• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular mechanism of mammalian mRNA surveillance

Research Project

Project/Area Number 15209013
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionYokohama City University Graduate School of Medical Science

Principal Investigator

OHNO Shigeo  Yokohama City University Graduate School of Medical Science, Department of Molecular Biology, Professor, 大学院・医学研究科, 教授 (10142027)

Co-Investigator(Kenkyū-buntansha) HIRAI Syu-ichi  Yokohama City University Graduate School of Medical Science, Department of Molecular Biology, Associate Professor, 大学院・医学研究科, 助教授 (80228759)
SUZUKI Atsushi  Yokohama City University Graduate School of Medical Science, Department of Molecular Biology, lecturer, 大学院・医学研究科, 講師 (00264606)
MIZUNO Keiko  Yokohama City University School of Medicine, Department of Molecular Biology, Assistant Professor, 医学部, 助手 (90221803)
AKIMOTO Kazunori  Yokohama City University School of Medicine, Department of Molecular Biology, Assistant Professor, 医学部, 助手 (70285104)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥47,320,000 (Direct Cost: ¥36,400,000、Indirect Cost: ¥10,920,000)
Fiscal Year 2004: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000)
Fiscal Year 2003: ¥23,140,000 (Direct Cost: ¥17,800,000、Indirect Cost: ¥5,340,000)
Keywordsnonsense mutaion / mRNA degradation / mRNA surveillance / P53 / protein kinase / PIK remated protein kinase / RNA helicase / ATPase
Research Abstract

Eukaryotes possess a system termed 'nonsense-mediated mRNA decay' (NMD) or 'mRNA surveillance', by which aberrant mRNAs with premature termination codons (PTCs) are removed from cells, thereby protecting them from accumulation of nonfunctional or potentially harmful polypeptides. Thus, Nonsense-mediated mRNA decay (NMD) is a quality control mechanism of mRNA. Proteins required for NMD (UPF1,2,3, and SMG-1, SMG-5,6,7) have been identified initially from yeast and C. elegans genetics but recent experiments on mammlas are revealing the physiological meaning and the molecular mechanism of NMD in human cells. Central player of NMD is the putative surveillance complex that recognizes PTC-containing mRNA in a manner dependent on both splicing and translation. Components of the surveillance complex include UPF1, an RNA helicase, and UPF2 and UPF3. SMG-1 phosphorylates UPF1 and SMG and SMG-7 help dephosphorylation of UPF1 by PP2A. Importantly, both phosphorylation by SMG-1 and dephosphorylation by PP2A of UPF1 are required for NMD in human cells. Biochemical experiments revealed that phosphorylation and dephosphorylation of UPF1 by SMG-1 and PP2A, respectively, cause the remodeling of the surveillance complex. These observations supports the idea raised by a series of molecular genetic experiments that SMG-1-mediated phsphorylation fo UPF1 is the critical step during the recognition of PTC-containing mRNA by the surveillance complex.
Although NMD is primarily the protective mechanism, there are many cases of genetic diseases that are exacerbated by NMD. Thus, suppression of NMD might be one of the potential therapeutic approach against gene mutations that generates nonsense mRNA. We now have the tools that can modulate NMD, it is now possible to examine the contributuin of NMD in a variety of cases that involves NMD. Genetic diseases and cancer are the primary candidates for such experiments that aims to suppress NMD through inhibition of SMG-1.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (39 results)

All 2004 2003 Other

All Journal Article (28 results) Patent(Industrial Property Rights) (4 results) Publications (7 results)

  • [Journal Article] Affixin interacts with alpha-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction.2004

    • Author(s)
      Yamaji S, Suzuki A, Kanamori H, Mishima W, Yoshimi R, Takasaki H, Takabayashi M, Fujimaki K, Fujisawa S, Ohno S, Ishigatsubo Y
    • Journal Title

      J.Cell Biol. 165(4)

      Pages: 539-551

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich's disease.2004

    • Author(s)
      Usuki F, Yamashita A, Higuchi I, Ohnishi T, Shiraishi T, Osame M, Ohno S
    • Journal Title

      Ann.Neurol. 55(5)

      Pages: 740-744

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity.2004

    • Author(s)
      Nishimura T, Kato K, Yamaguchi T, Fukata Y, Ohno S, Kaibuchi K
    • Journal Title

      Nat.Cell Biol. 6(4)

      Pages: 328-334

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The first CH domain of affixin activates Cdc42 and Rac1 through a1 phaPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor.2004

    • Author(s)
      Mishima W, Suzuki A, Yamaji S, Yoshimi R, Ueda A, Kaneko T, Tanaka J, Miwa Y, Ohno S, Ishigatsubo Y
    • Journal Title

      Genes Cells 9(3)

      Pages: 193-204

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] functional adhesion molecules (JAMs) : more molecules with dual functions?2004

    • Author(s)
      Ebnet K, Suzuki A, Ohno S, Vestweber D
    • Journal Title

      J.Cell Sci. 117(Pt1)

      Pages: 19-29

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] hUPF1のリン酸化と脱リン酸化によるmRNA監視複合体リモデリング2004

    • Author(s)
      山下暁朗, 鹿島勲, 大野茂男
    • Journal Title

      実験医学 22(4)

      Pages: 522-525

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Affixin interacts with α-actin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction2004

    • Author(s)
      Yamaji, S., Suzuki, A., Kanamori, H., Mishima, W., Yoshimi, R., Takasaki, H., Takabayashi, M., Fujimaki, K., Fujisawa, S., Ohno, S., Ishigatsubo, Y.
    • Journal Title

      J. Cell Biology 165(4)

      Pages: 539-551

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich's disease2004

    • Author(s)
      Usuki, F., Yamashita, A., Higuchi, I., Ohnishi, T., Shiraishi, T., Osame, M., Ohno, S.
    • Journal Title

      Annals of Neurology 55

      Pages: 740-744

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity2004

    • Author(s)
      Nishimura, T., Kato, K., Yamaguchi, T., Fukata, Y., Ohno, S., Kaibuchi, K.
    • Journal Title

      Nat. Cell Biol. 6(4)

      Pages: 328-334

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The first CH domain of affixin activates Cdc42 and Rac1 through alphaPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor2004

    • Author(s)
      Mishima, W., Suzuki, A., Yamaji, S., Yoshimi, R., Ueda, A., Kaneko, T., Tanaka, J., Miwa, Y., Ohno, S., Ishigatsubo, Y.
    • Journal Title

      Genes Cells 9(3)

      Pages: 193-204

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Junctional adhesion molecules (JAMs): more molecules with dual functions?2004

    • Author(s)
      Ebnet, K., Suzuki, A., Ohno, S., Vestweber, D.
    • Journal Title

      J. Cell Sci. 117(Pt 1)

      Pages: 19-29

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Affixin interacts with alpha-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell-substrate interaction.2004

    • Author(s)
      Fujisawa S, Ohno S, Ishigatsubo Y.
    • Journal Title

      J Cell Biol. 165(4)

      Pages: 539-551

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich's disease.2004

    • Author(s)
      Usuki F, Yamashita A, Higuchi I, Ohnishi T, Shiraishi T, Osame M, Ohno S.
    • Journal Title

      Ann Neurol. 55(5)

      Pages: 740-744

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity.2004

    • Author(s)
      Nishimura T, Kato K, Yamaguchi T, Fukata Y, Ohno S, Kaibuchi K.
    • Journal Title

      Nat Cell Biol. 6(4)

      Pages: 328-334

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The first CH domain of affixin activates Cdc42 and Rac1 through alphaPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor.2004

    • Author(s)
      Mishima W, Suzuki A, Yamaji S, Yoshimi R, Ueda A, Kaneko T, Tanaka J, Miwa Y, Ohno S
    • Journal Title

      Genes Cells 9(3)

      Pages: 193-204

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Junctional adhesion molecules (JAMs) : more molecules with dual functions?2004

    • Author(s)
      Ebnet K, Suzuki A, Ohno S, Vestweber D.
    • Journal Title

      J Cell Sci. 117(Pt1)

      Pages: 19-29

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phosphorylation of hUPF1 Induces Formation of mRNA Surveillance Complexes Containing hSMG-5 and hSMG-7.2003

    • Author(s)
      Ohnishi T, Yamashita A, Kashima I, Schell T, Anders K R, Grimson A, Hachiya T, Hentze M W, Anderson P, Ohno S
    • Journal Title

      Molecular Cell 12(5)

      Pages: 1187-1200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Self-association of PAR-3 mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions.2003

    • Author(s)
      Mizuno K, Suzuki A, Hirose T, Kitamura K, Kutsuzawa K, Futaki M, Amano Y, Ohnos S
    • Journal Title

      J.Biol.Chem 278(33)

      Pages: 31240-31250

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity.2003

    • Author(s)
      Yamanaka T, Horikoshi Y, Sugiyama Y, Ishiyama C, Suzuki A, Hirose T, Iwamatsu A, Shinohara A, Ohno S
    • Journal Title

      Current Biology 13(9)

      Pages: 734-743

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The second phase activation of protein kinase Cd at late G1 is required for DNA synthesis in serum-induced cell cycle progression.2003

    • Author(s)
      Kitamura K, Mizuno K, Etoh A, Akita Y, Miyamoto A, Nakayama K-I, Ohno S
    • Journal Title

      Genes to Cells 8

      Pages: 311-324

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Loss of von Hippel-Lindau protein causes cell density-dependent deregulation of CyclinD1 expression through Hypoxia-inducible factor.2003

    • Author(s)
      Baba M, Hirai S-I, Yamada-Okabe H, Hamada K, Tabuchi H, Kobayashi K, Kondo K, Yoshida M, Yamashita A, Kishida T, Nakaigawa N, Nagashima Y, Kubota Y, Yao M, Ohno S
    • Journal Title

      Oncogene 22(18)

      Pages: 2728-2738

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Protein kinase C 1/I (PKC 1/I): aPKC isotype essential for the development of multicellular organism.2003

    • Author(s)
      Suzuki A, Akimoto K, Ohno S
    • Journal Title

      J.Biochem (Tokyo) 133(1)

      Pages: 9-16

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phosphorylation of hUPF1 Induces Formation of mRNA Surveillance Complexes Containing hSMG-5 and hSMG-72003

    • Author(s)
      Ohnishi, T., Yamashita, A., Kashima, I., Schell, T., Anders, K.R., Grimson, A., Hachiya, T., Hentze, M.W., Anderson, P., Ohno, S.
    • Journal Title

      Molecular Cell 12

      Pages: 1187-1200

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Self-association of PAR-3 mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions2003

    • Author(s)
      Mizuno, K., Suzuki, A., Hirose, T., Kitamura, K., Kutsuzawa, K., Futaki, M., Amano, Y., Ohno, S.
    • Journal Title

      J. Biol. Chem. 278(33)

      Pages: 31240-31250

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mammalian Lg1 forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity2003

    • Author(s)
      Yamanaka, T., Horikoshi, Y., Sugiyama, Y., Ishiyama, C., Suzuki, A., Hirose, T., Iwamatsu, A., Shinohara, A., Ohno, S.
    • Journal Title

      Current Biology 13

      Pages: 734-743

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The second phase activation of protein kinase C δ at late G1 is required for DNA synthesis in serum-induced cell cycle progression2003

    • Author(s)
      Kitamura, K., Mizuno, K., Etoh, A., Akita, Y., Miyamoto, A., Nakayama, K-I., Ohno, S.
    • Journal Title

      Genes to Cells 8

      Pages: 311-324

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Loss of von Hippel-Lindau protein causes cell density-dependent deregulation of CyclinD1 expression through Hypoxia-inducible factor2003

    • Author(s)
      Baba, M., Hirai, S-I., Yamada-Okabe, H., Hamada, K., Tabuchi, H., Kobayashi, K., Kondo, K., Yoshida, M., Yamashita, A., Kishida, T., Nakaigawa, N., Nagashima, Y., Kubota, Y., Yao, M., Ohno, S.
    • Journal Title

      Oncogene 22

      Pages: 2728-2739

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Protein Kinase Cl/i (PKCl/i): A PKC isotype essential for the development of multicellular organisms2003

    • Author(s)
      Suzuki, A., Akimoto, K., Ohno, S.
    • Journal Title

      J. Biochemistry 133

      Pages: 9-16

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] SMG-1特異的siRNA及びmRNAサーベイランス機構抑制剤2003

    • Inventor(s)
      大野 茂男, 山下 暁朗, 大西 哲生
    • Industrial Property Rights Holder
      科学技術振興事業団, 横浜市
    • Industrial Property Number
      2003-191243
    • Filing Date
      2003-07-03
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] NMD阻害剤のスクリーニング方法2003

    • Inventor(s)
      大野 茂男, 鹿島 勲
    • Industrial Property Rights Holder
      セルフリーサイエンス
    • Industrial Property Number
      2004-304925
    • Filing Date
      2003-10-20
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] SMG-1特異的simRNA及びRNAサーベイランス機構抑制剤2003

    • Inventor(s)
      大野 茂男, 山下 暁朗, 大西 哲生
    • Industrial Property Rights Holder
      科学技術振興事業団, 横浜
    • Industrial Property Number
      2003-191243
    • Filing Date
      2003-07-03
    • Related Report
      2004 Annual Research Report
  • [Patent(Industrial Property Rights)] NMD阻害剤のスクリーニング方法2003

    • Inventor(s)
      大野 茂男, 鹿島 勲
    • Industrial Property Rights Holder
      セルフリーサイエンス
    • Filing Date
      2003
    • Related Report
      2004 Annual Research Report
  • [Publications] Ohnishi, T.: "Phosphorylation of hUPF1 Induces Formation of mRN Surveillance Complexes Containing hSMG-5 and hSMG-7"Molecular Cell. 12(5). 1187-1200 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuno, K.: "Self-association of PAR-3 mediated by the conserved N-terminal domain contributes to the development of epithelial tight junctions"J.Biol.Chem. 278(33). 31240-31250 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamanaka, T.: "Mammalian Lg1 forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity"Current Biology. 13(9). 734-743 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kitamura, K.: "The second phase activation of protein kinase Cd at late G1 is required for DNA synthesis in serum-induced cell cycle progression"Genes to Cells. 8. 311-324 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Baba, M.: "Loss of von Hippel-Lindau protein causes cell density-dependent deregulation of CyclinD1 expression through Hypoxia-inducible factor"Oncogene. 22(18). 2728-2738 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki, A.: "Protein kinase C 1/I (PKC 1/I) : aPKC isotype essential for the development of multicellular organism"J.Biochem (Tokyo). 133(1). 9-16 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 山下暁朗: "hUPF1のリン酸化と脱リン酸化によるmRNA監視複合体リモデリング"実験医学. 22(4). 522-525 (2004)

    • Related Report
      2003 Annual Research Report

URL: 

Published: 2003-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi