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Identification and clinical application of a novel regulatory proteins under hypoxic stress

Research Project

Project/Area Number 15590287
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionTOKYO MRTROPOLITAN ORGANIZATION FOR MEDICAL RESEARCH

Principal Investigator

KATO Hiroyuki  Tokyo Metropolitan Institute of Medical Science, researcher, 東京都臨床医学総合研究所, 研究員 (30301732)

Co-Investigator(Kenkyū-buntansha) SHIBASAKI Futoshi  Tokyo Metropolitan Institute of Medical Science, Dept.of Molecular Cell physiology, chief researcher, 副参事研究員 (90300954)
HOSHINO Makoto  Tokyo Metropolitan Institute of Medical Science, Dept.of Molecular Cell physiology, researcher, 研究員 (40212196)
KATO Hiroyuki  Tokyo Metropolitan Institute of Medical Science, Dept.of Molecular Cell physiology, Researcher (30301732)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsHypoxia / Histone deacetylase / nuclear import / nuclear export / Yeast two-hybrid system / re-oxygenation / ユビキチン-プロテアソーム系 / ピストン脱アセチル化酵素 / Yeast two-hybrid system
Research Abstract

Hypoxia-inducible factor (HIF)-1α is a transcription factor that controls expression of genes responsive to low oxygen tension, including vascular endothelial growth factor, erythropoien, and glycolytic enzymes. The activation of HIF-1a is regulated by binding to the transcriptional co-activator cAMP response element-binding protein-binding protein (CBP)/p300. Using the yeast two-hybrid screening system, we found that the inhibitory domain of HIF-1α strongly interacted with the C-terminal domain of histone deacetylase (HDAC)7. The o-nitrophenyl β-D-galactopyranoside assay revealed that regions containing amino acids 735-785 of HIF-1α and amino acids 669-952 of HDAC7 were minimum contact sites of the interaction. The binding of HDAC7 with HIF-1α was reproduced in HEK293 cells grown under normoxic and hypoxic condition (2%, O2). HDAC7 bound solely to HIF-1α among other HIF-α family members, including HIF-2α and HIF-3α, whereas HIF-1α only interacted with HDAC7 in the class HDAC family. Although HDAC7 was localized dominantly in the cytoplasm at normal oxygen concentrations, In the nucleus, HDAC7 increased transcriptional activity of HIF-1α through the formation of a complex with HIF-1α, HDAC7 and p300. Token together, these results indicated that HDAC7 is a novel transcriptional activator of HIF-1α. Currently we found that disscociation of HDAC7 from HDAC7/HIF-1α complex and the export of HDAC7 to the cytoplasm regulated HIF-1α degradation upon the transition from hypoxic oxygen condition to normal oxygen condition (re-oxygenation).

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (3 results)

All 2004

All Journal Article (3 results)

  • [Journal Article] Histone deacetylase 7 associates with Hypoxia-Inducible Transcription Factor and Increases Transcription Activity.2004

    • Author(s)
      Hiroyuki Kato et al.
    • Journal Title

      The Journal of Biological Chemistry 279

      Pages: 41996-41974

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Histone Deacetylase associates with Hypoxia-inducible Factor 1α and increase Transcriptional activity2004

    • Author(s)
      Hiroyuki KATO, Shiori TAMAMIZU-KATO, Futoshi SHIBASAKI
    • Journal Title

      The Journal of Biological Chemistry 279

      Pages: 41966-41974

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Histone Deacetylase 7 associates with Hypoxia-inducible Factor 1a and Increases Transcriptional Activity.2004

    • Author(s)
      Hiroyuki Kato, Shiori Tamamizu-Kato, Futoshi Shibasaki
    • Journal Title

      The Journal of Biological Chemistry 279

      Pages: 41966-41974

    • Related Report
      2004 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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