Mechanism regulating cellular proliferation by HB-EGF-ErbB4 signaling and its application
| Project/Area Number |
15K07046
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | Osaka University |
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Principal Investigator |
Iwamoto Ryo 大阪大学, 微生物病研究所, 准教授 (10213323)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 細胞増殖因子 / 心臓弁形成 / 増殖抑制 / 細胞・組織 / 形態形成 / シグナル伝達 / がん増殖 |
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| Outline of Final Research Achievements |
HB-EGF plays an indispensable role in suppression of cell proliferation during mouse valvulogenesis. HB-EGF binds to and activates ErbB1 and ErbB4. We investigated the role of ErbB receptors in valvulogenesis in vivo using ErbB1- and ErbB4-deficient mice, and an ex vivo model of endocardial cushion explants. HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4, and certain ErbB1-ligand(s) promotes the proliferation through a homodimer of ErbB1. A rescue experiment with the cleavable (JM-a) or uncleavable (JM-b) isoform of ErbB4 in ERBB4 null cells suggests that intracellular domain of ErbB4 rather than the membrane-anchored tyrosine kinase achieves the suppression. Moreover, cytoplasmic region that is contained in both CYT-1 and CYT-2 subtypes of ErbB4 is essential for the suppression. These results predict that HB-EGF-ErbB4 signaling axis may be applicable for cancer therapy of the next generation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によって、心臓弁形成過程の細胞増殖制御におけるHB-EGF-ErbB4による増殖抑制シグナルの分子機構を明らかにすることで、従来仮想的に考えられていたErbBシグナル間の制御機構が実際の生体において存在している事の証明となり、細胞生物学上非常に意義が大きい。さらに、これまでの抗がん剤等における分子標的治療では、その標的分子の機能を封じる方向であったが、本研究によって、標的分子を封じるのではなく、活性転換という形で「標的を生かして使う」という新たなコンセプトが導き出され、医学的方法論的にも意義が大きい。
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Report
(5 results)
Research Products
(8 results)
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[Journal Article] RNA Aptamer Binds Heparin-Binding Epidermal Growth Factor-Like Growth Factor with High Affinity and Specificity and Neutralizes Its Activity.2017
Author(s)
Masaki Yamato, Tetsuo Minamino, yamato masaki, Takashi Matsuzaki, Ryo Araki, Shota Tsuchida, Keiji Okuda, Hai Ying Fu, Shoji Sanada, Hiroshi Asanuma, Yoshihiro Asano, Masanori Asakura, Hiroomi Torii, Kentaro Noi, Hirotsugu Ogi, Ryo Iwamoto, Eisuke Mekada, Seiji Takashima, Yasushi Sakata, Masafumi Kitakaze
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Journal Title
Int. J. Gerontol.
Volume: 11
Issue: 3
Pages: 191-196
DOI
Related Report
Peer Reviewed
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[Journal Article] RNA Aptamer Binds Heparin-Binding Epidermal Growth Factor-Like Growth Factor with High Affinity and Specificity and Neutralizes Its Activity2017
Author(s)
Masaki Yamato, Tetsuo Minamino, yamato masaki, Takashi Matsuzaki, Ryo Araki, Shota Tsuchida, Keiji Okuda, Hai Ying Fu, Shoji Sanada, Hiroshi Asanuma, Yoshihiro Asano, Masanori Asakura, Hiroomi Torii, Kentaro Noi, Hirotsugu Ogi, Ryo Iwamoto, Eisuke Mekada, Seiji Takashima, Yasushi Sakata, Masafumi Kitakaze
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Journal Title
Int. J. Gerontol.
Volume: 印刷中
Related Report
Peer Reviewed
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[Journal Article] Characterization of a novel anti-human HB-EGF monoclonal antibody applicable for paraffin-embedded tissues and diagnosis of HB-EGF-related cancers.2016
Author(s)
Iwamoto,R., Takagi, M., Akatsuka, J., Ono, K., Kishi, Y., and Mekada, E.
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Journal Title
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
Volume: 35
Issue: 2
Pages: 1-10
DOI
Related Report
Peer Reviewed / Open Access
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