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. 1996 Jan;16(1):359–368. doi: 10.1128/mcb.16.1.359

The interferon-inducible p202 protein as a modulator of transcription: inhibition of NF-kappa B, c-Fos, and c-Jun activities.

W Min 1, S Ghosh 1, P Lengyel 1
PMCID: PMC231010  PMID: 8524315

Abstract

The antimicrobial, immunomodulatory, and cell growth-regulatory activities of the interferons are mediated by interferon-inducible proteins. One of these is p202, a nuclear protein that is encoded by the Ifi 202 gene from the interferon-activatable gene 200 cluster. Overexpression of p202 in transfected cells slows down cell proliferation. As shown earlier, p202 binds to the hypophosphorylated form of the retinoblastoma susceptibility protein. Here we report that p202 inhibits the activities of the NF-kappa B and the AP-1 enhancers both in transiently transfected cells and in transfected stable cell lines overexpressing p202. Furthermore, p202 binds the NF-kappa B p50 and p65 and the AP-1 c-Fos and c-Jun transcription factors in vitro and in vivo. NF-kappa B, c-Fos, and c-Jun participate in the transcription of various cellular and viral genes, and thus p202 can modulate the expression of these genes in response to interferons.

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Selected References

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  1. Abate C., Luk D., Curran T. Transcriptional regulation by Fos and Jun in vitro: interaction among multiple activator and regulatory domains. Mol Cell Biol. 1991 Jul;11(7):3624–3632. doi: 10.1128/mcb.11.7.3624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abate C., Luk D., Gentz R., Rauscher F. J., 3rd, Curran T. Expression and purification of the leucine zipper and DNA-binding domains of Fos and Jun: both Fos and Jun contact DNA directly. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1032–1036. doi: 10.1073/pnas.87.3.1032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  5. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  6. Beg A. A., Baldwin A. S., Jr The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. Genes Dev. 1993 Nov;7(11):2064–2070. doi: 10.1101/gad.7.11.2064. [DOI] [PubMed] [Google Scholar]
  7. Briggs J. A., Burrus G. R., Stickney B. D., Briggs R. C. Cloning and expression of the human myeloid cell nuclear differentiation antigen: regulation by interferon alpha. J Cell Biochem. 1992 May;49(1):82–92. doi: 10.1002/jcb.240490114. [DOI] [PubMed] [Google Scholar]
  8. Brown K., Gerstberger S., Carlson L., Franzoso G., Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485–1488. doi: 10.1126/science.7878466. [DOI] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Choubey D., Lengyel P. Binding of an interferon-inducible protein (p202) to the retinoblastoma protein. J Biol Chem. 1995 Mar 17;270(11):6134–6140. doi: 10.1074/jbc.270.11.6134. [DOI] [PubMed] [Google Scholar]
  11. Choubey D., Lengyel P. Interferon action: cytoplasmic and nuclear localization of the interferon-inducible 52-kD protein that is encoded by the Ifi 200 gene from the gene 200 cluster. J Interferon Res. 1993 Feb;13(1):43–52. doi: 10.1089/jir.1993.13.43. [DOI] [PubMed] [Google Scholar]
  12. Choubey D., Lengyel P. Interferon action: nucleolar and nucleoplasmic localization of the interferon-inducible 72-kD protein that is encoded by the Ifi 204 gene from the gene 200 cluster. J Cell Biol. 1992 Mar;116(6):1333–1341. doi: 10.1083/jcb.116.6.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Choubey D., Snoddy J., Chaturvedi V., Toniato E., Opdenakker G., Thakur A., Samanta H., Engel D. A., Lengyel P. Interferons as gene activators. Indications for repeated gene duplication during the evolution of a cluster of interferon-activatable genes on murine chromosome 1. J Biol Chem. 1989 Oct 15;264(29):17182–17189. [PubMed] [Google Scholar]
  14. Curran T., Franza B. R., Jr Fos and Jun: the AP-1 connection. Cell. 1988 Nov 4;55(3):395–397. doi: 10.1016/0092-8674(88)90024-4. [DOI] [PubMed] [Google Scholar]
  15. Dawson M. J., Trapani J. A. IFI 16 gene encodes a nuclear protein whose expression is induced by interferons in human myeloid leukaemia cell lines. J Cell Biochem. 1995 Jan;57(1):39–51. doi: 10.1002/jcb.240570106. [DOI] [PubMed] [Google Scholar]
  16. Du W., Thanos D., Maniatis T. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell. 1993 Sep 10;74(5):887–898. doi: 10.1016/0092-8674(93)90468-6. [DOI] [PubMed] [Google Scholar]
  17. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  18. Fletcher C., Heintz N., Roeder R. G. Purification and characterization of OTF-1, a transcription factor regulating cell cycle expression of a human histone H2b gene. Cell. 1987 Dec 4;51(5):773–781. doi: 10.1016/0092-8674(87)90100-0. [DOI] [PubMed] [Google Scholar]
  19. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gariglio M., Panico S., Cavallo G., Divaker C., Lengyel P., Landolfo S. Impaired transcription of the poly rI:rC- and interferon-activatable 202 gene in mice and cell lines from the C57BL/6 strain. Virology. 1992 Mar;187(1):115–123. doi: 10.1016/0042-6822(92)90300-e. [DOI] [PubMed] [Google Scholar]
  21. Getz M. J., Elder P. K., Benz E. W., Jr, Stephens R. E., Moses H. L. Effect of cell proliferation on levels and diversity of poly(A)-containing mRNA. Cell. 1976 Feb;7(2):255–65. doi: 10.1016/0092-8674(76)90025-8. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Gilmore T. D., Morin P. J. The I kappa B proteins: members of a multifunctional family. Trends Genet. 1993 Dec;9(12):427–433. doi: 10.1016/0168-9525(93)90106-r. [DOI] [PubMed] [Google Scholar]
  24. Glover J. N., Harrison S. C. Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA. Nature. 1995 Jan 19;373(6511):257–261. doi: 10.1038/373257a0. [DOI] [PubMed] [Google Scholar]
  25. Higashi Y., Sokawa Y., Watanabe Y., Kawade Y., Ohno S., Takaoka C., Taniguchi T. Structure and expression of a cloned cDNA for mouse interferon-beta. J Biol Chem. 1983 Aug 10;258(15):9522–9529. [PubMed] [Google Scholar]
  26. Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
  27. Jain J., McCaffrey P. G., Miner Z., Kerppola T. K., Lambert J. N., Verdine G. L., Curran T., Rao A. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993 Sep 23;365(6444):352–355. doi: 10.1038/365352a0. [DOI] [PubMed] [Google Scholar]
  28. Jonat C., Rahmsdorf H. J., Park K. K., Cato A. C., Gebel S., Ponta H., Herrlich P. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell. 1990 Sep 21;62(6):1189–1204. doi: 10.1016/0092-8674(90)90395-u. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Kallunki T., Su B., Tsigelny I., Sluss H. K., Dérijard B., Moore G., Davis R., Karin M. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 1994 Dec 15;8(24):2996–3007. doi: 10.1101/gad.8.24.2996. [DOI] [PubMed] [Google Scholar]
  31. Karin M. Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors. Curr Opin Cell Biol. 1994 Jun;6(3):415–424. doi: 10.1016/0955-0674(94)90035-3. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Kerr L. D., Ransone L. J., Wamsley P., Schmitt M. J., Boyer T. G., Zhou Q., Berk A. J., Verma I. M. Association between proto-oncoprotein Rel and TATA-binding protein mediates transcriptional activation by NF-kappa B. Nature. 1993 Sep 30;365(6445):412–419. doi: 10.1038/365412a0. [DOI] [PubMed] [Google Scholar]
  34. Kingsmore S. F., Snoddy J., Choubey D., Lengyel P., Seldin M. F. Physical mapping of a family of interferon-activated genes, serum amyloid P-component, and alpha-spectrin on mouse chromosome 1. Immunogenetics. 1989;30(3):169–174. doi: 10.1007/BF02421202. [DOI] [PubMed] [Google Scholar]
  35. Kopp E., Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994 Aug 12;265(5174):956–959. doi: 10.1126/science.8052854. [DOI] [PubMed] [Google Scholar]
  36. Landschulz W. H., Johnson P. F., McKnight S. L. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988 Jun 24;240(4860):1759–1764. doi: 10.1126/science.3289117. [DOI] [PubMed] [Google Scholar]
  37. Lee W., Haslinger A., Karin M., Tjian R. Activation of transcription by two factors that bind promoter and enhancer sequences of the human metallothionein gene and SV40. Nature. 1987 Jan 22;325(6102):368–372. doi: 10.1038/325368a0. [DOI] [PubMed] [Google Scholar]
  38. Lehming N., Thanos D., Brickman J. M., Ma J., Maniatis T., Ptashne M. An HMG-like protein that can switch a transcriptional activator to a repressor. Nature. 1994 Sep 8;371(6493):175–179. doi: 10.1038/371175a0. [DOI] [PubMed] [Google Scholar]
  39. Lengyel P. Biochemistry of interferons and their actions. Annu Rev Biochem. 1982;51:251–282. doi: 10.1146/annurev.bi.51.070182.001343. [DOI] [PubMed] [Google Scholar]
  40. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  41. Maran A., Maitra R. K., Kumar A., Dong B., Xiao W., Li G., Williams B. R., Torrence P. F., Silverman R. H. Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. Science. 1994 Aug 5;265(5173):789–792. doi: 10.1126/science.7914032. [DOI] [PubMed] [Google Scholar]
  42. Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
  43. Miyamoto S., Maki M., Schmitt M. J., Hatanaka M., Verma I. M. Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12740–12744. doi: 10.1073/pnas.91.26.12740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. 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]
  45. Opdenakker G., Snoddy J., Choubey D., Toniato E., Pravtcheva D. D., Seldin M. F., Ruddle F. H., Lengyel P. Interferons as gene activators: a cluster of six interferon-activatable genes is linked to the erythroid alpha-spectrin locus on murine chromosome 1. Virology. 1989 Aug;171(2):568–578. doi: 10.1016/0042-6822(89)90626-0. [DOI] [PubMed] [Google Scholar]
  46. Palombella V. J., Rando O. J., Goldberg A. L., Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. doi: 10.1016/s0092-8674(94)90482-0. [DOI] [PubMed] [Google Scholar]
  47. Quinn C. O., Scott D. K., Brinckerhoff C. E., Matrisian L. M., Jeffrey J. J., Partridge N. C. Rat collagenase. Cloning, amino acid sequence comparison, and parathyroid hormone regulation in osteoblastic cells. J Biol Chem. 1990 Dec 25;265(36):22342–22347. [PubMed] [Google Scholar]
  48. Ray A., Prefontaine K. E. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):752–756. doi: 10.1073/pnas.91.2.752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Rincón M., Flavell R. A. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J. 1994 Sep 15;13(18):4370–4381. doi: 10.1002/j.1460-2075.1994.tb06757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schüle R., Rangarajan P., Kliewer S., Ransone L. J., Bolado J., Yang N., Verma I. M., Evans R. M. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell. 1990 Sep 21;62(6):1217–1226. doi: 10.1016/0092-8674(90)90397-w. [DOI] [PubMed] [Google Scholar]
  51. Sen G. C., Lengyel P. The interferon system. A bird's eye view of its biochemistry. J Biol Chem. 1992 Mar 15;267(8):5017–5020. [PubMed] [Google Scholar]
  52. 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]
  53. Siebenlist U., Franzoso G., Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. doi: 10.1146/annurev.cb.10.110194.002201. [DOI] [PubMed] [Google Scholar]
  54. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  55. Tannenbaum C. S., Major J., Ohmori Y., Hamilton T. A. A lipopolysaccharide-inducible macrophage gene (D3) is a new member of an interferon-inducible gene cluster and is selectively expressed in mononuclear phagocytes. J Leukoc Biol. 1993 May;53(5):563–568. doi: 10.1002/jlb.53.5.563. [DOI] [PubMed] [Google Scholar]
  56. Thanos D., Maniatis T. Identification of the rel family members required for virus induction of the human beta interferon gene. Mol Cell Biol. 1995 Jan;15(1):152–164. doi: 10.1128/mcb.15.1.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Thanos D., Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995 Feb 24;80(4):529–532. doi: 10.1016/0092-8674(95)90506-5. [DOI] [PubMed] [Google Scholar]
  58. Thompson J. E., Phillips R. J., Erdjument-Bromage H., Tempst P., Ghosh S. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell. 1995 Feb 24;80(4):573–582. doi: 10.1016/0092-8674(95)90511-1. [DOI] [PubMed] [Google Scholar]
  59. Traenckner E. B., Wilk S., Baeuerle P. A. A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J. 1994 Nov 15;13(22):5433–5441. doi: 10.1002/j.1460-2075.1994.tb06878.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Trapani J. A., Browne K. A., Dawson M. J., Ramsay R. G., Eddy R. L., Show T. B., White P. C., Dupont B. A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-gamma in myeloid cells. Immunogenetics. 1992;36(6):369–376. doi: 10.1007/BF00218044. [DOI] [PubMed] [Google Scholar]
  61. Wagner S., Green M. R. DNA-binding domains: targets for viral and cellular regulators. Curr Opin Cell Biol. 1994 Jun;6(3):410–414. doi: 10.1016/0955-0674(94)90034-5. [DOI] [PubMed] [Google Scholar]
  62. Weber H., Valenzuela D., Lujber G., Gubler M., Weissmann C. Single amino acid changes that render human IFN-alpha 2 biologically active on mouse cells. EMBO J. 1987 Mar;6(3):591–598. doi: 10.1002/j.1460-2075.1987.tb04795.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  64. 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]
  65. Wigler M., Sweet R., Sim G. K., Wold B., Pellicer A., Lacy E., Maniatis T., Silverstein S., Axel R. Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell. 1979 Apr;16(4):777–785. doi: 10.1016/0092-8674(79)90093-x. [DOI] [PubMed] [Google Scholar]
  66. Williams T., Admon A., Lüscher B., Tjian R. Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements. Genes Dev. 1988 Dec;2(12A):1557–1569. doi: 10.1101/gad.2.12a.1557. [DOI] [PubMed] [Google Scholar]
  67. Williams T., Tjian R. Analysis of the DNA-binding and activation properties of the human transcription factor AP-2. Genes Dev. 1991 Apr;5(4):670–682. doi: 10.1101/gad.5.4.670. [DOI] [PubMed] [Google Scholar]
  68. Yang-Yen H. F., Chambard J. C., Sun Y. L., Smeal T., Schmidt T. J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990 Sep 21;62(6):1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]
  69. Yew P. R., Liu X., Berk A. J. Adenovirus E1B oncoprotein tethers a transcriptional repression domain to p53. Genes Dev. 1994 Jan;8(2):190–202. doi: 10.1101/gad.8.2.190. [DOI] [PubMed] [Google Scholar]
  70. Zauberman A., Barak Y., Ragimov N., Levy N., Oren M. Sequence-specific DNA binding by p53: identification of target sites and lack of binding to p53 - MDM2 complexes. EMBO J. 1993 Jul;12(7):2799–2808. doi: 10.1002/j.1460-2075.1993.tb05941.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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