転写制御の異常と細胞の増殖・分化

• Project/Area Number: 12215022
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo (2002-2004); Keio University (2000-2001)
• Principal Investigator: 井上 純一郎 東京大学, 医科学研究所, 教授 (70176428)
• Co-Investigator(Kenkyū-buntansha): 佐竹 正延 東北大学, 加齢医学研究所, 教授 (50178688) ; 仙波 憲太郎 東京大学, 医科学研究所, 助教授 (70206663) ; 秋山 泰身 慶應義塾大学, 理工学部, 講師 (50327665)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥78,000,000 (Direct Cost: ¥78,000,000); Fiscal Year 2004: ¥13,500,000 (Direct Cost: ¥13,500,000); Fiscal Year 2003: ¥13,500,000 (Direct Cost: ¥13,500,000); Fiscal Year 2002: ¥14,000,000 (Direct Cost: ¥14,000,000); Fiscal Year 2001: ¥14,000,000 (Direct Cost: ¥14,000,000); Fiscal Year 2000: ¥23,000,000 (Direct Cost: ¥23,000,000)
• Keywords: シグナル伝達 / NFκB / TRAF6 / HTLV-1 / Tax / DRG / 癌 / 発現制御 / 骨形成 / 免疫 / 発生 / 器官形成 / 発生・分化 / 免疫学 / NFkB / AP-1 / IKK / 無汗性外胚葉形成不全症 / 転写制御 / TRAFタンパク質 / Gタンパク質 / WT1 / PEBP2 / AML1

Research Abstract

転写制御の異常は細胞周期制御の破綻を導き、時には、癌化を誘導すると考えられているが、不明な点が多い。本研究では、「転写因子の活性制御機構及び、転写因子の異常によって生じる細胞機能の破綻を分子レベルで解明する」ことを目指す。特にNFκB活性化のがん化における役割、TRAF6によるNFκB活性化シグナル伝達機構及びTRAF6シグナルによる細胞増殖・分化の誘導機構の解明を目的として今年度は以下の結果を得た。1)HTLV-1 Taxタンパク質によるNFκB活性化にK63型ユビキチン付加酵素Ubc13およびTAK1活性化は必要ない。従ってTaxはIL-1やLPS等のシグナルとは異なる機構でIKKを活性化する。また、HTLV-1感染細胞ではTax依存的NFκB活性化とTax非依存的かっ恒常的NFκB活性化の両者が起こっている。2)TRAF6による細胞増殖機構に関与する考えられるDRG1とDRG2を同定した。さらにDRG1とDRG2の発現量をユビキチン化反応の阻害により維持する特異的結合タンパク質DFRP1とDFRP2を同定した。3)TRAF6がTLR3以外のTLRの下流で必須な役割を果たしていることを明らかにした。またTRAF6欠損により胸腺上皮細胞の分化不全が起こりその結果自己抗体が産生されることを示した。即ちTRAF6によるNFκBの活性化が自然免疫と獲得免疫において重要な役割を果たし、がん免疫に必須であることが明らかとなった。

Research Products

• [Journal Article] Identification of DRG family regulatory proteins (DFRPs) : specific regulation of DRG1 and DRG2. (2005)
  • Author(s): Ishikawa, K.et al.
  • Journal Title: Genes Cells 10 Pages: 139-150
• [Journal Article] RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. (2005)
  • Author(s): Gohda, J.et al.
  • Journal Title: EMBO J 24 Pages: 790-799
• [Journal Article] Dependence of Self-tolerance on TRAF6-directed Development of Thymic Stroma. (2005)
  • Author(s): Akiyama, T.et al.
  • Journal Title: Science (Epub ahead of print)
• [Journal Article] TIFAB inhibits TIFA, TRAP-interacting protein with a forkhead-associated domain. (2004)
  • Author(s): Matsumura, T.et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 317 Pages: 230-234
• [Journal Article] TNF Receptor-Associated Factor (TRAP) 6 is Essential for Myeloid Differentiation Factor (MyD) 88-Dependent Pathway but Not Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β(TRIF)-Dependent Pathway in Toll-like Receptor Signaling. (2004)
  • Author(s): Gohda, J.et al.
  • Journal Title: J.Immunol 173 Pages: 2913-2917
• [Journal Article] Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. (2004)
  • Author(s): Kawai, T.et al.
  • Journal Title: Nat.Immunol 10 Pages: 1061-1068
• [Publications] Kittaka, A.: "Synthesis of oligonucleotides with 6-formyl-2'-O-methyluridine and thermal stability of their duplexes"Heterocycles. 59. 207-215 (2003)
• [Publications] Gohda, J.: "Elimination of the vertabrate E.coli Ras-like protein homologue leads to cell cycle arrest at G1 phase and apoptosis"Oncogene. 22. 1340-1348 (2003)
• [Publications] Takatsuna, H.: "Identification of TIFA as an adapter protein that links TRAF6 to IRAK-1 in IL-1 receptor signaling"J.Biol.Chem.. 278. 12144-12150 (2003)
• [Publications] Matsumura, T.: "TRAF6-NF-κ B pathway is essential for IL-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes"Immunology. 109. 127-136 (2003)
• [Publications] Ohsugi, M.: "Cdc2-mediated phosphorylation of chromokinesin Kid controls its distribution to spindle and chromosomes"EMBO J.. 22. 2091-2103 (2003)
• [Publications] Matsuzawa-Watanabe, Y.: "Transcriptional activity of testis-determining factor SRY is modulated by the Wilms'tumor gene product, WT1"Oncogene. 22. 7900-7903 (2003)
• [Publications] Tanaka, S.: "Signal transduction pathways regulating osteoclast differentiation and function"J Bone Miner.Metab.. 21. 123-133 (2003)
• [Publications] Ishikawa, K.: "Cloning and characterization of Xenopus laevis drg2, a member of the developmentally regulated GTP-binding protein subfamily"Gene. 322. 105-112 (2003)
• [Publications] Niu, Y.: "MIP-T3 associates with IL-13RK1 and suppresses STAT6 activation in response to IL-13 stimulation"FEBS Letter. 550. 139-143 (2003)
• [Publications] Ito, E.: "A tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1, is induced by the Ewing's sarcoma-Wilms'tumor 1 fusion protein of desmoplastic small round cell tumor"Am.J.Path.. 163. 2165-2172 (2003)
• [Publications] Gohda, J.: "Down-regulation of TNF receptors by conophylline in human T-cell Leukemia cells"Int.J.Oncology. 23. 1373-1379 (2003)
• [Publications] Luftig, M.: "Epstein-Barr virus latent membrane protein 1 activation of NF κ B through IRAK1 and TRAF6"Proc.Natl.Acad.Sci.USA. 100. 15595-15600 (2003)
• [Publications] Ohazama, A.: "Traf6 is essential for murine tooth cusp morphogenesis"Development Dynamics. 229. 131-135 (2004)
• [Publications] Matsumura, T.: "TGF β down-regulates IL-1 α -induced TLR2 expression in murine hepatocytes"J.Leukoc.Biol.. In press. (2004)
• [Publications] Kanayama, A: "Taurine is involved in methionine 45 oxidation of IkBa and consequent inhibition of NFkB activation"J. Biol. Chem. 277. 24049-24056 (2002)
• [Publications] Naito, A: "TRAF6-deficient mice display hypohidrotic ectodermal dysplasia"Proc. Natl. Acad. Sci. USA. 99. 8766-8771 (2002)
• [Publications] Nishioka, B: "MAdCAM-1 plays an unexpected role in the development of mouse guard hair"J. Invest. Dermatol.. 119. 632-638 (2002)
• [Publications] Ariga.A: "Inhibition of TNF-α-induced nuclear translocation and activation of NF-kB by dehydroxymethyl-epoxyquinomicin"J. Biol. Chem. 277. 24625-24630 (2002)
• [Publications] Yoshida, H: "Different cytokines induce surface lymphotoxin-ab on IL-7 receptor-a cells that differentially engender lymph nodes and Peyer's patches"Immunity. 17. 823-833 (2002)
• [Publications] Takayanagi, H: "Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts"Dev. Cell. 3. 889-901 (2002)
• [Publications] Kittaka, A: "Synthesis of oligonucleotides with 6-formyl-2'-O-methyluridine and thermal stability of their duplexes"Heterocycles. 59. 207-215 (2003)
• [Publications] Gohda, J: "Elimination of the vertabrate E. coli Ras-like protein homologue leads to cell cycle arrestat G1 phase and apoptosis"Oncogene. (in press). (2003)
• [Publications] Takatsuna, H: "Identification of TIFA as an adapter protein that links TRAF6 to IRAK-1 in IL-1 receptor signaling"J. Biol. Chem. (in press). (2003)
• [Publications] Kobayashi, N: "Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis"EMBO.J. 20. 1271-1280 (2001)
• [Publications] Kittaka, A: "DNA Sequence Recognition by NFkB p50 Homodimer : Strict and Obscure Recognition Sites in the Binding Sequence"Nucleosides Nucleotides and Nucleic Acids.. 20. 669-672 (2001)
• [Publications] Kaji, K: "TNF α-induced osteoclastgenesis requires TRAF6"J.Bone Miner.Res. 16. 1593-1599 (2001)
• [Publications] Akiyama, T: "Mammalian homologue of E.Ras-like GTPase(ERA) is a possible apoptosis regulator with RNA binding activity"Genes Cells. 6. 987-1001 (2001)
• [Publications] Wang, C: "TAKI is a ubiquitindependent kinase of MKK and IKK"Nature. 412. 346-351 (2001)
• [Publications] Kawai, T: "Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes"J.Immunol. 167. 5887-5894 (2001)
• [Publications] Kobayashi,N.: "Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis"EMBO JOURNAL. (in press). (2001)
• [Publications] Sharma,K.M.: "Aurine Tricarboxylic Acid, a potent metal-chelating inhibitor of NFκB-DNA binding."Bioorg.Med.Chem. 8. 1819-1823 (2000)
• [Publications] Hatzoglou,A.: "Tumor necrosis factor receptor family member BCMA (B-cell maturation) associates with TRAF1,TRAF2 and TRAF3 and activates NF-kB, Elk-1 and c-Jun N-ter-minal kinase."J.Immunol. 165. 1322-1330 (2000)
• [Publications] Matsumoto,N.: "Synthesis of NF-κB activation inhibitors derived from epoxyquinomicin C."Bioorg.Med.Chem.Lett.. 10. 865-869 (2000)
• [Publications] Inoue,J.: "Tumor necrosis factor receptor-associated factor (TRAF) family : adapter proteins that mediate cytokine signaling."Exp.Cell Res. 254. 14-24 (2000)
• [Publications] 井上純一郎: "TRAF6シグナルの生理的役割"Molecular Medicine. Vol.37. 110-117 (2000)