Structural basis for carcinogenesis and cancer metastasis by oncogene products

• Project/Area Number: 17012009
• 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 (2007-2009); Tokyo Institute of Technology (2005-2006)
• Principal Investigator: NUREKI Osamu The University of Tokyo, 医科学研究所, 教授 (10272460)
• Co-Investigator(Kenkyū-buntansha): ISHITANI Ryuichiro 東京大学, 大学院・理学系研究科, 准教授 (90361568) ; 石谷 隆一郎 東京工業大学, 大学院生命理工学研究科, 助手 (30401186)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥123,800,000 (Direct Cost: ¥123,800,000); Fiscal Year 2009: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 2008: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 2007: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 2006: ¥25,000,000 (Direct Cost: ¥25,000,000); Fiscal Year 2005: ¥23,800,000 (Direct Cost: ¥23,800,000)
• Keywords: がん化 / がん細胞の転移 / 細胞骨格再構築 / 開口放出 / 転写因子 / 自然免疫 / X線結晶構造解析 / 発がん / がんの転移 / 創薬 / TGF-βシグナル / 細胞内ホメオスタシス / シグナル伝達 / レセプター / がん遺伝子 / 薬剤設計 / がん細胞の浸潤 / 細胞骨格再形成 / 細胞膜の開口放出 / 低分子量Gタンパク質 / Wnt / β-catenineシグナル

Research Abstract

To elucidate the mechanism of carcinogenesis, cancer metastasis and anti-tumor immune reaction, atomic structures of the player, the oncoproteins and anti-oncoproteins will be determined by X-ray crystallography. Based on the structures, new anti-cancer drug will be developed to achieve an efficient cancer treatment. For carcinogenesis, we focus on TGF-β signal under which many transcription regulatory molecules interplay for cellular development signal transduction. For cancer metastasis and invasion, we focus on proteins responsible for cytoskeleton reorganization and plasma membrane supply coupled with exocytosis. For innate immune reaction, we focus on Toll-like receptor (TLR) and its endogenous ligands, and on IRF transcriptional regulators acting mainly under the control of TLR to activate the transcription of proinflammatory cytokines and γ-interferon.

Research Products

• [Journal Article] Structure and function of a membrane component SecDF that enhances protein export (2011)
  • Author(s): T.Tsukazaki, H.Mori, Y.Echizen, R.Ishitani, S.Fukai, T.Tanaka, A.rederina, D.G.Vassylyev, T.Kohno, A.D.Maturana, K.Ito, O.Nureki
  • Journal Title: Nature in press
• [Journal Article] Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog (2011)
  • Author(s): L.Bonnefond, T.Arai, Y.Sakaguchi, T.Suzuki, R.Ishitani, O.Nureki
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 108 Pages: 3912-3917
• [Journal Article] Crystal structure of autotaxin and insight into GPCR activation by lipid mediators (2011)
  • Author(s): H.Nishimasu, S.Okudaira, K.Hama, E.Mihara, N.Dohmae, A.Inoue, R.Ishitani, J.Takagi, J.Aoki, O.Nureki
  • Journal Title: Nat.Struct.Mol.Biol. 18 Pages: 205-212
• [Journal Article] Crystal structure of autotaxin and insight into GPCR activation by lipid mediators (2011)
  • Author(s): H.Nishimasu
  • Journal Title: Nat.Struct.Mol.Biol. Volume: 18 Pages: 205-212
  • Peer Reviewed
• [Journal Article] Omnipotent role of archaeal elongation factor 1 alpha (EF1α in translational elongation and termination, and quality control of protein synthesis (2010)
  • Author(s): K.Saito, K.Kobayashi, M.Wada, I.Kikuno, A.Takusagawa, M.Mochizuki, T.Uchiumi, R.Ishitani, O.Nureki, K.Ito
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 107 Pages: 19242-19247
• [Journal Article] Structural Basis for mRNA Surveillance by Archaeal Pelota and GTP-bound EF1? Complex (2010)
  • Author(s): K.Kobayashi, I.Kikuno, K.Kuroha, K.Saito, K.Ito, R.Ishitani, T.Inada, O.Nureki
  • Journal Title: Proc.Natl.Acad.Sci.USA. 107 Pages: 17575-17579
• [Journal Article] Mg^<2+>-dependent gating of bacterial MgtE channel underlies Mg^<2+> homeostasis (2009)
  • Author(s): M.Hattori, N.Iwase, N.Furuya, Y.Tanaka, T.Tsukazaki, R.Ishitani, M.E.Maguire, K.Ito, A.Maturana, O.Nureki
  • Journal Title: EMBO J 28 Pages: 3602-3612
• [Journal Article] Structural basis for translational fidelity ensured by tRNA lysidine synthetase (2009)
  • Author(s): K.Nakanishi, L.Bonnefond, S.Kimura, T.Suzuki, R.Ishitani, O.Nureki.
  • Journal Title: Nature 461 Pages: 1144-1148
• [Journal Article] Structural basis of novel interactions between the small-GTPase and GDI-like domains in prokaryotic FeoB iron transporter. (2009)
  • Author(s): M.Hattori, Y.Jin, H.Nishimasu, Y.Tanaka, M.Mochizuki, T.Uchiumi, R.Ishitani, K.Ito, O.Nureki.
  • Journal Title: Structure 17 Pages: 1345-1355
• [Journal Article] Structure of a tRNA-dependent kinase essential for selenocysteine decoding. (2009)
  • Author(s): Y.Araiso, R.L.Sherrer, R.Ishitani, J.M.L.Ho, D.Soll, O.Nureki.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 106 Pages: 16215-16220
• [Journal Article] Structural basis of AdoMet-dependent aminocarboxypropyl transfer reaction catalyzed by tRNA-wybutosine synthesizing enzyme, TYW2. (2009)
  • Author(s): M.Umitsu, H.Nishimasu, A.Noma, T.Suzuki, R.Ishitani, O.Nureki
  • Journal Title: Proc.Natl.Acad.Sci.USA. 106 Pages: 15616-15621
• [Journal Article] Tuberous Sclerosis Tumor Suppressor Complex-like Complexes Act as GTPase-activating Proteins for Ral GTPases. (2009)
  • Author(s): R.Shirakawa, S.Fukai, M.Kawato, T.Higashi, H.Kondo, T.Ikeda, E.Nakayama, K.Okawa, O.Nureki, T.Kimura, T.Kita, H.Horiuchi.
  • Journal Title: J.Biol.Chem. 284 Pages: 21580-21588
• [Journal Article] Conserved Cysteine Residues of GidA Are Essential for Biogenesis of 5-Carboxymethylaminomethyluridine at tRNA Anticodon (2009)
  • Author(s): T.Osawa, K.Ito, H.Inanaga, O.Nureki, K.Tomita, T.Numata.
  • Journal Title: Structure. 17 Pages: 713-724
• [Journal Article] Atomic structure of a folate/FAD-dependent tRNA T54 methyltransferase (2009)
  • Author(s): H.Nishimasu, R.Ishitani, K.Yamashita, C.Iwashita, A.Hirata, H.Hori, O.Nureki
  • Journal Title: Proc.Natl.Acad.USA. 106 Pages: 8180-8185
• [Journal Article] Crystallization and preliminary X-ray diffraction analysis of GCIP/HHM transcriptional regulator (2009)
  • Author(s): A.Seto, H.Ikushima, T.Suzuki, Y.Sato, S.Fukai, K.Yuki, K.Miyazawa, K.Miyazono, R.Ishitani, O.Nureki
  • Journal Title: Acta Crystallogr.Sect.F. 65 Pages: 21-24
• [Journal Article] Pyrrolysyl-tRNA synthetase-tRNA(Pyl) structure reveals the molecular basis of orthogonality (2009)
  • Author(s): K.Nozawa, P.O'Donoghue, S.Gundllapalli, Y.Araiso, R.Ishitani, T.Umehara, D.Soll, O.Nureki
  • Journal Title: Nature 457 Pages: 1163-1167
• [Journal Article] Tuberous Sclerosis Tumor Suppressor Complex-like Complexes Act as GTPase-activating Proteins for Ral GTPases. (2009)
  • Author(s): R.Shirakawa, et al.
  • Journal Title: J.Biol.Chem. Volume: 284 Pages: 21580-21588
  • Peer Reviewed
• [Journal Article] Conformational transition of Sec machinery inferred from bacterial SecYE structures (2008)
  • Author(s): T.Tsukazaki, H.Mori, S.Fukai, R.Ishitani, T.Mori, N.Dohmae, A.Perederina, Y.Sugita, D.G.Vassylyev, K.Ito, O.Nureki
  • Journal Title: Nature 455 Pages: 988-991
• [Journal Article] Mg^<2+>-sensing mechanism of Mg^<2+> transporter MgtE probed by molecular dynamics study (2008)
  • Author(s): R.Ishitani, Y.Sugita, N.Dohmae, N.Furuya, M.Hattori, O.Nureki
  • Journal Title: Proc.Natl.Acad.USA. 105 Pages: 15393-15398
• [Journal Article] Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains (2008)
  • Author(s): Y.Sato, A.Oshikawa, A.Yamagata, H.Mimura, M.Yamashita, K.Ookata, O.Nureki, K.Iwai, M.Komada, S.Fukai
  • Journal Title: Nature 455 Pages: 358-362
• [Journal Article] Biochemical Characterization of the Rho GTPase-regulated Actin Assembly by Diaphanous-related Formins, mDia1 and Daam1, in Platelets (2008)
  • Author(s): T.Higashi, T.Ikeda, R.Shirakawa, H.Kondo, M.Kawato, M.Horiguchi, T.Okuda, K.Okawa, S.Fukai, O.Nureki, T.Kita, H.Horiuchi.
  • Journal Title: J.Biol.Chem. 283 Pages: 8746-8755
• [Journal Article] Regulation of platelet dense granule secretion by the Ral GTPase-Exocyst pathway (2008)
  • Author(s): M.kawato, R.Shirakawa, H.Kondo, T.Higashi, T.Ikeda, K.Okawa, S.Fukai, O.Nureki, T.Kita, H.Horiuchi
  • Journal Title: J.Biol.Chem. 283 Pages: 166-174
• [Journal Article] Biochemical Characterization of the Rho GTPase-regulated Actin Assembly by Diaphanous-related Formins, mDial and Daaml, in Platelets (2008)
  • Author(s): T. Higashi, T. Ikeda, R. Shirakawa, H. Kondo, M. Kawato, M. Horiguchi, T. Okuda, K. Okawa, S. Fukai, O. Nureki, T. Kita, H. Horiuchi
  • Journal Title: J. Biol. Chem. 283 Pages: 8746-8755
  • Peer Reviewed
• [Journal Article] Regulation of platelet dense granule secretion by the Ral GTPase-Exocyst pathway (2008)
  • Author(s): M. kawato, R. Shirakawa, H. Kondo, T. Higashi, T. Ikeda, K. Okawa, S. Fukai, O. Nureki, T. Kita. H. Horiuchi
  • Journal Title: J. Biol. Chem. 283 Pages: 166-174
  • Peer Reviewed
• [Journal Article] Crystallization and preliminary X-ray diffraction analysis of GCIP/HRM transcriptional regulator (2008)
  • Author(s): A. Seto, H. Ikushima, T. Suzuki , Y. Sato, S. Fukai, K. Yuki, K. Miyazawa, K. Miyazono, R. Ishitani and O. Nureki
  • Journal Title: Acta Crystallogr. Sect. F. 65 Pages: 21-24
  • Peer Reviewed
• [Journal Article] Crystal structure of human DAAM1 formin homology 2 domain (2007)
  • Author(s): M.Yamashita, T.Higashi, S.Suetsugu, Y.Sato, T.Ikeda, R.Shirakawa, T.Kita, T.Takenawa, H.Horiuchi, S.Fukai, O.Nureki
  • Journal Title: Genes Cells 12 Pages: 1255-1265
• [Journal Article] Crystal structure of the MgtE Mg2+ transporter (2007)
  • Author(s): M Hattori, Y.Tanaka, S.Fukai, R.Ishitani, O.Nureki
  • Journal Title: Nature 448 Pages: 1072-1075
• [Journal Article] Crystal structure of the Sec4p・Sec2p complex in the nucleotide exchanging intermediatetate (2007)
  • Author(s): Y.Sato, S.Fukai, R.Ishitani, O.Nureki
  • Journal Title: Proc.Natl.Acad.Sci.USA 104 Pages: 8305-8310
• [Journal Article] Asymmetric coiled-coil structure with guanine nucleotide exchange activity (2007)
  • Author(s): Sato, R.Shirakawa, H.Horiuchi, N.Dohmae, S.Fukai, O.Nureki
  • Journal Title: Structure 15 Pages: 245-252
• [Journal Article] Asymmetric coiled-coil structure with guanine nucleotide exchange activity (2007)
  • Author(s): Y.Sato, R.Shirakawa, H.Horiuchi, N.Dohmae, S.Fukai, O.Nureki
  • Journal Title: Structure 15 Pages: 245-252
• [Journal Article] Crystal structure of the Sec4poSec2p complex in the nucleotide exchanging intermediate state (2007)
  • Author(s): Y.Sato, S.Fukai, R.Ishitani, O.Nureki
  • Journal Title: Proc. Natl. Acad. Sci. USA 21(in press)
• [Journal Article] Complete crystallographic analysis of the dynamics of CCA-addition (2006)
  • Author(s): K.Tomita, R.Ishitani, S.Fukai, O.Nureki
  • Journal Title: Nature 443 Pages: 956-960
  • NAID: 130006997728
• [Journal Article] Structural basis of RNA-dependent recruitment of glutamine to the genetic code (2006)
  • Author(s): H.Oshikane, K.Sheppard, S.Fukai, Y.Nakamura, R.Ishitani, T.Numata, L.R.Sherrer, L.Feng, E.Schmitt, M.Panvert, S.Blanquet, Y.Mechulam, D.Soll, O.Nureki
  • Journal Title: Science 312 Pages: 1950-1954
• [Journal Article] Snapshots of tRNA sulfuration via an adenylated intermediate (2006)
  • Author(s): T.Numata, Y.Ikeuchi, S.Fukai, T.Suzuki, O.Nureki
  • Journal Title: Nature 442 Pages: 419-424
• [Journal Article] Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa (2006)
  • Author(s): T.Sengoku, O.Nureki, A.Nakamura, S.Kobayashi, S.Yokoyama
  • Journal Title: Cell 125 Pages: 287-300
• [Journal Article] Structural basis for sulfur relay to RNA mediated by heterohexameric TusBCD complex (2006)
  • Author(s): T.Numata, S.Fukai, Y.Ikeuchi., T.Suzuki., O.Nureki
  • Journal Title: Structure 14 Pages: 357-366
• [Journal Article] Structural basis of RNA-dependent recruitment of glutamine to the genetic code (2006)
  • Author(s): (12名)D.Soll, 0.Nureki
  • Journal Title: Science 312 Pages: 1950-1954
• [Journal Article] Structural basis for sulfur relay to RNA mediated by heterohexameric TusBCD complex (2006)
  • Author(s): T.Numata, S.Fukai, Y.Ikeuchi, T.Suzuki, O.Nureki
  • Journal Title: Structure 14 Pages: 357-366
• [Journal Article] Structural basis for anticodon recognition by methionyl-tRNA synthetase (2005)
  • Author(s): K.Nakanishi, Y.Ogiso, S.Fukai, O.Nureki
  • Journal Title: Nature Struct.Mol.Biol. 12 Pages: 931-932
• [Journal Article] Structural basis for lysidine formation by ATP pyrophosphatase accompanied with alysine-specific loop and a tRNA-recognition domain (2005)
  • Author(s): K.Nakanishi, S.Fukai, Y.Ikeuchi, A.Soma, Y.Sekine, T.Suzuki, O.Nureki
  • Journal Title: Proc.Natl.Acad.Sci.USA 21 Pages: 7487-7492
• [Journal Article] Roles of conserved amino acid sequence motifs in the SpoU(TrmH) RNA methyltransferase family (2005)
  • Author(s): K.Watanabe, O.Nureki, S.Fukai, R.Ishii, H.Okamoto, S.Yokoyama, Y.Endo, H.Hori
  • Journal Title: J Biol Chem 280 Pages: 10368-10377
• [Journal Article] Structural basis for lysidine formation by ATP pyrophosphatase accompanied with a lysine-specific loop and a tRNA-recognition domain (2005)
  • Author(s): K.Nakanishi, S.Fukai, Y.Ikeuchi, A.Soma, Y.Sekine, T.Suzuki, O.Nureki
  • Journal Title: Proc.Natl.Acad.Sci.USA 21 Pages: 7487-7492
• [Journal Article] Recent progress of structural biology of tRNA processing and modification (2005)
  • Author(s): K.Nakanishi, O.Nureki
  • Journal Title: Mol.Cells 19 Pages: 157-166
• [Journal Article] Structural basis for anticodon recognition by methionyl-tRNA synthetase (2005)
  • Author(s): K.Nakanishi, Y.Ogiso, T.Nakama, S.Fukai, O.Nureki
  • Journal Title: Nat.Struct.Mol.Biol 12 Pages: 931-932
• [Journal Article] Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa
  • Author(s): T.Sengoku, O.Nureki, A.Nakamura, S.Kobayashi, S.Yokoyama
  • Journal Title: Cell (in press)
• [Presentation] New structure-based drug design of cell motility activating factor, ATX (2011)
  • Author(s): O.Nureki
  • Organizer: BioPharma China Congress 2011
  • Place of Presentation: Shanghai, China
  • Year and Date: 2011-03-30
• [Presentation] Multiple conformational states of Sec machinery components implicated from bacterial SecYE crystal structure (2009)
  • Author(s): O.Nureki
  • Organizer: VIII European Symposium of The Protein Society
  • Place of Presentation: Zurich, Switzerland
• [Presentation] 11^<th> International Congress on Amino Acids, Peptides and Proteins (2009)
  • Author(s): O.Nureki
  • Organizer: Genetic code expansion by non-canonical tRNA synthetases
  • Place of Presentation: Vienna, Austria
• [Presentation] 発がんとがん転移の構造生物学 (2008)
  • Author(s): 濡木理(以下10名)
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-30
• [Presentation] Crystal structure of the MgtE Mg^<2+> transporter (2008)
  • Author(s): O.Nureki
  • Organizer: Gordon Research Conference
  • Place of Presentation: CA, USA
• [Presentation] Gating control mechanism of magnesium transporter MgtE (2008)
  • Author(s): O.Nureki
  • Organizer: The Joint 2^<nd> Pacific Rim International Conference on Protein Science
  • Place of Presentation: Cairns, Australia
• [Presentation] Stop codon recoding mechanism revealed by the suppressor tRNAPyl and PylS complex structure (2008)
  • Author(s): O.Nureki
  • Organizer: ULP-JSPS forum
  • Place of Presentation: Strasbourg, France
• [Presentation] Genetc code extension and establishment by aminoacyl-tRNA synthetase and tRNA modification enzymes (2008)
  • Author(s): O.Nureki
  • Organizer: aaRS2008
  • Place of Presentation: Veyrier du Lac, France
• [Presentation] Structural basis for highly specific chemical reaction in the genetic code translation (2007)
  • Author(s): O.Nureki
  • Organizer: A Three-day Symposium on Advances in Structural Biology and Structure Prediction
  • Place of Presentation: Hyderabad, India
• [Presentation] Structural basis for highly specific chemical reaction in the genetic code translation (2007)
  • Author(s): O.Nureki
  • Organizer: International Symposium on Chemical Biology
  • Place of Presentation: Kolkata, India
• [Presentation] Structural Insights into Translational Quality Control (2007)
  • Author(s): O.Nureki
  • Organizer: American Society for Microbiology General 107^<th> Meeting
  • Place of Presentation: Toronto, Canada
• [Presentation] Structural insights into the modification in the tRNA anticodon region (2007)
  • Author(s): O.Nureki
  • Organizer: FEBS-CNRS Workshop
  • Place of Presentation: Aussois, France
• [Presentation] Structural insights into the gating control in bacterial transporters (2007)
  • Author(s): O.Nureki
  • Organizer: AsCA'07 (Plenary lecture)
  • Place of Presentation: Taipei, Taiwan
• [Presentation] Deep knot folding of methyltransferase structures (2006)
  • Author(s): O.Nureki
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Vermont, USA
• [Presentation] Structural Basis of RNA-Dependent Recruitment of Amino Acid to the Genetic Code (2006)
  • Author(s): O.Nureki
  • Organizer: International Conference on aaRSs
  • Place of Presentation: San Diego, USA
• [Presentation] Structural biology on translation of genetic code (2005)
  • Author(s): O.Nureki
  • Organizer: The 10th Symposium on Recent Advances in Biophysics (Plenary Lecture)
  • Place of Presentation: Taipei, Taiwan(2005)
• [Book] 日本結晶学会誌 (2011)
  • Author(s): 西増弘志, 喬木淳一, 青木淳賢, 濡木理
  • Publisher: 脂質メディエーター産生酵素ATXの結晶構造(刊行確定)
• [Book] RNA修飾マシーナリーの時間分解能での反応機構(蛋白質核酸酵素) 51巻 (2006)
  • Author(s): 濡木理
  • Publisher: 共立出版社
• [Book] RNA修飾マシーナリーの時間分解能での反応機構 (2006)
  • Author(s): 濡木 理
  • Publisher: 蛋白質核酸酵素
• [Book] 細胞の生と死を統括するアミノアシルtRNA合成酵素複合体(蛋白質核酸酵素) 50巻 (2005)
  • Author(s): 濡木理
  • Publisher: 共立出版社
• [Book] RNA成熟マシーン(実験医学) 22巻 (2005)
  • Author(s): 濡木理
  • Publisher: 羊土社
• [Book] ヒト由来トリプトファニルtRNA合成酵素による血管新生抑制機構の構造的基盤 (2005)
  • Author(s): 濡木 理
  • Total Pages: 5
  • Publisher: 日本生物物理学会
• [Remarks] ホームページ等
  • URL: http://www.nurekilab.net/