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Molecular Mechanism of Circadian Signal Generation in Mammals

Research Project

Project/Area Number 01440024
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionOsaka University

Principal Investigator

NAKAGAWA Hachiro  Division of Protein Metabolism Institute for Protein Research Osaka University Professor, たんぱく質研究所, 教授 (20029937)

Co-Investigator(Kenkyū-buntansha) OKADA Masato  Division of Protein Metabolism Institute for Protein Research Osaka University I, たんぱく質研究所, 助手 (10177058)
NAGAI Katsuya  Division of Protein Metabolism Institute for Protein Research Osaka University A, たんぱく質研究所, 助教授 (70029966)
松田 義宏  大阪大学たんぱく質研究所, 助手 (80165836)
Project Period (FY) 1989 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥25,000,000 (Direct Cost: ¥25,000,000)
Fiscal Year 1992: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1991: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1990: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 1989: ¥10,200,000 (Direct Cost: ¥10,200,000)
KeywordsCircadian Rhythm / Protein tyrosine kinase / CSK / Cell cycle / D type G1 cyclin / Suprachiasmatic nucleus / LD-cycle / Retinohypothalamic tract / 概日時計 / 網膜視床下部路 / p60^<c-src> / D型G1サイクリン / c-fos / 視交叉上核 / キスカル酸受容体 / MAP kinase / VGF / pp60°^<ーsro> / 電位依存性カルシウムチャンネル / チロシンキナ-ゼ / がん原遺伝子 / Ca^<2+>チャンネル / 脳へのエネルギ-供給 / VIP / NGF / pp60^<c-src>Rinase / ホスホイノシチドサイクル / Ca^<++>チャンネル / Inositol polyphosphatase
Research Abstract

1. Involvement of protein-tyrosine kinase (PTK) in generation of the circaadian rhythm. We found that continuous infusion of insulin into rat brain eliminated the circadian rhythms completely. From this finding, we examined the problem of whether PTK was really involved in the circadian signal generation. During the course of this investigation, we isolated a new type of PTK from neonatal rat brain and named it CSK. We showed that this enzyme specifically phosphorylates the C-terminal tyrosine residues of src-family PTKs and that it inhibited the latter activities. We obtained several lines of evidence that CSK might play critical roles in neuronal differentiation, immumne regulation and carcinogenesis. We showed that PTK activity of p60^<c-src> in the suprachiasmatic nucleus (SCN) exhibited the daily change, but we have not obtained evidence yet that CSK is specifically involved in this mechanism. 2. Relationship between rhythm generation and cell cycle. We isolated a D type G1 cyclin, a regulatory protein for cell cycle, from matured brain, in which neurons lose their proliferating abilities. We are now examining how cell cycle regulation and circadian signal generation are interconnected. 3. Central regulation of energy metabolism. It is known that the SCN is roughly divided into two parts, the dorsomedial and ventrolateral parts, and that the cicadian clock is located in the former and the retinohypothalamic tract which is involved in synchronization of the circadian period to an environmental LD cycle is projected to the latter. We found that the regulatory center for energy supply to the brain is located in the latter and obtained evidence suggesting that these functions are cooperatively regulated with the circadian signal generation.

Report

(5 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • 1989 Annual Research Report
  • Research Products

    (43 results)

All Other

All Publications (43 results)

  • [Publications] T.Tamaru: "Identification of cells expressing a D type G1 cyclin in matured brain:Implication for its role in neuronal funotion." Neuroscience Letters. (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] A.Asada: "Changes in NGF receptor-like lmmunoreactive substance in the suprachiasmatic nucleus of the hypothalamus in blind rats." Journal of Clinical Biochemistry and Nutrition. 13. 93-106 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] H.Sabe: "Activation of c-src in cells bearing v-crk and its syppression by CSK." Molecular and Cellular Biology. 12. 4706-4713 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] N.Nagai: "Effect of orbital enucleation on glucose homcostasis and morphology of the suparchiasmatic nucleus." Brain Research. 589. 243-252 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M.Okada: "CSK:a Protein-tyrosine kinase involved in regulation of src family kinases." journal of Biological Chemistry. 266. 24249-24252 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S.Nada: "Cloning of complementary DNA for a protein-tyrosine kinase that spedifically phosphorylates a negative regulatory site of p60^<c-src>." Nature. 351. 69-72 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K.Nagai: "Central Regulation of Energy Metabolism with Special Reference to Circadian Rhythm" CRC Press, 194 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 中川 八郎: "脳と生物時計ーからだのリズムのメカニズム" 共立出版株式会社, 220 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Tamaru: "Identification of cells expressing a D type G1 cyclin in matured brain:Implication for its role in neuronal function." Neuroscience latters.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] A.Asada: "Changes in NGF receptor-like immuno-reactive substance in the suprachiasmatic nucleus of the hypothalamus in blind rats." Journal of Clinical Biochemistry and Nutrition. 13. 93-106 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] H.Sabe: "Activation of c-src in cells bearing v-crk and its suppression by CSK." Molecular and Cellular Biology. 12. 4706-4713 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] N.Nagai: "Effect of orbital enucleation on glucose homeostasis and morphology of the suprachiasmatic nucleus." Brain Research. 589. 243-252 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M.Okada: "CSK:a Protein-tyrosine kinase involved in regulation of src family kinases." Journal of Biological Chemistry. 266. 24249-24252 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S.Nada: "Cloning of complementary DNA for a protein-tyrosine kinase that specically phosphorylates a negative regulatory site of p60^<c-src>." Nature. 351. 69-72 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] K.Nagai: CRC Press,Boca Raton. Central Regulation of Energy Metabolism with Special Reference to Circadian Rhythm., (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] H.Nakagawa: Kyoritsu Shuppan Tokyo. The Brain and Biological Clock., (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] S. Nada: "Mouse embryo lacking CSK have constitutive activation of src family tyrosine kinases and developmental arrest at N eurula stage." Cell. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] K. Nagai: "Reduced increase in plasma renin activity on water deprivation in blind hereditary microphthalmic rats." Neuroscience Letters. 149. 217-220 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] A. Asada: "Changes in NGF receptor-like immunoreactive substance in the suprachiasmatic nucleus of the hypothalamus in blind rats." Journal of Clinical Biochemistry and Nutrition. 13. 93-106 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] T. Hirano: "Circadian variation of [^3H]dopamine handling in adrenal chromoaffine cells of mice." Neuroscience Letters. 146. 159-162 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] N. Nagai: "Effect of orbital enucleation on glucose homeostasis and morphology of the suprachiasmatic nucleus." Brain Research. 589. 243-252 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M. Okada: "CSK: a Protein-tyrosine kinase involved in regulation of src family kinase" Journal of Biological Chemistry. 266. 24249-24252 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] S.Nada: "Cloning of complementary DNA for a protein tyrosine kinase that specifically phosphorylates a negative regulatory site of pp60°^<ーsro>" Nature. 351. 69-72 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] M.Okada: "CSK:a proteinーtyrosine kinase involved in regulation of src family kinases" J.Biol.Chem.266. 24249-24252 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] K.Nagai: "Effect of glucagon in macronutrint selfーselection:Glucagon enhanced protein intake" Brain Res.Bull.27. 409-415 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] A.Asada: "Changes in NGF receptorーlike immunoreactive substance in the suprachiamatic nucleus of the hypothalamus in blind rats" 投稿中.

    • Related Report
      1991 Annual Research Report
  • [Publications] 永井 克也: "脳へのエネルギ-供給と概日時計" ホルモンと臨床. 43. 35-39 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 中川 八朗: "生物時計の研究から光の意義を見出す" 学士会会報. Iー1(794). 141-145 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] 中川 八郎: "脳と生物時計ーからだのリズムのメカニズムー" 共立出版社 東京, 220 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] K.Nagai: "Central Regulation of Energy Metabolism with Special Reference to Circadian Rhythm" CRC Press,Boca Raton,U.S.A., 188 (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nobuko Itowi: "Effects of histamine and αーfluoromethylhistidine injections on circadian phase of freeーrunning rhythms" Physiology & Behavior. 47. 549-554 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Shinーichiro Sano: "Oligosaccharideーrelated epitope specific for a hrainーspecific glycoprotein,1D4 antigen" Journal of Neurochemistry. 55. 1252-1257 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Shigeyuki Nada: "Molecular cloning of a proteinーtyrosine kinase that specifically phosphorylates a negativeーregulatory site of p60^<cーsrc>" Nature.

    • Related Report
      1990 Annual Research Report
  • [Publications] Hideki Masutani: "Possible involvement of calcium channels in generation of the circadian temporal signal in the suprachiasmatic nucleus" Neuroscience Letters.

    • Related Report
      1990 Annual Research Report
  • [Publications] Nobuo Nagai: "The role of the suprachiasmatic nucleus in hyperglycemia by intracranial injection of VIP in rats"

    • Related Report
      1990 Annual Research Report
  • [Publications] Akiko Asada: "Changes in the NGF receptorーlike substance in the suprachiasmatic nucleus in surgically and congenitally blind rats"

    • Related Report
      1990 Annual Research Report
  • [Publications] 中川 八郎: "脳と生物時計" 共立出版株式会社, 170 (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] Masato Okada: "A protein tyrosine kinase involved in regulation of pp60^<c-src>function" Journal of Biological Chemistry. 264. 20886-20893 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shin-ichiro Sano: "A novel brain specific antigen:A glycoprotein electrophoretically similar but immmunochemically different from Type B nucleoside diphosphatase" Journal of Biochemistry. 105. 457-460 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Koichi Takimoto: "Purification and characterization of membrane-bound inositol polyphosphatase" Jouranl of Biochemistry. 106. 684-690 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Tetsuo Hirano: "Uptake of[^3H]dopamine in the mouse adrenal medulla during dark and light period" Journal of Autonomic Nervous System. 28. 89-93 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Takando Fujii: "Involvement of adrenergic mechanism in hyperglycemia due to SCN stimulation" Hormone and Metabolic Research. 21. 643-700 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 中川八郎: "概日時計研究法ー哺乳動物における問題点" 病態生理. 8. 707-715 (1989)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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