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BIOMODULATOR FUNCTIONS OF PROTEOLYSIS

Research Project

Project/Area Number 08278103
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionJUNTENDO UNIVERITY

Principal Investigator

KOMINAMI Eiki  JUNTENDO UNIVERSITY SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (10035496)

Co-Investigator(Kenkyū-buntansha) WASHIMA Seiichika  TOKYO METROPOLITAN INSTITUTE FOR MEDICAL SCIENCE, HEAD, 部長 (60008571)
NATORI Shunji  NATORI SPECIAL LABORATORY, INSTITUTE OF PHYSICAL AND CHEMICAL RESEARCH (RIKEN), CHIEF SCIENTIST, 名取特別研究室, 特別招聘研究員 (50012662)
YOKOSAWA Yoshihide  GRADUATE SCHOOL OF PHARMACEUTICAL SCIENCES, HOKKAIDO UNIVERSITY, PROFESSOR, 大学院・薬学研究科, 教授 (90012765)
UCHIYAMA Yasuo  OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学研究科, 教授 (10049091)
OHSUMI Yoshinori  NATIONAL INSTITUTE FOR BASIC BIOLOGY, PROFESSOR, 教授 (30114416)
三浦 正幸  筑波大学, 医学部, 講師 (50202338)
Project Period (FY) 1996 – 1999
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥254,900,000 (Direct Cost: ¥254,900,000)
Fiscal Year 1999: ¥58,000,000 (Direct Cost: ¥58,000,000)
Fiscal Year 1998: ¥54,100,000 (Direct Cost: ¥54,100,000)
Fiscal Year 1997: ¥51,800,000 (Direct Cost: ¥51,800,000)
Fiscal Year 1996: ¥91,000,000 (Direct Cost: ¥91,000,000)
KeywordsBIOMODULATOR / PROTEOLYSIS / LYSOSOME / AUTOPHAGY / CONJUGATION SYSTEM / CATHEPSIN / APOPTOSIS / CASPASE / 細胞周期 / 細胞分化 / 細胞死 / プロテアーゼ / 自食作用 / カルパスタチン / 細胞文化 / 恒常性の維持 / ユビキチン / カルパイン
Research Abstract

Biomodulator functions of intracellular proteolytic systems have been studied and following results were obtained. 1.lysosomal/vacuolar system : Macroautophagy mediates the bulk turnover of cytoplasmic material during starvation conditions. Ohsumi isolated 16 genes required for autophagy in yeast and has shown some of the molecular hallmarks of the autophagic pathway, including the role of two novel conjugation systems. The systems essential for the completion of autophagosomes include Apg12p and Apg8p as modifiers and Apg7p, Apg10p and Apg3p for conjugation enzymes. The mechanistic features of these conjugation systems are reminiscent of the proteasome-mediated degradation of substrates covalently tagged by ubiquitin. Kominami has been recently characterized mammalian homologs of some of the yeast autophagy proteins. These studies may provide further insight into the mechanism of mammalian macroautophagy. Kominami and Uchiyama showed that deficiency of a lysosomal proteinase, TPP-I or cathepsin D causes lysosomal storage of a hydrophobic protein, finally leading to late infantile form of neuronal ceroid lipofuscinosis, or a new type of this disease, respectively. Natori has shown importance of proteolysis by cathepsins B and L during metamorphosis of Sarcophagia. 2.Knockout mice of caspase-11 and caspases-1, 3, 7 and 9 were produced by Miura and Kuida, respectively and their biological functions and activation cascades were analysed. Involvement of calpain and proteasome systems in caspase-dependent apoptosis and caspase-independent apoptosis were also analysed.

Report

(5 results)
  • 2000 Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (63 results)

All Other

All Publications (63 results)

  • [Publications] Kabeya, Y., et al.: "LC3, a mammalian homolog of yeast Apg8p, is localized in -"EMBO J .. 19. 5720-5728 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kirisako T, et al.: "The reversible modification regulates the membrane-binding state of -"J Cell Biol.. 151. 263-276 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kamada Y., et al.: "Tor-mediated induction of autophagy via an Apg1 protein kinase complex."J Cell Biol.. 150. 1507-1513 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Noda T, et al.: "Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways."J Cell Biol.. 148. 465-480 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koike, M., et al.: "Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons."J.Neurosci.. 15. 6898-6906 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawahara, H., et al.: "Developmentally regulated, alternative splicing of the Rpn10 gene-"EMBO J.. 19. 4144-4153 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sato-Kusubata, K., et al.: "Persistent activation of Gs. through limited proteolysis by calpain."Biochem.J.. 347. 733-740 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Isei Tanida, et al.: "Apg7p/Cvt2p : a novel protein activating enzyme essential for autophagy."Mol.Biol.Cell. 10. 1367-1379 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno, T., et al.: "Autolysosomal membrane-associated betaine homocysteine -"J.Biol.Chem.. 274. 15222-15229 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Klionsky DJ, et al.: "Vacuolar import of proteins and organelles from the cytoplasm."Annu Rev Cell Dev Biol.. 15. 1-32 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Blomgren, K., et al.: "Calpastatin is up-regulated n response to hypoxia, and is a suicide-"J.Biol.Chem.. 274. 14046-14052 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kabeya, Y., et al.: "LC3, a mammalian homolog of yeast Apg8p, is localized in autophagosome membranes after processing"EMBO J.. 19. 5720-5728 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kirisako T.et al.: "The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway."J Cell Biol.. 16,151. 263-276 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kamada Y.et al.: "Tor-mediated induction of autophagy via an Apg1 protein kinase complex."J Cell Biol.. 150(6). 1507-1513 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Noda T., et al.: "Apg9p/Cvt7p is an integral membrane protein required for transport vesicle formation in the Cvt and autophagy pathways."J Cell Biol.. 148. 465-480 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Koike, M., et al.: "Cathepsin D Deficiency Induces L ysosomal Storage with Ceroid Lipofuscin in Mouse CNS neurons."J.Neurosci. 15. 6898-6906 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawahara, H., et al.: "Developmentally regulated, Iternative splicing of the Rpn10 gene generates multiple forms of 26S proteasomes."EMBO J.. 19. 4144-4153 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sato-Kusubata, K., et al.: "Persistent activation of Gs.through limited proteolysis by calpain."Biochem.J.. 347. 733-740 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanida, I., et al.: "Apg7p/Cvt2P : a novel protein activating enzyme essential for autophagy."Mol.Biol.Cell. 10. 1367-1379 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno, T., et al.: "Autolysosomal membrane-associated betaine homocysteine methyltransferase. Limited degradation fragment of a sequestered cytosolic enzyme monitoring autophagy."J.Biol.Chem.. 274. 15222-15229 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Klionsky DJ, et al.: "Vacuolar import of proteins and organelles from the cytoplasm."Annu Rev Cell Dev Biol.. 15. 1-32 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Blomgren, K.: "Calpastatin is up-regulated n response to hypoxia, and is a suicide substrate to calpain after neonatal cerebral hypoxia-ischemia."J.Biol.Chem.. 274. 14046-14052 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanida, I. , et al.: "Apg7p/Cvt2p: a novel protein activating enzyme essential for autophagy"Mol. Biol. Cell. 10. 1367-1379 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ueno, T. , et al.: "Autolysosomal membrane-associated betaine homocysteine methyl-transferase. Limited degradation fragment of a sequestered cytosolic -----"J. Biol. Chem.. 274. 15222-15229 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kirisako, T. , et al.: "Formation process of autophagosome is traced with Apg8/Aut7p in yeast"J. Cell Biol.. 147. 435-446 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Klionsky DJ. , et al.: "Vacuolar import of proteins and organelles from the cytoplasm"Annu Rev Cell Dev Biol. 15. 1-32 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kanuka, H. , et al.: "Control of cell death pathway by Dapaf-1, a Drosophila Apaf-1/CED-4 -----"Molecular Cell. 275. 757-769 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Igaki, T. , et al.: "Drob-1, a Drosophila memebr of the Bcl-2/CED-9 family that promotes cell death"Proc. Natl. Acad. Sci. USA. 97. 662-667 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takeuchi, J. , et al.: "Rpn9 is required for efficient assembly of the yeast 26S proteasome"Mol. Cell. Biol.. 19. 6575-6584 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Uehara, T. , et al.: "Transient NF-kB activation stimulated by interleukin-1β may be partly -----"J. Biol. Chem.. 274. 15875-15882 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kishimoto, T.: "Activation of MPF at meiosis reinitiation in starfish oocytes"Develop. Biol.. 214. 1-8 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S. Yamaguchi, et al.: "A novel egg-derived tyrosine phosphatase (EDTP), that participates -----"Eur. J. Biochem. 259. 946-953 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Blomgren, K. , et al.: "Calpastatin is up-regulated in response to hypoxia, and is a suicide -----"J. Biol. Chem.. 274. 14046-14052 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Isahar, K. , et al.: "Regulation of a novel pathway for cell death by lysosomal aspartic and -----"Neuroscience. 91. 233-249 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kishimoto, T.: "Encyclopedia of Reproduction"Knobil, E. Neill, J. D. eds. (Academic Press, San Diego). 8 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tanida,I.,et al.: "Apg7p/Cvt2p:a novel protein activating enzyme essential for autophagy" Mol.Biol.Cell. In press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ezaki,J.,et al.: "A lysosomal proteinase,the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product,is essential for degradation of a hydrophobic protein,.-------" J.Neurochem.In press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mizushima,N.,et al.: "A novel protein conjugation system essential for autophagy." Nature. 395. 395-398 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kametaka,S,,et al.: "Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast." J.Biol.Chem.273. 22284-22291 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Wang,S.,Miura,M.,et all.: "Murine caspase-11,an ICE interacting protease,is essential for activation of ICE." Cell. 92. 501-509 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kanuka,H.,et al.: "Pro-apoptotic activity of C.elegans CED-4 in Drosophila: implicated mechanisms for caspase activation." Proc.Natl.Acad.Sci.USA. 96. 145-150 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujimuro,M.et al.: "Growth-dependent change of the 26S proteasome in budding yeast." Biochem.Biophys.Res.Commun.251. 818-823 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujimuro,M.et al.: "Sonlp is a component of the 26S proteasome of the yeast Saccharomyces cerevisiae." FEBS Lett.423. 149-154 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okano-Uchida,T.et al.: "In vivo Regulation of cyclin A/Cdc2 and cyclin B/Cdc2 through meiotic and early cleavage cycles in starfish." Develop.Biol.197. 39-53 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsubara,Y.: "Transient up-regulation of a prolyl-endopeptidase activity in the microsomal fraction of rat liver during its postnatal development." Eur.J.Biochem.252. 178-183 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ishino,T.et al.: "cDNA Cloning of Prolyl Endopeptidase and Its Involvement in DNA Synthesis by Swiss 3T3 Cells." J.Biochem.97. 540-545 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kawahara,A.et al.: "Caspase-independent cell killing by Fas-associated protein with death domain." J.Cell Biol.143. 1353-1360 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ishidoh,K.,et al.: "Egr family member proteins are involved the activation of the cathepsin L gene in ν-src transformed cells." Biochem.Biophy.Res.Commun.238. 665-669 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Baba,M.,et al.: "Two distinct pathways targeting proteins from the cytoplasm to the vacuole/lysosome." J.Cell Biol.139. 1687-1695 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tachibana,K.et al.: "MAP kinase links the fertilization signal transduction pathway to the Gl/S-phase transitionin starfish eggs." EMBOJ.16. 4333-4339 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakajima,Y.,et al.: "A novel protease in the pupal yellow body of Sarcophaga peregrina (flesh fly)." J.Biol.Chem.272. 23805-23810 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Wang,S., Miura,M., et al.: "Murine caspase-11,an ICE interacting protease,is essential for activation of ICE." Cell. in press (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fujjumuro,M.et al.: "Dynamics of ubiquitin conjugation during heat-shock response revealed by using a monoclonal antibody specific to multi-ubiquitin chains." Eur.J.Biochem.249. 427-433 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ueno,T., Kominami E.: "Proteolysis in Cell Function" V.K.Hopsu-Havu,M.Jarvinen,and H.Kirschke (IOS Press, Amsterdam), 576 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ishidoh K., Kominami E.: "Medical Aspects of Proteases and Protease Inhibitors" N.Katunuma,H.Kido,H.Fritz,and Travis (IOS Press,Amsterdum), 205 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ezaki,J.,et al.: "Specific delay in the degradation of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid lipofscinosis is derived from cellular proteolytic ------" J.Neurochem.67. 1677-1687 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Homma,K.et al.: "Purification,characterization,and cDNA cloning of a novel growth factor from the conditioned medium of NIH-Sape-4,an embryonic cell line of ------" J.Biol.Chem.271. 13770-13775 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Aizawa,H.,et al.: "Activation of the proteasome during Xenopus egg activation implies a link between proteasome activation and intracellular calcium release." Biochem.Biophys.Res.Commun.218. 224-228 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tsubuki,S.,et al.: "Differential inhibiton of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine." J.Biochem.119. 572-576 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tachibana,K.,et al.: "MAP kinase links the fertilization signal transduction pathway to the G1/S-phase transition in starfish eggs." EMBOJ.(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Wang,S.,Miura,M.,et al.: "Identification and characterization of Ich-3,a member of the ICE/Ced-3 family and an upstream regulator of ICE." J.Biol.Chem.271. 20580-20587 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nitatori,T.,et al.: "Intracellular protein catabolism,Advances in experimental medicine and biology." Suzuki,K.,Bond,J.S.,Prebum Press,New York and London, 10 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ueno,T.et al.: "Intracellular Protein Catabolism" V.K.Hopsu-Have,IOS Press,Amsterdam (in press), (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2019-02-15  

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