KRASとYAP1は,EMTと腫瘍生存率を調節するために収束します
Diane D Shao1, Wen Xue2, Elsa B Krall1
1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell
|June 24, 2014
まとめ
腫瘍性RASがん細胞は,生存のために変異RASに依存しています. 研究者らは,YAP1がRASの代わりとなり,上皮質-メゼンキマ移行 (EMT) を調節し,癌の進行に影響を及ぼすことがわかった.
科学分野:
- 分子生物学は分子生物学である.
- がん研究 がん研究
- 遺伝学 遺伝学とは
背景:
- 腫瘍性RAS変異は癌細胞の生存を促進しますが,この依存性のメカニズムは完全に理解されていません.
- RASの機能を補うことができる遺伝子を特定することは,がん細胞の脆弱性を理解するために不可欠です.
研究 の 目的:
- 癌細胞における腫瘍性RASを機能的に置換できる遺伝子を特定する.
- RASの腫瘍遺伝子の依存性の基礎にある分子メカニズムを解明する.
主な方法:
- 誘導可能なKRAS抑制によるKRAS依存性結腸がん細胞系における15,294の開いた読み取りフレームの体系的な発現.
- KRAS抑制による細胞生存と変異における遺伝子機能の分析.
- クラス駆動型のネズミの肺がんモデルにおけるYAP1信号の調査.
主要な成果:
- KRASが抑制されたときに生存を促進する147の遺伝子が特定されました.
- 転写共同活性化剤YAP1は細胞活性を救出し,KRAS誘発変異に不可欠でした.
- 肺がんモデルのKRAS抑制に対する獲得抵抗において,YAP1シグナル伝達の増加が観察されました.
- KRASとYAP1は,転写因子FOSに収束し,上皮細胞-メゼンキーマ移行 (EMT) プログラムを活性化することが判明しました.
結論:
- YAP1によるEMTの転写調節は,腫瘍性RAS信号伝達の重要な構成要素である.
- YAP1は,RAS依存がんにおける潜在的な治療標的である.
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