転写制御の異常と細胞の増殖・分化

• 研究課題/領域番号: 12215022
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 東京大学 (2002-2004); 慶應義塾大学 (2000-2001)
• 研究代表者: 井上 純一郎 東京大学, 医科学研究所, 教授 (70176428)
• 研究分担者: 佐竹 正延 東北大学, 加齢医学研究所, 教授 (50178688) ; 仙波 憲太郎 東京大学, 医科学研究所, 助教授 (70206663) ; 秋山 泰身 慶應義塾大学, 理工学部, 講師 (50327665)
• 研究期間 (年度): 2000 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 78,000千円 (直接経費: 78,000千円); 2004年度: 13,500千円 (直接経費: 13,500千円); 2003年度: 13,500千円 (直接経費: 13,500千円); 2002年度: 14,000千円 (直接経費: 14,000千円); 2001年度: 14,000千円 (直接経費: 14,000千円); 2000年度: 23,000千円 (直接経費: 23,000千円)
• キーワード: シグナル伝達 / NFκB / TRAF6 / HTLV-1 / Tax / DRG / 癌 / 発現制御 / 骨形成 / 免疫 / 発生 / 器官形成 / 発生・分化 / 免疫学 / NFkB / AP-1 / IKK / 無汗性外胚葉形成不全症 / 転写制御 / TRAFタンパク質 / Gタンパク質 / WT1 / PEBP2 / AML1

研究概要

転写制御の異常は細胞周期制御の破綻を導き、時には、癌化を誘導すると考えられているが、不明な点が多い。本研究では、「転写因子の活性制御機構及び、転写因子の異常によって生じる細胞機能の破綻を分子レベルで解明する」ことを目指す。特にNFκB活性化のがん化における役割、TRAF6によるNFκB活性化シグナル伝達機構及びTRAF6シグナルによる細胞増殖・分化の誘導機構の解明を目的として今年度は以下の結果を得た。1)HTLV-1 Taxタンパク質によるNFκB活性化にK63型ユビキチン付加酵素Ubc13およびTAK1活性化は必要ない。従ってTaxはIL-1やLPS等のシグナルとは異なる機構でIKKを活性化する。また、HTLV-1感染細胞ではTax依存的NFκB活性化とTax非依存的かっ恒常的NFκB活性化の両者が起こっている。2)TRAF6による細胞増殖機構に関与する考えられるDRG1とDRG2を同定した。さらにDRG1とDRG2の発現量をユビキチン化反応の阻害により維持する特異的結合タンパク質DFRP1とDFRP2を同定した。3)TRAF6がTLR3以外のTLRの下流で必須な役割を果たしていることを明らかにした。またTRAF6欠損により胸腺上皮細胞の分化不全が起こりその結果自己抗体が産生されることを示した。即ちTRAF6によるNFκBの活性化が自然免疫と獲得免疫において重要な役割を果たし、がん免疫に必須であることが明らかとなった。

研究成果

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