Functional analysis and development for anti-tumor compounds targeted PRDM14 relating to cancer stemness based on protein-protein interaction
| Project/Area Number |
16H04710
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
長門石 曉 東京大学, 医科学研究所, 特任准教授 (30550248)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2016: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | がん幹細胞性 / タンパク質相互作用 / 創薬スクリーニング系 / タンパク質 / 薬学 / 遺伝子 / トランスレーショナルリサーチ / 蛋白質 / 癌 |
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| Outline of Final Research Achievements |
Inhibiting PRDM14 expression in breast and pancreatic cancers has been reported to reduce cancer stem-like phenotypes, which are associated with aggressive tumor properties. To develop a pharmaceutical treatment, the mechanism and interacting partners of PRDM14 need to be clarified. We obtained several candidates that were pulled down with PRDM14 in TNBC cells and identified them by mass spectrometry. Two candidates, GRP78 and HSP90a,were confirmed by immunoprecipitation assay. Surface plasmon resonance analysis using GST-PRDM14 showed that these two proteins directly interacted with PRDM14 and that the interactions required the C-terminal region of PRDM14. We also confirmed the interactions in living cells by NanoLuc luciferase-based bioluminescence resonance energy transfer (NanoBRET) assay. We also found out other candidates interacted with PRDM14 via SPR assay and NanoBRET assay, then we started to construct screening system for new drug discovery.
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| Academic Significance and Societal Importance of the Research Achievements |
PRDM14分子は正常細胞に発現がなく、ES細胞と腫瘍細胞に発現が限られる。一方、相互作用を呈するタンパク質には多くの分子標的となるoncogeneが含まれるものの、それらは正常細胞にも発現があるため、その発現を抑制することは副作用に繋がる。PRDM14との相互作用でがん細胞の幹細胞性が担われている可能性が高いため、その抑止により分化誘導の可能性が生じ、抗がん剤の感受性も高くなると考えられる。更には、すでに核酸創薬でPRDM14の発現を抑えることで、乳がん、膵がんに効果があることが判明しているため、本研究により導出される低分子化合物はこれらの疾患に有効な可能性が高い。
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Report
(4 results)
Research Products
(38 results)
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[Journal Article] Structural basis for amino-acid export by DMT superfamily transporter YddG2016
Author(s)
H. Tsuchiya, S. Doki, M. Takemoto, T. Ikuta, T. Higuchi, K. Fukui, Y. Usuda, E. Tabuchi, S. Nagatoishi, K. Tsumoto, T. Nishizawa, K. Ito, N. Dohmae, R. Ishitani and O. Nureki
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Journal Title
Nature
Volume: 534
Issue: 7607
Pages: 417-420
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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