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Development of novel therapy for heart failure using Cdk9 as a target molecule

Research Project

Project/Area Number 18390239
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionKeio University

Principal Investigator

SANO Motoaki  Keio University, School of Medicine, Assistant professor (30265798)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
Keywordscardiac hypertrophy / transcription / energy metabolism / signal transduction / P-TEFb / PGC-1α / HEXIM-1 / ミトコンドリア / 心不全 / アポトーシス
Research Abstract

Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alpha
Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1alpha is a short lived and aggregation-prone protein. PGC-1alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeti … More ng of the polyubiquitinated PGC-1alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1alpha Exogenous expression of the PGC-1alpha C-terminal fragment interfered with degradation of full-length PGC-1alpha and enhanced its coactivation properties. We concluded that PGC-1alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.
HEXIM-1 alleviated hypoxia-induced right ventricular hypertrophy
HEXIM-1 is an endogenous inhibitor of Cdk9. To examine the effect of Cdk9 inhibition on the development of cardiac hypertrophy, we developed loss of function model of Cdk9 activity by transgenic over-expression of HEXIM-1. Cardiac-specific HEXIM-1 TG mice and wild-type littermates were subjected to hypoxia (11% O_2). Right ventricular hypertrophy produced by hypoxia was milder in HEXIM-1 TG mice compared to wild-type littermates. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (24 results)

All 2008 2007 2006

All Journal Article (14 results) (of which Peer Reviewed: 8 results) Presentation (6 results) Book (4 results)

  • [Journal Article] Intramolecular Control of Protein Stability, Subnuclear Compartmentalization, and Coactivator Function of Peroxisome Proliferator-activated Receptor γ Coactivator 1α2007

    • Author(s)
      Sano M, Tokudome S, et. al.
    • Journal Title

      J Biol Chem 282

      Pages: 25970-25980

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Menage-a-trois 1 is indisoensable for the transcriptional function of PPARγ coactivatior-12007

    • Author(s)
      Sano M, Izumu, Y, et. al.
    • Journal Title

      Cell Metabolism 5

      Pages: 129-142

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Bone Marrow Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload2007

    • Author(s)
      Endo J, Sano M, et. al.
    • Journal Title

      Circulation 116

      Pages: 604-612

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Intramolecular Control of Protein Stability, Subnuclear Compartmentalization, and Coactivator Function of Peroxisome Proliferator-activated Receptor y Coactivator la2007

    • Author(s)
      Sano, M, Tokudome, S, et. al.
    • Journal Title

      J Biol Chem 282

      Pages: 25970-25980

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Menage-a-trois 1 is indisoensable for the transcriptional function of PPARy coactivatior-12007

    • Author(s)
      Sano, M, Izumu, Y, et. al.
    • Journal Title

      Cell Metabolism 5

      Pages: 129-142

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Bone Marrow Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload2007

    • Author(s)
      Endo, J, Sano, M, et. al.
    • Journal Title

      Circulation 116

      Pages: 604-612

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Intramolecular Control of Protein Stability, Subnuclear Compartmentalization,and Coactivator Function of Peroxisome Proliferator-activated Receptor γ Coactivator 1α.2007

    • Author(s)
      Sano M, Tokudome S, et. al.
    • Journal Title

      J Biol Chem 282

      Pages: 25970-25980

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Menage-a-trois 1 is indisoensable for the transcriptional function of PPARγ coactivatior-1.2007

    • Author(s)
      Sano M, Izumu, Y, et. al.
    • Journal Title

      Cell Metabolism 5

      Pages: 129-142

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells.2007

    • Author(s)
      Liu Y, Asakura M, Inoue H, Nakamura T, Sano M, et. al.
    • Journal Title

      Proc Natl Acad Sci U S A. 104

      Pages: 3859-3864

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bone Marrow Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload.2007

    • Author(s)
      Endo J, Sano M, et. al.
    • Journal Title

      Circulation 116

      Pages: 1176-1184

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sama3a maintains normal heart rhythm through sympatic innervation patterning.2007

    • Author(s)
      Ieda M, kanazawa H, Sano M
    • Journal Title

      Nat Med 13

      Pages: 604-612

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Menage-a-trois 1 is critical for the transcriptional function of PPARγ coactivator-12007

    • Author(s)
      Sano M, Izumi Y, et al.
    • Journal Title

      Cell Metabolism In press

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Nerve growth factor is critical for cardiac sensory innervation and rescue neuropathy in diabetic hearts.2006

    • Author(s)
      Ieda M, Kanazawa H, Sano M et al.
    • Journal Title

      Circulation 114

      Pages: 2351-63

    • Related Report
      2006 Annual Research Report
  • [Journal Article] ミトコンドリアと転写制御からみた循環器疾患2006

    • Author(s)
      佐野元昭, 福田恵一
    • Journal Title

      実験医学 増刊 疾患のサイエンス Vo1.24-No.10

      Pages: 1440-1445

    • Related Report
      2006 Annual Research Report
  • [Presentation] アルデハイドに対する心筋ストレス応答機構の解明2007

    • Author(s)
      佐野 元昭
    • Organizer
      第10回 日本組織工学会
    • Place of Presentation
      東京
    • Year and Date
      2007-11-09
    • Related Report
      2007 Annual Research Report
  • [Presentation] Dysregulation of PGC-1 contributes to the energy disturbance in the heart failure2007

    • Author(s)
      Motoaki Sano
    • Organizer
      第11回 日本心不全学会
    • Place of Presentation
      東京
    • Year and Date
      2007-11-09
    • Related Report
      2007 Annual Research Report
  • [Presentation] 転写共役因子PPARg coactivator-1 (PGC-1)の細胞内局在とタンパクレベルの制御機構2007

    • Author(s)
      佐野 元昭
    • Organizer
      第25回 日本ヒト細胞学会
    • Place of Presentation
      東京
    • Year and Date
      2007-08-03
    • Related Report
      2007 Annual Research Report
  • [Presentation] PPARg coactivator 1α(PGC、1α)のタンパク質レベルでの量、核内局在、転写活性化作用は、ユビキチン・プロテアソーム系を介する分子内相互作用によって制御きれている2007

    • Author(s)
      Motoaki Sano
    • Organizer
      第24回ISHR日本部会
    • Place of Presentation
      イタリア(ボローニャ)
    • Year and Date
      2007-06-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Intramolecular Control of Protein Stability, Subnuclear Compartmentalization, and Coactivator Function of Peroxisome Proliferator-activated Receptor y Coactivator la2007

    • Author(s)
      Motoaki, Sano
    • Organizer
      International Society of Heart Research (ISHR)
    • Place of Presentation
      Bologna, Italy
    • Year and Date
      2007-06-22
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] PPARg coactivator 1α (PGC-1α)のタンパク質レベルでの量、核内局在、転写活性化作用は、ユビキチン・プロテアソーム系を介する分子内相互作用によって制御されている2007

    • Author(s)
      Motoaki Sano
    • Organizer
      第24回 ISHR日本部会
    • Place of Presentation
      イタリア(ボローニャ)
    • Year and Date
      2007-06-22
    • Related Report
      2007 Annual Research Report
  • [Book] 新しい心不全治療の標的分子としてのCdk9の役割とその活性制御機構2008

    • Author(s)
      佐野 元昭、清水 宣明
    • Publisher
      細胞工学(秀潤社)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] Annual Review 2008「PGC-1と心機能・心筋代謝」2008

    • Author(s)
      佐野 元昭
    • Publisher
      中外医学社(in press)
    • Related Report
      2007 Annual Research Report
  • [Book] 細胞工学 心不全の発症・進展の分子機構にせまる「エネルギー代謝異常と心不全」2007

    • Author(s)
      佐野 元昭
    • Publisher
      秀潤社
    • Related Report
      2007 Annual Research Report
  • [Book] 細胞「心筋細胞代謝異常と心不全」2007

    • Author(s)
      佐野 元昭、福田 恵一
    • Publisher
      ニュー・サイエンス社
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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