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Subcellular localization of the proteins implicated in DNA damage-induced cell death

Research Project

Project/Area Number 13670859
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionNational Research Institute for Child Health and Development

Principal Investigator

MIYASHITA Toshiyuki  National Research Institute for Child Health and Development, Dept. of Genetics, Division Head, 研究所・成育遺伝研究部疾患遺伝子構造研究室, 室長 (60174182)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsapoptosis / DNAdamage / caspage / Bim / NF-κB / isoform / 細胞死 / Fas / p53 / CNA損傷 / ミトコンドリア / 選択的スプライシング
Research Abstract

Apoptosis or programmed cell death is a physiologic process that is regulated by evolutionarily conserved genes. Dysregulation of apoptosis can contribute to many major diseases including cancer, autoimmune disorders and certain neurodegenerative diseases. DNA damage-induced apoptosis is accomplished by proapoptotic members of the Bcl-2 family, such as Bim, and a family of cysteine proteases termed caspases. During the period of two years we got the results as follows.
We have cloned and characterized six novel isoforms of human Bim, designated as Bimα1, α2, and β1-β4, which are generated by alternative splicing. Among the novel isoforms, only Bimα1 and α2 contained a BH3 domain and were proapoptotic, although less potent than the classical isoforms. These two isoforms localized, at least in part, in mitochondria. Expression profiles of bim isoforms were highly variable among normal tissues at least in humans, suggesting a tissue-specific transcriptional regulation of bim.
Caspase-8 and -10 can induce NF-κB activation in protease-independent manner. Investigation of the signaling pathways leading to caspase-8 and -10-mediated NF-κB activation using the GST pull-down assay revealed that, among upstream kinases that activate NF-κB, NIK and RIP, but not RICK or IKKα/β could directly bind to caspase-8and -10. By using dominant-negative mutants and small interfering RNA technology, we also demonstrated that NIK and IKKα are required for this process.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (37 results)

All Other

All Publications (37 results)

  • [Publications] Cuddeback SM, et al.: "Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax."J Biol Chem. 276. 20559-20565 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamura-Oho Y, et al.: "Distinctive tissue distribution and phosphorylation of IRSp53 isoforms"Biochem Biophys Res Commun. 289. 957-960 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamura-Oho Y, et al.: "Distinctive tissue distribution and phosphorylation of IRSp53 isoforms"Biochem Biophys Res Commun. 289. 957-960 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shikama Y, et al.: "Comprehensive studies on subcellular localizations and cell death-inducing activities of eight GFP-tagged apoptosis-related caspases"Exp Cell Res. 264. 315-325 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] U M, et al.: "Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregates"Cell Death Differ. 8. 377-386 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] U M, et al.: "Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family"FEBS Lett. 509. 135-141 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoue H, et al.: "Dexamethasone-resistant human Pre-B leukemia 697 cell line evolving elevation of intracellular glutathione level : an additional resistance mechanism"Jpn J Cancer Res. 93. 582-590 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shikama Y, et al.: "Death effector domain-only polypeptides of caspase-8 and -10 specifically inhibit death receptor-induced cell death"Biochem Biophys Res Commun. 291. 484-493 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida NL, et al.: "Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays"Biochem Biophys Res Commun. 293. 1254-1261 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujii K, et al.: "Mutations in the human homologue of Drosophila patched in Japanese nevoid basal cell carcinoma syndrome patients"Hum Mutat. 21. 451-452 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujii K, et al.: "Gorlin syndrome with ulcerative colitis in a Japanese girl"Am J Med Genet. (in press ).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yanagisawa H, et al.: "HSpin1, a transmembrane protein interacting with Bcl-2/Bcl-_<XL>, induces a caspase-independent autophagic cell death"Cell Death Differ. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shikama Y, et al.: "Caspase-8 and caspase-10 activate NF-κB through RIP, NIK and IKKα kinases"Eur J Immunol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamura-Oho Y, et al.: "Dentatorubral-pallidoluysian atrophy (DRPLA) protein is phosphorylated by c-Jun NH2-Terminal Kinase"Hum Mol Genet. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 宮下俊之: "アポトーシスに関与する遺伝子とその異常に起因する疾患"小児内科. 34. 1725-1730 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Cuddeback, S.M., et al.: "Molecular Cloning and Characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax"J. Biol. Chem.. 276(23). 20559-20565 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamura-Oho, Y., et al.: "Distinctive tissue distribution and phosphorylation of IRSp53 isoforms"Biochem. Biophys. Res. Commun.. 289(5). 957-960 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shikama, Y., et al.: "Comprehensive studies on subcellular localizations and cell death-Inducing activities of eight GFP-tagged apoptosis-related caspases"Exp. Cell Res.. 264(2). 315-325 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] U, M., et al.: "Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregates"Cell Death Diff.. 8(4). 377-386 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] U, M., et al.: "Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family"FEBS Lett.. 509(1). 135-141 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoue, H-, et al.: "Dexamethasone-resistant human pre-B leukemia 697 cell line evolving elevation of intracellular glutathione level : an additional resistance mechanism"Jpn. J. Cancer Res.. 93(5). 582-590 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shikama, Y., et al.: "Death effector domain-only polypeptides of caspase-8 and -10 specifically inhibit death receptor-induced cell death"Biochem. Biophys. Res. Commun.. 291(3). 484-493 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida, N.-L., et al.: "Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays"Biochem. Biophys. Res. Commun.. 293(4). 1254-1261 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujii, K., et al.: "Mutations in the human homologue of Drosophila patched in Japanese nevoid basal cell carcinoma syndrome patients"Hum. Mutat.. 21(4). 451-452 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoue, H., et al.: "Dexamethasone-resistant Human Pre-B Leukemia 697 Cell Line Evolving Elevation of Intracellular Glutathione Level : AN Additional Resistance Mechanism"Japanese Journal of Cancer Research. 93(5). 582-590 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shikama, Y., et al.: "Death effector domain-only polypeptides of caspase-8 and -10 specifically inhibit death receptor-induced cell death"Biochemical and Biophysical Research Communications. 291(3). 484-493 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, N.L., et al.: "Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays"Biochemical and Biophysical Research Communications. 293(4). 1254-1261 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujii, K., et al.: "Mutations in the human homologue of Drosophila patched in Japanese nevoid basal cell carcinoma syndrome patients"Human Mutation. 21(4). 451-452 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujii, K., et al.: "Gorlin syndrome with ulcerative colitis in a Japanese girl"American Journal of Medical Genetics. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Yanagisawa, H., et al.: "HSpin1, a transmembrane protein interacting with Bcl-2/Bcl-xL, induces a caspase-independent autophagic cell death"Cell Death and Differentiation. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 宮下 俊之: "アポトーシスに関与する遺伝子とその異常に起因する疾患"東京医学社. 6 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shikama, Y., et al.: "Comprehensive studies on subeellular localizations and cell death-inducing activities of eight GFP-tagged apoptosis-related caspases"Experimental Cell Research. 264(2). 315-325 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Cuddeback, S. M., et al.: "Molecular cloning and characterization of Bif-1. A novel Src homology 3domain-containing protein that associates with Bax"Journal of Biological Chemistry. 276(23). 20559-20565 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] U, M., et al.: "Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregartes"Cell Death and Differentiation. 8(4). 377-386 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] U, M., et al.: "Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapontotic Bcl-2 family"FEBS Letters. 509(1). 135-141 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okamura-Oho, Y., et al.: "Distinctive tissue distribution and phosphorylation of IRSp53 isoforms"Biochemical and Biophysical Research Communications. 289(5). 957-960 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shikama, Y., et al.: "Death effector domain-only polypeptides of caspase-8 and -10 specifically inhibit death receptor-induced cell death"Biochemical and Biophysical Research Communications. 291(3). 484-493 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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