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On the Possible Control of Allergic Inflammation based on Molecular Mechanism of Serotonin Synthesizing Enzyme

Research Project

Project/Area Number 16591872
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionTeikyo University of Science & Technology

Principal Investigator

HASEGAWA Hiroyuki  Teikyo University of Science & Technology, Biosciences, Professor (10092983)

Co-Investigator(Kenkyū-buntansha) NAKANISHI Nobuo  Meikai University, Dentistry, Instructor (20118574)
SAWABE Keiko  Teikyo University of Science and Technology, Biotechnology, Research Center, Part-time Researcher (10399008)
大黒 一哉  帝京科学大学, 理工学部, 助手 (00233081)
Project Period (FY) 2004 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,650,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥150,000)
Fiscal Year 2007: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2006: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsTryptopha hydroxylase / Serotonin biosynthesis / Enzyme regulation by phosphorylation / Ubiquitination / Proteasomes / Site-directed mutagenesis / RBL2H3 / トリプトファン水酸化酵素抗体 / 部位特異的突然変異
Research Abstract

Tryptophan hydroxykase, the rate limiting enzyme in serotonin biosynthesis, exists in two isoforms. In 2003, TPH2 gene was identified and the gene product was named TPH2 while the long known gene product was newly referred to TPH1. The level of tryptophan hydroxylase in cells of RBL2H3, a mast-cell line, was shown to be under very rapid molecular turnover driven by the Ubiquitin-Proteasome system in the cell. The degradation process is triggered by protein phosphorylation of the enzyme. The phosphorylation site(s) responsible for triggering is(are) not known. In this study, three major progresses were achieved: 1)Polyclonal mono-specific antibodies were raised against TPH1 and TPH2. By the use of these antibodies, dominant distribution of TPH2 in the brain and TPH1 in the peripheral tissues were confirmed. However, we found that TPH1 was also detected in the brain and TPH2 in the non-neural cells in the periphery. Further, we located TPH1 in the intestinal absorption epithelia which had been believed to lack in the hydroxylase. 2) We reported previously that in vitro immune stimulation to RBL2H3 cells with IgE-antigen complex, triggered a rapid and prominent induction of TPH1. In this study, it was demonstrated that NF-kB pathway was involved in the signal transduction of the TPH1-induction. 3) Variant TPH1 vectors were developed of which 3 serine residues (S58, S260, and S443) on the protein surface were replaced with either alanine or glutamic acid by means of site-directed mutagenesis. The variants were all active when transected to HeLa cells, a cell line lack in TPH. Currently, the variants are under examination whether they are susceptible to the molecular degradation in RBL2H3 cells which are furnished with the all the required Ubiquitin-Proteasome system specific to the wild type TPH1.

Report

(5 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (43 results)

All 2008 2007 2006 2005 2004 2003 Other

All Journal Article (34 results) (of which Peer Reviewed: 10 results) Presentation (6 results) Book (2 results) Remarks (1 results)

  • [Journal Article] Role of a Serotonin Precursor in Development of Gut Microvilli2008

    • Author(s)
      Nakamura, K., et. al.
    • Journal Title

      Am J Pathol 172

      Pages: 333-44

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Role of a Serotonin Precursor in Development of Gut Microvilli.2008

    • Author(s)
      Nakamura, K., T. Sato, A. Ohashi, H. Tsurui, H. Hasegawa
    • Journal Title

      Am J Pathol 172(2)

      Pages: 333-44

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Role of a Serotonin Precursor in Development of Gut Microvilli2008

    • Author(s)
      K. Nakamura
    • Journal Title

      Am J Pathol 172

      Pages: 333-344

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new gain-of-function allele in chimpanzee tryptophan hydroxylase 2 and the comparison of its enzyme activity with that in humans and rats2007

    • Author(s)
      Hong, K.W., et. al.
    • Journal Title

      Neurosci Lett 412

      Pages: 195-200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Developmental role of tryptophan hydroxylase in the nervous system2007

    • Author(s)
      Nakamura, K., et. al.
    • Journal Title

      Mol Neurobiol 35

      Pages: 45-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] A new gain-of-function allele in chimpanzee tryptophan hydroxylase 2 and the comparison of its enzyme activity with that in humans and rats.2007

    • Author(s)
      Hong, K. W., Y. Sugawara, H. Hasegawa, I. Hayasaka, R. Hashimoto, S. Ito, M. Inoue-Murayama
    • Journal Title

      Neurosci Lett 412(3)

      Pages: 195-200

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Developmental role of tryptophan hydroxylase in the nervous system.2007

    • Author(s)
      Nakamura, K., H. Hasegawa
    • Journal Title

      Mol Neurobiol 35(1)

      Pages: 45-54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Developmental role of tryptophan hydroxylase in the nervous system2007

    • Author(s)
      K. Nakamura
    • Journal Title

      Mol Neurobiol 35

      Pages: 45-54

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new gain-of-function allele in chimpanzee tryptophan hydroxylase 2 and the comparison of its enzyme activity with that in humans and rats2007

    • Author(s)
      K. W. Hong
    • Journal Title

      Neurosci Lett 412

      Pages: 195-200

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recent Studies on Sepiapterin and Biopterin Transport in Mammalian Cells2007

    • Author(s)
      H. Hasegawa
    • Journal Title

      Proceedings of 13th International Symposium on Chemistry & Biology of Pteridines & Folates

      Pages: 259-273

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A new gain of function allele in chimpanzee tryptophan hydroxylase 2 and the comparison of its enzyme activity with that in humans and rats2007

    • Author(s)
      Hong, K. W.
    • Journal Title

      Neurosci Lett 412

      Pages: 195-200

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Requirement of tryptophan hydroxylase during development for maturation of sensorimotor gating2006

    • Author(s)
      Nakamura, K., et. al.
    • Journal Title

      J Mol Biol 363

      Pages: 345-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels2006

    • Author(s)
      Nakamura, K., et. al.
    • Journal Title

      J Neurosci 26

      Pages: 530-4

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Requirement of tryptophan hydroxylase during development for maturation of sensorimotor gating.2006

    • Author(s)
      Nakamura, K., Y. Koyama, K. Takahashi, H. Tsurui, Y. Xiu, M. Ohtsuji, Q. S. Lin, Y. Sugawara, K. Sawabe, A. Ohashi, T. Ohnuma, H. Arai, H. Nishimura, H. Hasegawa, S. Hirose
    • Journal Title

      J Mol Biol 363(2)

      Pages: 345-54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels.2006

    • Author(s)
      Nakamura, K., Y. Sugawara, K. Sawabe, A. Ohashi, H. Tsurui, Y. Xiu, M. Ohtsuji, Q. S. Lin, H. Nishimura, H. Hasegawa, S. Hirose
    • Journal Title

      J Neurosci 26(2)

      Pages: 530-34

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels2006

    • Author(s)
      Nakamura, K.
    • Journal Title

      J Neurosci 26

      Pages: 530-534

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Requirement of tryptophan hydroxylase during development for maturation of sensorimotor gating2006

    • Author(s)
      Nakamura, K.
    • Journal Title

      J Mol Biol 363

      Pages: 345-354

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels2006

    • Author(s)
      Nakamura Kazuhiro
    • Journal Title

      J Neurosci 26・2

      Pages: 530-534

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Distinctive iron requirement of tryptophan 5-monooxygenase:TPH1 requires dissociable ferrous iron2005

    • Author(s)
      Hasegawa, H., et. al.
    • Journal Title

      Biochem Biophys Res Commun 338

      Pages: 277-84

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Distinctive iron requirement of tryptophan 5-monooxygenase : TPH1 requires dissociable ferrous iron.2005

    • Author(s)
      Hasegawa, H., A. Ichiyama
    • Journal Title

      Biochem Biophys Res Commun 338(1)

      Pages: 277-84

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Distinctive iron requirement of tryptophan 5-monooxygenase : TPH1 requires dissociable ferrous iron2005

    • Author(s)
      Hasegawa Hiroyuki
    • Journal Title

      Biochem Biophys Res Commun 338・1

      Pages: 277-284

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Delivery of exogenous tetrahydrobiopterin (BH4) to cells of target organs : role of salvage pathway and uptake of its precursor in effective elevation of tissue BH42005

    • Author(s)
      Hasegawa Hiroyuki
    • Journal Title

      Mol Genet Metab 86・S1

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increase in tetrahydrobiopterin release from PC12 cells under hypotonic culture conditions is inhibited by HgCl22005

    • Author(s)
      Nakanishi Nobuo
    • Journal Title

      Pteridines 16

      Pages: 1-5

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Cellular accumulation of tetrahydrobiopterin following its administration is mediated by two different processes ; direct uptake and indirect uptake mediated by a methotrexate-sensitive process2005

    • Author(s)
      Sawabe Keiko
    • Journal Title

      Mol Genet Metab 86・S1

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Accumulated BH4 in mouse liver caused by administration of either 6R- or 6SBH4 consisted solely of the 6R-diastereomer : evidence of oxidation to BH2 and enzymic reduction2005

    • Author(s)
      Sawabe Keiko
    • Journal Title

      Mol Genet Metab 86・S1

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Intestinal uptake of 6(R)-L-erythro-tetrahydrobioterin is distinctive from liver-type MTX-sensitive accumulation process2005

    • Author(s)
      Keiko Sawabe
    • Journal Title

      Pteridines 16

      Pages: 6-10

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Increase in biopterin pool after tetrahydrobiopterin administration is due to uptake and conversion of secondarily produced dihydrobiopterin.2004

    • Author(s)
      Keiko Sawabe
    • Journal Title

      Pterins, Folates and Neurotransmitters in Molecular Medicine

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Tetrahydrobiopterin uptake in supplemental administration : elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process2004

    • Author(s)
      Keiko Sawabe
    • Journal Title

      J.Pharmacol.Sci. 96

      Pages: 124-133

    • NAID

      10014166544

    • Related Report
      2004 Annual Research Report
  • [Journal Article] トリプトファン水酸化酵素-1 mRNAにおいて,2種類の3'-UTRがその発現に及ぼす影響について2004

    • Author(s)
      菅原 ゆうこ
    • Journal Title

      健康創造研究会誌 3

      Pages: 46-54

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Increase in tetrahydrobiopterin release from PC12 cells under hypotonic2004

    • Author(s)
      Nobuo Nakanishi
    • Journal Title

      Pteridines 16(in press)

      Pages: 46-54

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 活性型ビオプテリン(BH4)の体内レベル維持における腎機能の役割 : 尿酸取り込み阻害剤ベンズブロマロンによる検討

    • Author(s)
      沢辺 恵子
    • Journal Title

      静岡実験動物研究会会報 (印刷中)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] ラットにおけるテトラヒドロビオプテリン(BH4)の血液内(血球-血漿)動態について

    • Author(s)
      末武 康子
    • Journal Title

      静岡実験動物研究会会報 (印刷中)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Recent Studies on Sepiapterin and Biopterin Transport in Mammalian Cells

    • Author(s)
      Hasegawa, H.
    • Journal Title

      The proceedings of 13th International Symposium on Chemistry & Biology of Pteridines & Folates (印刷中)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] テトラヒドロビオプテリンの取り込み機構:MTX感受性のBH_4蓄積について

    • Author(s)
      沢辺 恵子
    • Journal Title

      静岡実験動物研究会会報 (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Presentation] Entero-hepatic circulation of BH4, another route of exogenous-BH4 transport2008

    • Author(s)
      K. Sawabe
    • Organizer
      International conference Tetrahydrobiopterin, PKU, and NOS
    • Place of Presentation
      St. Moritz, Switzerland
    • Year and Date
      2008-03-24
    • Related Report
      2007 Annual Research Report
  • [Presentation] Non-reduced Biopterin is a potential replacement of(6R)tetrahydrobiopterin for BH4-supplementation2007

    • Author(s)
      長谷川 宏幸
    • Organizer
      第81回日本薬理学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2007-03-19
    • Related Report
      2007 Annual Research Report
  • [Presentation] Demonstration of transcellular transport of tetrahydrobiopterin across Caco-2 cells as a model of intestinal uptake2007

    • Author(s)
      澤邊 恵子
    • Organizer
      第81回日本薬理学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2007-03-19
    • Related Report
      2007 Annual Research Report
  • [Presentation] Immunohistochemical and enzymological detection of tryptophan hydroxylase in villus epithelium of intestinal mucosa2007

    • Author(s)
      Ohashi, A., et. al.
    • Organizer
      26th International winter-workshop clinical, chemical, & biochemical aspects of pteridines
    • Place of Presentation
      St.Christoph,Austria
    • Year and Date
      2007-03-06
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Immunohistochemical and enzymological detection of tryptophan hydroxylase in villus epithelium of intestinal mucosa.2007

    • Author(s)
      Ohashi, A., K. Nakamura, T. Sato, H. Hasegawa.
    • Organizer
      26th International winter-workshop clinical, chemical, & biochemical aspects of pteridines
    • Place of Presentation
      St. Christoph/Arlberg, Austria
    • Year and Date
      2007-03-06
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 大橋晶子,中村和裕,佐藤拓,長谷川宏幸.トリプトファン水酸化酵素(TPH)の2つのアイソファームTPH1,TPH2に特異的な抗体の作成と免疫組織化学による小腸上皮組織のTPHの検出2006

    • Author(s)
      大橋 晶子, 他
    • Organizer
      第10回活性アミンに関するワークショップ
    • Place of Presentation
      東京
    • Year and Date
      2006-08-27
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] Proceedings of 13th International Symposium on Chemistry & Biology of Pteridines & Folates2007

    • Author(s)
      Hasegawa, H., et. al.
    • Publisher
      SPS Publication,Germany
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] Pterines, Folates and Neurotransmitters in Molecular Medicine2003

    • Author(s)
      Sawabe, K., et. al.
    • Publisher
      SPS Publications,Germany
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.ntu.ac.jp/dept/bio/btrc/h/hasegawa/30.html

    • Related Report
      2007 Final Research Report Summary

URL: 

Published: 2004-04-01   Modified: 2016-04-21  

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