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1997 Fiscal Year Final Research Report Summary

ROLES OF POLY (ADP-RIBOSE) IN CARCINOGENESIS,CELL DIFFERENTIATION AND PROGRAMMED CELLDEATH

Research Project

Project/Area Number 08458195
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

UEDA Kunihiro  KYOTO UNIVERSITY,INSTITUTE FOR CHEMICAL RESEARCH,PROOFESSOR, 化学研究所, 教授 (00027070)

Co-Investigator(Kenkyū-buntansha) ADACHI Yoshifumi  KYOTO UNIVERSITY,INSTITUTE FOR CHEMICAL RESEARCH,ASSISTANTPROFESSOR, 化学研究所, 助手 (50201893)
KIDO Takahiro  KYOTO UNIVERSITY,COLLEGE OF MEDICAL TECHNOLOGY,ASSISTANTPROFESSOR, 医療技術短期大学部, 助手 (60234308)
Project Period (FY) 1996 – 1997
KeywordsPoly (ADP-ribose) / Poly (ADP-ribose) synthease / Apoptosis / Caspase-3 / Phosphorylation / DNA-dependent protein kinase / Abeta amyloid / Neurodegeneration
Research Abstract

1.Discovery of poly (ADP-ribose) synthetase (PARS) inhibitors : We found a weak to intermediary potency to inhibit the PARS activity in a popular solvent, dimethylsulfoxide, a cardiotonic drug, vesnarinone, and pyrolysis products of protein, Trp-P-1 and PhIP.
2.Analysis of PARS functions in cancer cell differentiation : We succeeded in inducing teratocarcinoma EC cell differentiation with vesnarinone or PhIP.We found also that, in the EC cells induced to differentiate by all-trans-retinoic acid, poly (ADP-ribose) synthesis increases transiently and then decreases markedly, and that these changes are effected by automodification and subsequent limited proteolysis of PARS.
3.Elucidation of PARS roles in the cell life-deathprogram : We found that, upon induction of apoptosis of leukemic T-cells by exposure to a high-dose of radioisotopes such as ^<35>S or ^<32>P,PARS is phosphorylated and then rapidly cleaved by a protease, caspase-3, and that this cleavageoccurring in-between the bipartite nuclear localization signal leads to an extranuclearloss of PARS.We identified DNA-dependentprotein kinase as the enzyme responsible for the PARS phosphorylation.
4.Analysis of poly (ADP-ribose) change during neurodegeneration ; We found a dramatic change, stimuation or reduction, in the PARS activity in PC-12 cells induced to degenerateby Alzheimer's amyloid Abeta peptide dose-and time-dependently.
5.Discovery of poly (ADP-ribose) response after focal ischemia in brain : We found a marked increase of poly (ADP-ribose) synthesis in rat brain regions affectedby artificialischemia and later in the surrounding area (penumbra)., which conincided with the occurrence of delayd neuronal death.
These findings, taken together, indicate a central role of PARS in the basic cell fubctions, in particular, determination of the fate, survival versus death, of the cell after DNA damage.

  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] Ueda, K.: "Possible role of poly (ADP-ribose) synthetase in neuronal degeneration" Acta Neurobiol.Exp.57・Suppl.47 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawamata, J., et.al.: "Novel G16S (GGC-AGC) mutation in the SOD-1 gene in a patient with apparently sporadic young-onset amyotrophic lateral sclerosis" Human Mutation. 9・4. 356-358 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka, S., et.al.: "Inferior temporal lobe atrophy and APOE genotypes in Alzheimer's disease. X-ray computed tomography,magnetic resonance imaging and Xe-133 SPECT studies" Dement.Geriatr.Cogn.Disord.9・1. 90-98 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Banasik, M., et.al.: "Dual inhibitory effects of dimethyl sulfoxide on poly (ADP-ribose) synthetase" J.Enz.Inhib.(in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tokime, T., et.al.: "Enhanced poly (ADP-ribosyl) ation after focal ischemia in rat brain" J.Cereb.Blood Flow Metab.(in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka, S., et.al.: "Association of microsatellite polymorphism in the CYP2D locus with Lewy body variant of Alzheimer's disease" Neurology. 20(in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Adachi, Y., et.al.: "12th International Symposium on ADP-ribosylation Reactions,Abstracts" Alvarez-Gonzalez,R.(Ed.), 108 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ueda, K., et.al.: "1st Japan-Italy Bilateral Seminar on ADP-riboses and Nitric Oxide, Abstracts" Ueda,K.(Ed.), 52 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ueda, K., Nishikimi, A., Ariumi, Y., Tokime, T., Teraoka, H., Strosznajder, J., Tanakam, S., and Adachi, Y.: "Possible role of poly (ADP-ribose) synthetase in neuronal degeneration" Acta Neurobiol.Exp.57-Suppl.47 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawamata, J., Shimohama, S., Takano, S., Harada, K., Ueda, K., and Kimura, J.: "Novel G16S (GGC-AGC) mutation in the SOD-1 gene in a patient with apparently sporadic young-onset amyotrophic lateral sclerosis" Human Mutation. 9-4. 356-358 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka, S., Kawamata, J., Shimohama, S., Akaki, H., Akiguchi, I., Kimura, J., and Ueda, K.: "Inferior temporallobe atrophy and APOE genotypes in Alzheimer's disease. X-ray computed tomography, magnetic resonance imaging and Xe-133 SPECT studies" Dement.Geriatr.Cogn.Disord.9-1. 90-98 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Banasik, M., and Ueda, K.: "Dualinhibitory effects of dimethyl sulfoxide on poly (ADP-ribose) synthetase" J.Enz.Inhib.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tokime, T., Nozaki, K., Sugino, T., Kikuchi, H., Hashimoto, N., and Ueda, K.: "Enhanced poly (ADP-ribosyl) ation after focal ischemia in rat brain" J.Cereb.Blood Flow Metab.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka, S., Chen, X., Xia, Y., Kang, D.E., Matoh, N., Sundsmo, M., Thomas, R.G., Katzman, R., Thal, L.J., Trojanowski, J.Q., Saitoh, T., Ueda, K., and Masliah, E.: "Association of microsatellite polymorphism in the CYP2D locus with Lewy body variant of Alzheimer's disease" Neurology. 20(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Adachi, Y., Nishikimi, A., Teraoka, H., and Ueda, K.: "Apoptotic degradation and subcellular localization of PARP regulated by phoshorylation." 12th International Symposium on ADP-ribosylation Reactions : From Bacterial Pathogenesis to Cancer, Abstracts. 108 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ueda, K.: "Introduction (to the 1st Japan-Italy Bilateral Seminar on ADP-riboses and Nitric Oxide : Role in Cell Differentiation, Growth and Death)" 1st Japan-Italy Bilateral Seminar on ADP-riboses and Nitric Oxide : Role in Cell Differentiation, Growth and Death, Abstracts. 52 (1997)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-16  

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