| Project/Area Number |
12219217
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MIYAZONO Kohei The University of Tokyo, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (90209908)
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| Co-Investigator(Kenkyū-buntansha) |
IMAMURA Takeshi The Cancer Institute of the Japanese Foundation for Cancer Research, Department of Biochemistry, Chief, 癌研究所生化学部, 部長(研究職) (70264421)
MIYAZAWA Keiji The Uriversity of Tokyo, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (40209896)
WATABE Tetsuro The Universty of Tokyo, Graduate School of Mediche, Assistant of Professor, 大学院医学系研究科, 助手 (00334235)
SAITOH Masao The Universty of Tokyo, Graduate School of Medicine, Assistant of Professor, 大学院医学系研究科, 助手 (90345041)
加藤 光保 (財)癌研究会, 癌研究所生化学部, 主任研究員 (20194855)
井上 博文 (財)癌研究会, 癌研究所生化学部, 研究員 (70321635)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥407,900,000 (Direct Cost: ¥407,900,000)
Fiscal Year 2004: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2003: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2002: ¥89,500,000 (Direct Cost: ¥89,500,000)
Fiscal Year 2001: ¥89,000,000 (Direct Cost: ¥89,000,000)
Fiscal Year 2000: ¥50,400,000 (Direct Cost: ¥50,400,000)
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| Keywords | TGF-β / Smad / signal transduction / oncogene / anti-oncogene / ubiquitination / transcription factor / angiogenesis / BMP / ユビチキン化 / c-myc / 受容体 / Smurf1 / Wntシグナル / シグナルクロストーク / がんの浸潤・転移 |
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| Research Abstract |
We have studied the roles of TGF-β signaling, which is involved in progression and metastasis of cancer. We were particularly interested in identification of molecules that regulate TGF-β signaling and their roles in vivo.
1) We have found that E3 ubiquitin ligase Smurf1 induces nuclear export, and locates inhibitory Smad7 to the plasma membrane, leading to ubiquitin-dependent degradation of TGF-(3 receptors. Smurf1 has a C2 domain at its N-terminal portion. Deletion mutant that lacks the C2 domain of Smurf1 is able to bind Smad7 and induce its nuclear export. However, the mutant is not located at the plasma membrane, and fails to interact with TGF-β receptors. Thus, the C2 domain of Smurf1 plays a critical role in inhibition of TGF-β signaling.
2) Arkadia is a RING type E3 ubiquitin ligase. Similar to HECT type E3 ligase Smurf1, it binds to inhibitory Smads. However, in contrast to Smurf1 which induces degradation of receptors through binding to Smad7, Arkadia failed to bind to TGF-β receptors. Thus, Arkadia enhanced TGF-β signaling through degradation of Smad7, but not the receptors.
3) We have shown that a TGF-β receptor kinase inhibitor induces proliferation and sheet formation of endothelial cells derived from mouse embryonic stem cells. Moreover, inhibition of TGF-β, signaling results in induction of claudin-5, leading to the maintenance of integrity of vascular tissues.
4) We have shown that Smad7 inhibits metastasis of mouse breast tumor. DNA microarray analyses revealed that more than 200 genes are regulated by Smad7 in this breast cancer cell line. Some of them are genes encoding transcription factors and extracellular matrix proteins, suggesting that these molecules may be involved in metastasis of breast cancer.
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