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Molecular mechanism of signal transduction mediated by Rel/NFkB

Research Project

Project/Area Number 05454642
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Molecular biology
Research InstitutionThe University of Tokyo

Principal Investigator

INOUE Jun-ichiro  Univ.Tokyo, Inst.Med.Sci.Associate Professor, 医科学研究所, 助教授 (70176428)

Project Period (FY) 1993 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 1995: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1994: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1993: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsTranscription factor / Rel / NFkappaB / Signal transduction / Molecular biology / NFkB / 蛋白質間相互作用
Research Abstract

1. Molecular Mechanism of Rel/NFkappaB activation
Activation of Rel/NFkappaB is achieved by the signal-induced rapid phosphorylation and degradation of inhibitory protein IkappaBalpha. To explore the molecular mechanism of signal-induced depletion of IkappaBalpha, we have delineated the domain in IkappaBalpha that is required for the regulation. In contrast to the previous reports, the PEST-like sequences dispensable for TNFalpha-induced degradation whereas the six ankyrin repeats are required. However, neither ankyrin repeats nor carboxyl-terminal region including the PEST-like sequences are required for TNFalpha-induced phosphorylation.
2. Signal transduction pathway emanating from membrane receptors to Rel/IkappaBalpha complex
We have found that signals emanating from CD40 link to Rel/NFkappaB activation. To identify molecules which transduce CD40 signalings, we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the cytoplasmic tail of CD40, cDNAs encoding a putative signal transducer protein, designated TRAF5 and TRAF6, have been molecularly cloned. Overexpression of TRAF5 or TRAF6 activates transcription factor NFkappaB.Thus, we are looking for the down stream transducer of these proteins. Furthermore we have demonstrated that cupric ion blocks NFkappaB activation through inhibiting the signal-induced phosphorylation of IkappaBalpha Target molecule of cupric ion remain to be identified.
3. Identification of novel kappaB proteins
To identify novel IkappaB cDNAs, an expression cDNA library has been screened using p65 subunit of NFkappaB as a probe. This study is still in the progress.
4. Chromosomal assignment of rel, NFkappaB and IkappaB genes in Rat
We have indentified that NFKB-1 (p50, IkappaBgamma) in on the Rat chromosome #2. Assignment of rel and IkappaBalpha is still in the Progress.

Report

(4 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • 1993 Annual Research Report
  • Research Products

    (58 results)

All Other

All Publications (58 results)

  • [Publications] Hirai,H.: "Tax protein of human T cell leukemia virus type 1 (HTL-V) binds to the ankyrin motifs of IκB and induces nuclear translocation of NFκB proteins for transcriptional activation." Proc.Natl.Acad.Sci.USA. 91. 3584-3588 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Otuka,M.: "Novel zinc chelators which inhibit the binding of HIV-EP1 (HIV enhancer binding protein) to NFκB recognition sequence." J.Med.Chem.37. 4267-4269 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Otuka,M.: "Novel zinc chelators with dual activity in the inhibition of the κB site binding proteins,HIV-EP1 and NFκB." J.Med.Chem.38. 3264-3270 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Suzuki,K.: "Molecular cloning of cDNA encoding the Xenopus homologue of mammalian RelB." Nuc.Acids Res. 23. 4664-4669 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Satake,H.: "Cupric ion blocks NFκB activation through inhibiting the signal-induced phosphorylation of IκBα." Biochem.Biophys.Res.Commun.216. 568-573 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishida,T.: "CD40signaling-mediated induction of Bcl-xL,Cdk4 and Cdk6 : Implication of their co-operation in selective B cell growth." J.Immunol.155. 5527-5535 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tokai,N.: "Kid,a novel Kinesin-like DNA binding protein,is localized to chromosomes and the mitotic spiindles." EMBO J.15. 457-467 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shiio,Y.: "Bcl-3 induces Rb via interaction with E4TF1/GABP : Implication for muscle cell differentiation." Oncogene. 12. 1837-1845 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hirano,M.: "MEK kinase is involved in TNFα-induced NFκB activation and degradation of IκBα." J.Biol.Chem.271. 13234-13238 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Aoki,T.: "The ankyrin repeats but not the PEST-like sequences are required for signal dependent degradation of IκBα." Oncogene. 12. 1159-1164 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Uchiumi,F.: "Inhibitory effect of tannic acid on human immunodeficiency virus promoter activity induced by 12-o-tetradecanoylphorbol-13-acetate in Jurkat T-cells." Biochem.Biophys.Res.Commun.220. 411-417 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Otuka,M.: "Synthetic inhibitors of regulatory proteins involved in the signaling pathways of the replication of human immunodeficiency virus 1." Bioorg.Med.Chem.(in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishida,T.: "TRAF5,a novel TRAF family protien,mediates CD40 signaling." Proc.Natl.Acad.Sci.USA.(in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Horie,R.: "A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate (TPA) and is expressed in alveolar macrophages." Blood. (in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "rel遺伝子" 蛋白質 核酸 酵素. 38. 89-90 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "rel関連遺伝子の産物を介するシグナル伝達" 生化学. 65. 1402-1417 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "Rel/NFκBファミリー蛋白質-細胞質から核へのメッセンジャー-" 医学の歩み. 5. 360-363 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "Relドメイン-免疫グロブリン様構造を有するDNA結合部位" 実験医学. 13. 147-152 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "核内癌遺伝子産物による癌化メカニズム" Molecular Medicine. 82. 496-501 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Verma,I: "Growth factors in perinatal development" Raven Press,Ltd.,NY, 10 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shiio,Y.: "Meth.Enzymol." Academic Press, 3 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "転写因子NFκBとrel癌遺伝子" 南江堂, 15 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 井上純一郎: "癌化のシグナル伝達機構" 中外医薬社, 11 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hirai, H., Suzuki, T., Fujisawa, J., Inoue, J.and Yoshida, M.: "Tax protein of human T cell leukemia virus type 1 (HTLV-1) binds to the ankyrin motifs of IkappaB and induces nuclear translocation of NFkappaB proteins for transcriptional activation." Pro.Natl.Acad.Sci.USA. 91. 3584-3588 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Otuka, M., Fujita, M., Aoki, T., Sugiura, Y., Ishii, S., Yamamoto, T., and Inoue, J.: "Novel zinc chelators which inhibit the binding of HIV-EP1 (HIV enhancer binding protein) to NFkappaB recognition sequence" J.Med.Chem. 37. 4267-4269 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shiio, Y., Itoh, M.and Inoue, J.: "Epitope tagging" Meth.Enzymol. 254. 497-502 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Otuka, M., Fujita, M., Aoki, T., Sugiura, Y., Ishii, S., Yamamoto, T., and Inoue, J.: "Novel zinc chelators with dual activity in the inhibition of the kappaB site binding proteins" J.Med.Chem.38. 3264-3270 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishida, T., Kobayashi, N., Tojo, T., Ishida, S., Yamamoto, T.and Inoue, J.: "CD40 signaling-mediated induction of Bcl-xL,Cdk4 and Cdk6 : Implication of their co-operation in selective B cell growth" J.Immunol.155. 5527-5535 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Suzuki, K., Yamamoto, T.and Inoue, J.: "Molecular cloning of cDNA encoding the Xenopus homologue of mammalian RelB" Nuc.Acids Res.23. 4664-4669 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Satake, H., Suzuki, K., Aoki, T., Otuka, M., Sugiura, Y., Yamamoto, T.and Inoue, J.: "Cupric ion blocks NFkappaB activation through inhibiting the signal-induced phosphorylation of IkappaBalpha" Biochem.Biophys.Res.Commun.216. 568-573 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tokai, N., Fujimoto-Nishiyama, A., Toyoshima, , Y., Yonemura, S., Tsukita, S., Inoue, J.and Yamamoto, T.: "Kid, a novel Kineshin-like DNA binding protein, is localized to chromosomes and the mitotic spiindles" EMBO J.15. 457-467 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shiio, Y., Sawada, J., Handa, H., Yamamoto, T.and Inoue, J.: "Bcl-3 induces Rb via interaction with E4TF1/GABP : Implication for muscle cell differentiation" Oncogene. 12. 1837-1845 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Aoki, T., Sano, Y., Yamamoto, T.and Inoue, J.: "The ankyrin repeats but not the PEST-like sequences are required for signal dependent degradation of IkappaBalpha" Oncogene. 12. 1159-1164 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hirano, M., Osaka, S., Aoki, T., Hirai, S., Hosaka, M., Inoue, J.and Ohno, S.: "MEK kinase is involved in TNFalpha-induced NFkappaB activation and degradation of IkappaBalpha" J.Biol.Chem.271. 13234-13238 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Uchiumi, F., Maruta, H., Inoue, J., Yamamoto, T.and Tanuma, S.: "Inhibitory effect of tannic acid on human immunodeficency virus promoter activity induced by 12-o-tetra decanoylphorbol-13-acetate in Jurkat T-cells" Biochem.Biophys.Res.Commun.220. 411-417 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Otuka, M., Fujuta, M., Sugiura, Y., Yamamoto, T., Inoue, J., Maekawa, T.and Ishii, S.: "Synthetic inhibitors of regulatory proteins involved in the signaling pathways of the replication of human immunodeficiency virus 1." Bioorg.Med.Chem.(in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishida, T., Tojo, T., Aoki, T., Kobayashi, N., Onishi, T., Watanabe, T., Yamamoto, T.and Inoue, J.: "TRAF5, a novel TRAF family protein, mediates CD40 signaling." Proc.Natl.Acad.Sci.USA. 93. 9437-9442 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Horie, R., Ito, K., Tatewaki, M., Nagai, M., Aizawa, S., Higashihara, M., Ishida, T., Inoue, J., Takizawa, H.and Watanabe, T.: "A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate (TPA) and is expressed in alveolar macrophages." Blood. (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishida T., Mizushima S., Azuma S., Kobayashi N., Tojo T., Suzuki K., Aizawa S., Watanabe T., Mosialos G., Kieff E., Yamamoto T.and Inoue J.: "Identification of TRAF6, a novel TRAF protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region." J.Biol.Chem.(in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "rel gene" Protein, Nucleic acid, Enzyme. 38. 89-90 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "Signal transduction mediated by the product of rel-related genes" Biochemistry. 65. 1402-1417 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "Rel/NFkappaB family protein--A messenger from cytoplasm to Nuclei" Igaku no Ayumi. 5. 360-363 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "Rel/domain--A DNA binding domain with immunoglobulin-like structure" Experimental Medicine. 13. 147-152 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "Transformation by nuclear oncogene products" Molecular Medicine. 32. 496-501 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "Transcription factor NFkappaB and rel gene" Nanko-do. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Inoue, J.: "Oncogenic signal transduction" Chugai Iyaku-sha. (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ohtsuka,M.: "Novel zinc chelators with dual activity in the inhibition of the κB site binding proteins,HIV-EP1 and NFκB." J.Med.Chem.38. 3264-3270 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shiio,Y.: "Bcl-3 induces Rb via interaction with E4TF1/GABP:Implication for muscle cell differentiation" Oncogene. (in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ishida,T.: "CD40 signaling-mediated induction of Bcl/X_L Cdk6:Implication of their co-operation in selective B cell growth." J.Immunol.155. 5527-5535 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Suzuki,K.: "Molecular cloning of cDNA encoding the Xenopus homologue of mammalian RelB." Nuc.Acids.Res.23. 4664-4669 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Aoki,T.: "The ankyrin repeats but not the PEST-like sequences are required for signal dependent degradation of IκBα." Oncogene. (in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Satake,H.: "Cupric in blocks NFκB activation through inhibition the signal-induced phosphorylation of IκBα." Biophys.Res.Commun.216. 568-573 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hirai,H.: "Tax protein of human T cell leukemia virus type 1(HTL V-1)binds to the ankyrin motifs of IkB and induces nuclear translocation of NFkB proteins for transcriptional activation" Proc.Natl.Acad.Sci.USA. 91. 3584-3588 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ohtsuka,M.: "Novel zinc chelators which inhibit the binding of HIV-EP1(HIV enhancer binding protein)to NFkB recognition sequences." J.Med.Chem.37. 4267-4269 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Shiio,Y.: "Epitope tagging" Meth.Enzymol.(in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Junichiro Inoue: "Bcl-3,a member of the IkB proteins,has distinct specificity towards Rel family of Proteins." Oncogene. 8. 2067-2073 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hiroshi Hirai: "Tax protein of human T cell leukemia virus type 1(HTLV-1)binds to the ankyrin motifs of IκB and induces nuclear translocation of NFκB proteins for transcriptional activation" Proc.Natl.Acad.Sci USA. (in press).

    • Related Report
      1993 Annual Research Report
  • [Publications] Inder M.Verma: "Growth Factors in perinatal development" Raven Press,Ltd.,NY, 10 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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