細胞がん化のシグナル伝達の解析と特異的阻害剤の探索

• Project/Area Number: 08266113
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: 上原 至雅 国立感染症研究所, 生物活性物質部, 部長 (50160213)
• Co-Investigator(Kenkyū-buntansha): 深澤 秀輔 国立感染症研究所, 生物活性物質部, 主任研究官 (10218878) ; 野瀬 清 昭和大学, 薬学部, 教授 (70012747) ; 早川 洋一 東京大学, 分子細胞生物学研究所, 助教授 (20208606) ; 内藤 幹彦 東京大学, 分子細胞生物学研究所, 助教授 (00198011) ; 井本 正哉 慶応大学, 理工学部, 助教授 (60213253) ; 沖 俊一 玉川大学, 学術研究所, 教授 (40264676) ; 小宮山 寛機 北里研究所, 基礎研究所, 所長 (00106676) ; 済木 育夫 富山医科薬科大学, 和漢薬研, 教授 (80133776)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥114,500,000 (Direct Cost: ¥114,500,000); Fiscal Year 1999: ¥7,500,000 (Direct Cost: ¥7,500,000); Fiscal Year 1998: ¥37,000,000 (Direct Cost: ¥37,000,000); Fiscal Year 1997: ¥37,000,000 (Direct Cost: ¥37,000,000); Fiscal Year 1996: ¥33,000,000 (Direct Cost: ¥33,000,000)
• Keywords: 足場非依存性増殖 / シグナル伝達 / スクリーニング / U0126 / Rasがん遺伝子 / Srcがん遺伝子 / MAPキナーゼ / p7056キナーゼ / Srcチロシンキナーゼ / Ablチロシンキナーゼ / アポトーシス / 細胞接着 / 血管新生 / RB / p21^<waf1> / 転移 / がん遺伝子 / がん抑制遺伝子 / cyclin D1 / CDKインヒビター / Ets-1 / がん化シグナル / 細胞周期 / チロシンキナーゼ阻害剤 / マクロライド / がん転移 / 転写因子 / 接着

Research Abstract

1.MEK阻害剤U0126がKi-rasでトランフォームしたラット繊維芽細胞(Ki-ras/NRK)の形態を扁平化し、足場非依存性増殖を阻害した。シグナル伝達分子の活性化状態を調べると、U0126はMAPKの経路だけでなく、p70S6Kの経路も阻害していた。別のMEK阻害剤である PD98059はKi-ras/NRKの足場非依存性増殖は阻害しなかったが、p70S6Kの阻害剤rapamycinと併用してMAPK、p70S6Kの両経路を遮断するとKi-ras/NRKの形態と足場依存性は正常化した。v-srcでトランスフォームした細胞に対しては、U0126及びPD98059とp70S6Kの組み合わせとも、形態を扁平化させたが、足場非依存性増殖は阻害しなかった。
2.足場非依存性増殖の選択的阻害を指標としたスクリーニングにより見出した新規テルペノイドTPU-0015の作用を解析した。TPU-0015はヒト大腸癌細胞株DLD-1に対し、細胞周期のG2/M期を蓄積させアポトーシスを誘導した。

Research Products

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