腫瘍性RABタンパク質の特定
Douglas B Wheeler1, Roberto Zoncu2, David E Root3
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
まとめ
RAB35小グアノシントリフォスファターゼ (GTPase) はPI3K/AKT経路を調節する. この経路を活性化し,細胞の生存と変容を促進します.
科学分野:
- 分子生物学
- 細胞生物学
- 腫瘍学
背景:
- フォスファチチドリノシトール3'-OHキナーゼ (PI3K) /AKT経路は,細胞の成長,生存,代謝に不可欠です.
- PI3K/AKT経路の調節不全は,ヒトの癌ではよく見られる.
- 内膜のトラフィックは細胞信号伝達において役割を果たしますが,PI3K/AKT経路とのつながりは完全に理解されていません.
研究 の 目的:
- 短いヘアピンRNAスクリーンを用いて,AKTリン酸化の新しい調節体を特定する.
- PI3K/AKT経路におけるRAB35小グアノシントリフォスファターゼ (GTPase) の役割を調査する.
- 人間の腫瘍におけるRAB35変異の腫瘍発生可能性を調査する.
主な方法:
- AKTのリン酸化に影響を与える遺伝子を特定するための短いヘアピンRNA (shRNA) のスクリーニング.
- 主要活性型RAB35変異体の発現
- タンパク質の相互作用を評価するための免疫降水測定法.
- 細胞変容検査とアポトーシス抑制試験
主要な成果:
- RAB35はPI3K/ AKT経路の調節体として特定されました.
- RAB35の減少はAKTのリン酸化を抑制し,その活性変異体は経路を構成的に活性化しました.
- RAB35は成長因子受容体より下流でPDK1とmTORC2より上流で機能する.
- 人間の腫瘍からの体内RAB35変異は,PI3K/AKTシグナル伝達を構成的に活性化し,アポトーシスを抑制し,細胞を変異させた.
- 腫瘍性RAB35誘発受容体の内膜への輸送
結論:
- RAB35はPI3K/AKT経路の重要なレギュラーである.
- RAB35の変異は,PI3K/ AKTシグナル伝達を構成的に活性化することによって,腫瘍形成に寄与する可能性があります.
- RAB35によって調節されない内膜密輸は,潜伏した腫瘍性メカニズムを表す可能性があります.
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