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生物時計遺伝子によるリズム発振分子機構の解析

Research Project

Project/Area Number 11233204
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKobe University

Principal Investigator

岡村 均  神戸大, 医学(系)研究科(研究院), 教授 (60158813)

Co-Investigator(Kenkyū-buntansha) 西村 正高  神戸大学, 大学院・医学系研究科, 助手 (40324917)
八木田 和弘  神戸大学, 大学院・医学系研究科, 助手 (90324920)
山口 瞬  神戸大学, 大学院・医学系研究科, 助教授 (70304087)
重吉 康文  近畿大学, 医学部, 教授 (20275192)
藤堂 剛  京都大学, 放射線研究センター, 教授 (90163948)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥112,500,000 (Direct Cost: ¥112,500,000)
Fiscal Year 2002: ¥30,000,000 (Direct Cost: ¥30,000,000)
Fiscal Year 2001: ¥30,000,000 (Direct Cost: ¥30,000,000)
Fiscal Year 2000: ¥25,500,000 (Direct Cost: ¥25,500,000)
Fiscal Year 1999: ¥27,000,000 (Direct Cost: ¥27,000,000)
KeywordsCRY / 時計遺伝子 / サーカディアンリズム / 転写因子 / 遺伝子改変マウス / ショウジョウバエ / mPer1プロモーター / トランスジェニックマウス / ルシフェラーゼ / 概日リズム / cry遺伝子 / dbp / Cry / ノックアウトマウス / フォルスコリン / 単一細胞のリズム / mPer1ゲノム
Research Abstract

生体リズムの情報伝達系を分子のレベルで明らかにするため以下の研究を行った。(1)クリプトクローム(CRY)は光回復酵素を祖先型タンパクとするフラボタンパクファミリーの一員である。一次構造の類似性のみでなく、その高次構造も光回復酵素とよく似ていること。CRYは、CLOCK, BMAL, PERタンパクと相互作用することにより時計遺伝子の転写抑制を行っている。CRYは、CLOCK, BMALヘテロダィマーに直接結合するが、それによりヘテロダイマーのDNAへの結合が阻害される事はなく、安定なCRY/CLOCK/BMAL DNAの複合体が形成される。(2)時計遺伝子のコアフィードバックループから出力する新しいタイプの時計転写因子PAR/E4BP4系を発見した。(3)mPerlプロモーター・luciferase遺伝子導入トランスジェニックマウスを作成し、生体内での時計遺伝子発現のリアルタイムモニター系(Nature 2001)、生体外での薬剤の時計遺伝子のリアルタイムアッセイ系を確立した(Nature2001;Curr Biol,2001)。(4)rat-1線維芽細胞系を用いて、線維芽細胞にも視交叉上核と同様の時計のコアフィードバックループがあり、時を刻むことを証明した(Science,2001)。(5)時計の主要振動遺伝子であるPER2が、細胞質-核内をシャトルし、ユビキチン化して分解されることを発見した。(6)マウスmPer1,mPer2遺伝子をショウジョウバエ無リズム変異体Per0に導入し、行動リズムの回復を観察した。

Report

(3 results)
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Yamaguchi, S.: "Real time monitoring of clock gene expression in the living mouse"Nature. 409. 684 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamamoto, S.: "Expression of the Per1 gene in the hamster : Brain atlas and circadian characteristics in the suprachiasmatic nucleus"J. Comp. Neurol.. 430. 518-532 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mitsui, S.: "Antagonistic role of E4BP4 and PAR Proteins in the circadian oscillatory mechanism"Genes Develop. 15. 995-1006 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yagita, K.: "Molecular mechanisms of the biologicalclock in Cultured fibroblasts"Science. 292. 278-292 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hitomi, K.: "Role of two histidines in the (6-4) photolyase reaction"J. Biol. Chem.. 276. 10103-10109 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ishikawa, T.: "Mutagenic and non-mutagenic bypass of DNA lesions by Drosophila DNA polymerases dpolh and dpoli"J. Biol. Chem.. 276. 15155-15163 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yagita K. et al.: "Dimerization and nuclear entry of mPER proteins in mammalian cells"Genes & Development. 14巻. 1353-1363 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamaguchi S. et al.: "Role of DBP in the circadian oscillatory mechanism"Molucular and Cellular Biology. 20巻. 4773-4781 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yagita K. et al.: "Forikolin induces circadian gene expression of rPer1, rPer2 and dbp in mammalian rat-1 fibroblasts"FEBS Letter. 465巻. 79-82 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yan L. et al.: "Distribution and circadian expression of dbp in SCN and extra-SCN areas in the mouse brain."Journal of Neuroscience Research. 59巻. 291-295 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Moriya T. et al.: "N-methyl-D-aspartate receptor subtype 2C is not involved in circadian oscillation or photic entrainment of the biological clock in mice."Journal of Neuroscience Research. 61巻. 663-673 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamaguchi S. et al.: "The 5' upstream region of mPer1 gene contains two promoters and is responsible for circadian oscillation."Current Biology. 10巻. 873-876 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Horikawa K. et al.: "Non-photic entrainment by 5-HT1A/7 receptor agonists accompanying with reduction of Per1 and Per2 expression."Journal of Neuroscience. 20巻. 5867-5873 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okamura, H., et al.: "Photic induction of mPer1 and mPer2 in Cry-deficient mice lacking a biological clock"Science. 286. 2531-2534 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Maebayashi, Y., et al.: "A putative transcription factor with seven zino-finger motif identified in the developing suprachiasmatic nucleus by the differential display-PCR method"J. Neurosci. 10176-10183 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ibata, Y., et al.: "Functional morphology of the suprachiasmatic nucleus"Front. Neuroendocrinol.. 20. 241-268 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yan, L., et al.: "Per1 and Per2 gene expression in the rat suprachiasmatic nucleus: circadian profile and the compartment-specific response to light"Neuroscience. 94. 141-150 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takumi, T., et al.: "A mammalian orthologue of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1"Genes Cells.. 4. 67-75 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 岡村均、重吉康史: "生物時計の分子機構"細胞工学. 18. 698-707 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西塚泰美、貝淵弘三、丸山敬: "細胞のシグナリングSelected Reviews"中山書店. 399 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 海老原史樹文: "生物時計の分子生物学"シュプリンガー・フェアラーク東京. 201 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2018-03-28  

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