アポトーシス機構の解析とその発がん、制がん研究への応用

• 研究課題/領域番号: 08265107
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 国立がんセンター
• 研究代表者: 口野 嘉幸 国立がんセンター研究所, 生物物理部, 部長 (60124418)
• 研究分担者: 中島 琢磨 東京理科大学, 工学部, 助手 (90256678) ; 田沼 靖一 東京理科大学, 薬学部, 教授 (10142449) ; 三浦 正幸 大阪大学, 医学部, 助教授 (50202338) ; 藤田 直也 東京大学, 分生研, 助手 (20280951) ; 松沢 昭雄 東京大学, 医科研, 助教授 (50012745)
• 研究期間 (年度): 1996 – 1998
• 研究課題ステータス: 完了 (1998年度)
• 配分額: 84,000千円 (直接経費: 84,000千円); 1998年度: 28,000千円 (直接経費: 28,000千円); 1997年度: 28,000千円 (直接経費: 28,000千円); 1996年度: 28,000千円 (直接経費: 28,000千円)
• キーワード: Myc / アデノウイルスE1A / 制がん剤 / Bax / FasL / アポトーシスシグナル / カスパーゼ3様プロテアーゼ / アポトーシス耐性 / アポトーシス / LPS / Pim-1キナーゼ / リンパ腫 / ICE / CED-3 family proteases / myc関連遺伝子 / Fas / エンドトキシンLPS / トポイソメラーゼIIα / アポトーシスエンドヌクレアーゼ

研究概要

アポトーシスはがん遺伝子、がん抑制遺伝子をはじめ、抗がん剤や放射線など細胞の内外に存在する様々な因子によって誘導・制御されている。本研究班ではこれら性質の異なった刺激によって活性化されるアポトーシスシグナルの伝達機構を各班員が独自に開発した実験系を用いて解析した。その結果c-mycやアデノウイルスE1Aなどのがん遺伝子をはじめ、がん抑制遺伝子としてのs-mycやp53の標的遺伝子であるbaxの発現、さらには制がん剤処理など、様々な刺激によって誘導されるアポトーシスにおいてもカスパーゼ3様プロテアーゼの活性化が共通して要求されることを見いだし、カスパーゼ3様プロテアーゼがアポトーシス実行において中心的役割を果たしていることを明らかにした。またがん遺伝子やがん抑制遺伝子の変異や発現亢進、がん遺伝子との協調発現によって細胞のがん化に関与する遺伝子の発現がしばしば細胞にアポトーシス耐性を与えていることを明らかにした。これら一連の研究成果は抗がん剤等のアポトーシスにおける作用点や作用機構を知る手掛かりとなり、アポトーシスを標的とした新たながんの治療法の開発に利用できるものと期待される。一方s-MycやFasLを発現させたがん細胞の移植実験からアポトーシスを介したlocal inflammationが宿主の抗腫瘍免疫能の活性化を惹き起こすことを見出し、アポトーシスを利用したがんに対する免疫療法の可能性を示唆した。最後に本研究において活性型Rasがアポトーシスとは異なったタイプの細胞死を誘導することを明らかにした。この細胞死はカスパーゼの活性化を要求せず、p53やBcl-2による制御も受けない。このような特徴をもつカスパーゼ非依存的細胞死誘導システムは、多くのアポトーシス耐性を獲得したがんの治療法として非常に有用であると思われる。この発見はまたこれまで不明な点が多かったプログラム細胞死の全体像を分子レベルで理解していく上で非常に意義があると思われる。

研究成果

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