PMLは,mTORの抑制を通じて,HIF-1α翻訳と新血管生成を阻害する
Rosa Bernardi1, Ilhem Guernah, David Jin
1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA.
Nature
|August 18, 2006
まとめ
プロミエロサイト性白血病 (PML) タンパク質は,タンパク質合成を調節することにより,新しい血管形成 (新血管生成) を抑制します. PMLの喪失は,腫瘍の成長と血管の発達を促進し,新しい治療標的を提供します.
科学分野:
- 腫瘍学 腫瘍学
- 分子生物学は分子生物学である.
- がん研究 がん研究
背景:
- プロミエロサイト性白血病 (PML) 腫瘍抑制剤の喪失は,様々なヒトがんと関連しています.
- PMLの既知の機能には,成長停止,細胞衰老,アポトーシスの誘発が含まれています.
研究 の 目的:
- PMLのネオアニオゲネシスにおける役割を,不血症および腫瘍性両方の条件下で調査する.
- PMLが新しい血管形成を調節する分子メカニズムを解明する.
主な方法:
- タンパク質翻訳,特に低酸素誘導因子1alpha (HIF-1alpha) 合成に対するPMLの影響を調査した.
- PML,ラパミシン (mTOR) の哺乳類標的,およびRheb.との相互作用を調べました.
- ラパミシン治療に対するPml-/-細胞と腫瘍の感受性を評価した.
- マウスとヒトのサンプルでリボソームタンパク質S6のリン酸化と腫瘍血管新生を分析した.
主要な成果:
- PMLは,体内における新血管形成の重要な阻害剤として作用する.
- PMLはmTORの活動を抑制し,それによって低酸素状態でのHIF-1α合成を制御します.
- PMLはmTORと物理的に相互作用し,その核の蓄積を促進し,Rheb.との関連を否定的に規制します.
- Pml-/-細胞と腫瘍はラパミシンに対する感受性が高く,血管新生とリボソームタンパク質S6のリン酸化が増加している.
結論:
- PMLは,mTORシグナル伝達と新血管新生の新型抑制剤として特定されています.
- この発見は,PMLが腫瘍の血管化と成長を制御する上で果たす重要な役割を強調しています.
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