癌抑制遺伝子の作用機構

• 研究課題/領域番号: 06283215
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 東京大学 (1998-1999); 大阪大学 (1994-1997)
• 研究代表者: 秋山 徹 東京大学, 分子細胞生物学研究所, 教授 (70150745)
• 研究分担者: 石館 宇夫 東京大学, 分子細胞生物学研究所, 助手 (70301116)
• 研究期間 (年度): 1994 – 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 117,000千円 (直接経費: 117,000千円); 1999年度: 29,000千円 (直接経費: 29,000千円); 1998年度: 23,000千円 (直接経費: 23,000千円); 1997年度: 20,000千円 (直接経費: 20,000千円); 1996年度: 15,000千円 (直接経費: 15,000千円); 1995年度: 15,000千円 (直接経費: 15,000千円); 1994年度: 15,000千円 (直接経費: 15,000千円)
• キーワード: 癌抑制遺伝子 / 大腸癌 / APC / Wntシグナル / β-catenin / TCF / G蛋白質 / Axin / D-Axin / Slimb / βTrCP / ICAT / APCL / SPAL / がん抑制遺伝子 / hDLG / b-catenin / D2 / WT1 / 細胞周期 / 大腸がん / DLG / guanylate kinase / ドメイン / SH3ドメイン / armadillo / G1-S移行 / Wilms腫瘍 / Cyclin-CDR / 細胞同期 / cyclin / CDK / 癌 / リン酸化

研究概要

(1)Wntシグナル伝達経路は癌化や形態形成に重要な役割をはたしている。Wntシグナルによりβ-cateninは安定化しTCF/LEFと複合体をつくり標的遺伝子の転写を活性化する。我々は、新規β-catenin結合蛋白質を見出し(ICATと命名)、ICATがβ-cateninとTCFの相互作用を阻害することにより標的遺伝子の転写活性化を阻害することを明らかにした。さらに、ICATはWntシグナルを阻害することによりXenopusの体軸形成を阻害する活性をもつことを明らかにした。(2)APC遺伝子は家族性大腸腺腫症の原因遺伝子で一般の大腸癌の大多数でも変異をおこしている。我々は、APC遺伝子産物のarmadilloリピートに結合する新規蛋白質を見出しAsefと命名した。APCとAsefは、大腸、海馬など在が一致し、β-cateninを含む複合体を形成していると考えられた。Asefは、Dblファミリーに属すRac特異的なguanine nucleotide exchange factor(GEF)で、APCと結合することにより活性化した。さらに、MDCK細胞にAsefを過剰発現するとAPC依存的に形態変化、rufflingを誘導した。APC-Asef複合体はアクチン細胞骨格ネットワーク、細胞形態、細胞運動などの制御に関与している可能性があると考えられた。

研究成果

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