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KAKEN_23102006seika.pdf
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Title |
Title |
細胞機能を制御する新規天然有機化合物の開拓・創製研究
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Kana |
サイボウ キノウ オ セイギョスル シンキ テンネン ユウキ カゴウブツ ノ カイタク・ソウセイ ケンキュウ
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Saibo kino o seigyosuru shinki tennen yuki kagobutsu no kaitaku sosei kenkyu
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Discovery of natural products that modulate cellular responses
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井本, 正哉
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イモト, マサヤ
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Imoto, Masaya
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慶應義塾大学・理工学部・教授
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科研費研究者番号 : 60213253
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掛谷, 秀昭
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カケヤ, ヒデアキ
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Kakeya, Hideaki
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京都大学・薬学研究科(研究院)・教授
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Research team member
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科研費研究者番号 : 00270596
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田代, 悦
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タシロ, エツ
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Tashiro, Etsu
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慶應義塾大学・理工学部・専任講師
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Research team member
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科研費研究者番号 : 00365446
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2016
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科学研究費補助金研究成果報告書
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2015
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本研究では疾患モデル細胞系を用いて天然物リガンドの探索・創製を目指して研究を行った。放線菌ライブラリーから新規ARアンタゴニストの探索を行なった結果, 新規化合物Antarlide A-Eを発見した。また, オートファジー制御化合物の探索を行った結果, XanthohumolがVCPに結合してその機能を阻害することでオートファジーを阻害することを見出した。またNonactinがβ-catenin変異型がん細胞種に対して合成致死を誘導することを見いだした。またβ-cateninが変異したがん細胞株を移植したマウスに対してNonactinは顕著な腫瘍退縮効果を示した。
In the course of screening for a new AR antagonist, we isolated novel compounds, antarlides A-E, from the Streptomyces sp. BB47. In addition, antarlide B inhibited the transcriptional activity of not only wild type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists.We next observed that xanthohumol (XN), a prenylated chalcone, modulates autophagy. By using XN-immobilized beads, valosin-containing protein (VCP) was identified as a XN-binding protein. These data indicated that XN inhibited the function of VCP, thereby allowing the impairment of autophagosome maturation. We also screened the compound that induced cell death selectively in tumor cell lines harboring β-catenin mutation from an in-house natural product library, and finally we isolated and found that nonactin. Furthermore, nonactin induced tumor regression only in β-catenin mutated HCT116 xenograft mice.
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研究種目 : 新学術領域研究(研究領域提案型)
研究期間 : 2011~2015
課題番号 : 23102006
研究分野 : ケミカルバイオロジー
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