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Study of medianism for the cell growth inhibition by HB-EGF in cardiac valve development

Research Project

Project/Area Number 18570176
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cell biology
Research InstitutionOsaka University

Principal Investigator

IWAMOTO Ryo  Osaka University, Research Institute for Microbial Diseases, Associate Professor (10213323)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsHB-EGF / EGFR / ErbB / HSPG / Snail / Valvulogenesis / Intercellular signaling / Extracellular matrix / 細胞・組織 / 発生・分化 / 増殖因子
Research Abstract

HB-EGF is a member of the EGF family of growth factors that has a high affinity for heparin and heparan sulfate (HS), and is known to be involved in cardiac valve development. HB-EGF suppresses proliferation of mesenchymal cells in this process. In this research, we investigated the regulatory mechanisms involved in the HB-EGF-induced cell growth inhibition in cardiac valve development (valvulogenesis).
1) Significance of the interaction of HB-EGF with HS-proteoglycans (HSPGs) in valvulogenesis. We generated the knock-in mice expressing a heparin-binding domain-truncated form (HB^<Δbb>) of the molecule, which lacks HS-binding activity. HB^<Δbb/Δbb> mice developed enlarged cardiac valves with abnormal hyperproliferation of the mesenchymal cells during valvulogenesis, phenotypes similar to that in HB-EGF null (HB^<dcl/del>) mice. In vitro study using endocardial cushion explants culture demonstrated requirement of HB-EGF-HSPGs interaction for HB-EGF-EGFR signal-mediated growth-inhibition … More of mesenchymal cells. These results indicate that interaction of HB-EGF with HSPGs promotes growth-inhibition of differentiated mesenchymal cells in developing cardiac valve. (Manuscript in preparation)
2) HB-EGF and Snail signaling negatively regulates proliferation of mesenchymal cells during valvulogenesis. We found that the expression of Snail was dramatically decreased in HB^<del/del> mutant valves during remodeling process in valvulogenesis. Exogenously introduced Snail and HB-EGF into the HB^<del/del> mutant valves were able to rescue the overproliferation of mesenchymal cells. These results demonstrate that HB-EGF inhibits proliferation of mesenchymal cells via Snail during valve remodeling. (Manuscript in preparation)
3) Perinatal distal lung development: another physiological process in which HB-EGF induces cell growth inhibition. HB^<del/del> newborns displayed abnormally thick alveolar walls, occurring from E18.5, that reduced the terminal saccular space area, with a increase in cell proliferation, indicating that HB-EGF suppresses distal lung cell proliferation. Furthermore, an analysis of alveolar morphology and proliferation in HB-EGF and TGFα double mutant newborns revealed that HB-EGF and TGFa function synergistically in this suppression. Crosses between HB^<del/del> mice and waved 2 mice, a hypomorphic EGFR mutant strain, suggest that HB-EGF and EGFR cooperate in this process. Thus, HB-EGF has a suppressive function that contributes to decelerating distal lung cell proliferation synergistically with TGFa through EGFR in perinatal distal lung development. (Dev. Dyn. 2008, 237, 247-258) Less

Report

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

    (28 results)

All 2008 2007 2006 Other

All Journal Article (15 results) (of which Peer Reviewed: 7 results) Presentation (11 results) Remarks (2 results)

  • [Journal Article] HB-EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development.2008

    • Author(s)
      Minami, S., et. al.
    • Journal Title

      Dev. Dyn. 237

      Pages: 247-258

    • 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] HB-EGF decelerates cell proliferation synergistically with TGFa in perinatal distal lung development2008

    • Author(s)
      Minami, S., et. al.
    • Journal Title

      Dev. Dyn 237

      Pages: 247-258

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] KB-EGF decelerates cell proliferation synergistically with TGFα in perinatal distal lung development.2008

    • Author(s)
      Minami, S., et. al.
    • Journal Title

      Dev. Dyn. 237

      Pages: 247-258

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity.2007

    • Author(s)
      Kageyama, T., et. al.
    • Journal Title

      J. Biochem. 142

      Pages: 95-104

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Multiple-state reactions between the epidermal growth factor receptor and Grb2 as observed by using single-molecule analysis.2007

    • Author(s)
      Morimatsu, M., et. al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA. 104

      Pages: 18013-18018

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Maternal heparin-binding-EGF deficiency limits pregnancy success in mice.2007

    • Author(s)
      Xie, H., et. al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA. 104

      Pages: 18315-18320

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity2007

    • Author(s)
      Kageyama, T., et. al.
    • Journal Title

      J. Biochem 142

      Pages: 95-104

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Multiple-state reactions between the epidermal growth factor receptor and Grb2 as observed by using single-molecule analysis2007

    • Author(s)
      Morimatsu, M., et. al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA 104

      Pages: 18013-18018

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Maternal heparin-binding-EGF deficiency limits pregnancy success in mice2007

    • Author(s)
      Xie, H., et. al.
    • Journal Title

      Proc. Natl. Acad. Sci. USA 104

      Pages: 18315-18320

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] ErbB and HB-EGF signaling in heart development and function.2006

    • Author(s)
      Iwamoto, R., et. al.
    • Journal Title

      Cell Struct.Funct. 31

      Pages: 1-14

    • 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] Cytoplasmic domain phosphorylation of heparin-binding EGF-like growth factor.2006

    • Author(s)
      Wang, X., et. al.
    • Journal Title

      Cell Struct.Funct. 31

      Pages: 15-27

    • 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] ErbB and HB-EGF signaling in heart development and function2006

    • Author(s)
      Iwamoto, R., et. al.
    • Journal Title

      Cell Struct. Funct 31

      Pages: 1-14

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Cytoplasmic domain phosphorylation of heparin-binding EGF-like growth factor2006

    • Author(s)
      Wang, X., et. al.
    • Journal Title

      Cell Struct. Funct 31

      Pages: 15-27

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Cytoplasmic domain phosphorylation of heparin-binding EGF-like growth factor.2006

    • Author(s)
      Wang, X., et al.
    • Journal Title

      Cell Struct. Funct. 31

      Pages: 15-27

    • Related Report
      2006 Annual Research Report
  • [Journal Article] ErbB and HB-EGF signaling in heart development and function.2006

    • Author(s)
      Iwamoto, R., Mekada, E.
    • Journal Title

      Cell Struct. Funct. 31

      Pages: 1-14

    • Related Report
      2006 Annual Research Report
  • [Presentation] Regulation of HB-EGF function by HSPGs.2007

    • Author(s)
      岩本 亮
    • Organizer
      第40回日本発生生物学会・第59回日本細胞生物学会合同大会
    • Place of Presentation
      福岡
    • Year and Date
      2007-05-29
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Regulation of HB-EGF function by HSPGs2007

    • Author(s)
      Iwamoto, R
    • Organizer
      JSDB-JSCB 2007
    • Place of Presentation
      Fukuoka
    • Year and Date
      2007-05-29
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Regulation of HB-EGF function by HSPGs.2007

    • Author(s)
      岩本 亮
    • Organizer
      第40回日本発生生物学会・第59回日本細胞生物学会合同大会
    • Place of Presentation
      福岡(福岡国際会議場)
    • Year and Date
      2007-05-29
    • Related Report
      2007 Annual Research Report
  • [Presentation] HB-EGF is required for normal lung morphogenesis during canalicular stage.2007

    • Author(s)
      南 誠剛
    • Organizer
      第40回日本発生生物学会・第59回日本細胞生物学会合同大会
    • Place of Presentation
      福岡
    • Year and Date
      2007-05-28
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] HB-EGF is required for normal lung morphogenesis during canalicular stage2007

    • Author(s)
      Minami, S., et. al.
    • Organizer
      JSDB-JSCB 2007
    • Place of Presentation
      Fukuoka
    • Year and Date
      2007-05-28
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] HB-EGF bound to HSPGs on the cell surface induces growth inhibition of EGFR-expressing cells2006

    • Author(s)
      高崎 理紗
    • Organizer
      日本分子生物学会2006フォーラム
    • Place of Presentation
      名古屋
    • Year and Date
      2006-12-08
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] HB-EGF bound to HSPGs on the cell surface induces growth inhibition of EGFR-expressing cells2006

    • Author(s)
      Takazaki, R., et. al.
    • Organizer
      MBSJ Forum 2006
    • Place of Presentation
      Nagoya
    • Year and Date
      2006-12-08
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Interaction of HB-EGF with heparan sulfate proteoglycan is required for normal cardiac valve development2006

    • Author(s)
      岡部昌樹
    • Organizer
      日本分子生物学会2006フォーラム
    • Place of Presentation
      名古屋
    • Year and Date
      2006-12-07
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Interaction of HB-EGF with heparan sulfate proteoglycan is required for normal cardiac valve development2006

    • Author(s)
      Okabe, M., et. al.
    • Organizer
      MBSJ Forum 2006
    • Place of Presentation
      Nagoya
    • Year and Date
      2006-12-07
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] ヘパラン硫酸プロテオグリカンによる増殖因子HB-EGFの生理機能制御2006

    • Author(s)
      岩本 亮
    • Organizer
      日本分子生物学会2006フォーラム
    • Place of Presentation
      名古屋
    • Year and Date
      2006-12-06
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Regulation of HB-EGF function by heparan sulfate proteoglycans2006

    • Author(s)
      Iwamoto, R
    • Organizer
      MBSJ Forum 2006
    • Place of Presentation
      Nagoya
    • Year and Date
      2006-12-06
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://cell-biology.biken.osaka-u.ac.jp/MekadaLabHP/Iwamoto/Iwamoto.html

    • Related Report
      2007 Final Research Report Summary
  • [Remarks]

    • URL

      http://cell-biology.biken.osaka-u.ac.jp/MekadaLabHP/Iwamoto/Iwamoto.html

    • Related Report
      2007 Annual Research Report

URL: 

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

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