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

• 研究課題/領域番号: 08266113
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 国立感染症研究所
• 研究代表者: 上原 至雅 国立感染症研究所, 生物活性物質部, 部長 (50160213)
• 研究分担者: 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)
• 研究期間 (年度): 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 114,500千円 (直接経費: 114,500千円); 1999年度: 7,500千円 (直接経費: 7,500千円); 1998年度: 37,000千円 (直接経費: 37,000千円); 1997年度: 37,000千円 (直接経費: 37,000千円); 1996年度: 33,000千円 (直接経費: 33,000千円)
• キーワード: 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

研究概要

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。

研究成果

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