J., Decker, T., Kessler, D.S., Darnell, J.E. EMBO J. (1990) [Pubmed]
  15. Function of Stat2 protein in transcriptional activation by alpha interferon. Qureshi, S.A., Leung, S., Kerr, I.M., Stark, G.R., Darnell, J.E. Mol. Cell. Biol. (1996) [Pubmed]
  16. Gene induction by interferons: functional complementation between trans-acting factors induced by alpha interferon and gamma interferon. Bandyopadhyay, S.K., Kalvakolanu, D.V., Sen, G.C. Mol. Cell. Biol. (1990) [Pubmed]
  17. Protein kinase activity required for an early step in interferon-alpha signaling. Kessler, D.S., Levy, D.E. J. Biol. Chem. (1991) [Pubmed]
  18. Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA. Bluyssen, H.A., Levy, D.E. J. Biol. Chem. (1997) [Pubmed]
  19. Subunit of an alpha-interferon-responsive transcription factor is related to interferon regulatory factor and Myb families of DNA-binding proteins. Veals, S.A., Schindler, C., Leonard, D., Fu, X.Y., Aebersold, R., Darnell, J.E., Levy, D.E. Mol. Cell. Biol. (1992) [Pubmed]
  20. Combinatorial association and abundance of components of interferon-stimulated gene factor 3 dictate the selectivity of interferon responses. Bluyssen, H.A., Muzaffar, R., Vlieststra, R.J., van der Made, A.C., Leung, S., Stark, G.R., Kerr, I.M., Trapman, J., Levy, D.E. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  21. Interferon regulatory factor subcellular localization is determined by a bipartite nuclear localization signal in the DNA-binding domain and interaction with cytoplasmic retention factors. Lau, J.F., Parisien, J.P., Horvath, C.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  22. Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: modulation of interferon response and CCAAT/enhancer binding protein beta expression. Weiden, M., Tanaka, N., Qiao, Y., Zhao, B.Y., Honda, Y., Nakata, K., Canova, A., Levy, D.E., Rom, W.N., Pine, R. J. Immunol. (2000) [Pubmed]
  23. Roles of Stat1, Stat2, and interferon regulatory factor-9 (IRF-9) in interferon tau regulation of IRF-1. Stewart, M.D., Choi, Y., Johnson, G.A., Yu-Lee, L.Y., Bazer, F.W., Spencer, T.E. Biol. Reprod. (2002) [Pubmed]
  24. A non-classical ISRE/ISGF3 pathway mediates induction of RANTES gene transcription by type I IFNs. Cremer, I., Ghysdael, J., Vieillard, V. FEBS Lett. (2002) [Pubmed]
  25. Interaction of retinoic acid and interferon in renal cancer cell lines. Nanus, D.M., Geng, Y., Shen, R., Lai, H.K., Pfeffer, S.R., Pfeffer, L.M. J. Interferon Cytokine Res. (2000) [Pubmed]
  26. Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3. Martinez-Moczygemba, M., Gutch, M.J., French, D.L., Reich, N.C. J. Biol. Chem. (1997) [Pubmed]
  27. Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes. Sakamoto, S., Potla, R., Larner, A.C. J. Biol. Chem. (2004) [Pubmed]
  28. Interferon (IFN) beta acts downstream of IFN-gamma-induced class II transactivator messenger RNA accumulation to block major histocompatibility complex class II gene expression and requires the 48-kD DNA-binding protein, ISGF3-gamma. Lu, H.T., Riley, J.L., Babcock, G.T., Huston, M., Stark, G.R., Boss, J.M., Ransohoff, R.M. J. Exp. Med. (1995) [Pubmed]
  29. Modulation of interferon signaling in human fibroblasts by phorbol esters. Petricoin, E.F., Hackett, R.H., Akai, H., Igarashi, K., Finbloom, D.S., Larner, A.C. Mol. Cell. Biol. (1992) [Pubmed]
  30. Primary leukemia cells resistant to alpha-interferon in vitro are defective in the activation of the DNA-binding factor interferon-stimulated gene factor 3. Xu, B., Grandér, D., Sangfelt, O., Einhorn, S. Blood (1994) [Pubmed]
  31. The locus-specific enhancer activity of the class I major histocompatibility complex interferon-responsive element is associated with a gamma-interferon (IFN)-inducible factor distinct from STAT1alpha, p48, and IFN regulatory factor-1. Vallejo, A.N., Pease, L.R. J. Biol. Chem. (1996) [Pubmed]
  32. Toll-like receptor-dependent and -independent Viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1. Severa, M., Coccia, E.M., Fitzgerald, K.A. J. Biol. Chem. (2006) [Pubmed]
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