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DHODHは,ニューラル・クライストとメラノーマの転写延長を調節する
Richard Mark White1, Jennifer Cech, Sutheera Ratanasirintrawoot
1Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|March 25, 2011
まとめ
BRAF ((V600E) 神経頂細胞における腫瘍遺伝子の活性化が,発達を阻害することによってメラノーマを誘発する. デヒドロロロテート脱水素酶 (DHODH) をレフルノミドのような化合物で抑制すると,神経の発達とメラノーマの成長が抑制されます.
科学分野:
- 発達生物学 発達生物学について
- がん生物学 がん生物学
- 遺伝学 遺伝学とは
背景:
- メラノマは,胚の神経の細胞から発生した変形したメラノサイトから発生します.
- ニューラル・クライストの発達経路とメラノーマにおけるBRAF腫瘍遺伝子変異の相互作用は完全に理解されていません.
- BRAF (V600E) は,ヒトメラノーマで最も頻繁に変異した遺伝子です.
研究 の 目的:
- ゼブラフィッシュを用いてニューラルクライストの系統におけるBRAF ((V600E) 活性化の転写イベントの開始を特定する.
- メラノーマの病原性におけるこれらの早期の転写イベントの役割を調査する.
- ニューラルクライスト発達の小分子抑制剤をスクリーニングすることにより,メラノーマの潜在的な治療標的を特定する.
主な方法:
- 使用されたゼブラフィッシュ胚は,mitfa:BRAF (V600E) に対してトランスジェニックであり,p53.3が欠けています.
- ニューラルクライスト系統の小分子抑制剤を特定するために化学的遺伝子スクリーンを実施しました.
- メラノーマ発症に及ぼす影響について,同定された化合物を試験し,in vitroおよびマウスの異種移植で試験した.
主要な成果:
- BRAF ((V600E) がニューラル・クライスト細胞で活性化すると,多効性ニューラル・クライストマーカーに富んだ遺伝子シグネチャーと末端分化障害が生じます.
- デヒドロロロテート脱水素酶 (DHODH) 阻害剤,例えばレフルノミドは,斑馬魚における神経の発達を無効化し,哺乳類の神経の幹細胞の自己再生を減少させた.
- DHODHの阻害は,ニューラル・クライストの発達とメラノーマの成長のための重要な遺伝子の転写延長を抑制し,メラノーマの成長を in vitro と in vivo で大幅に減少させました.
結論:
- ニューラル・クライストの発達における早期の転写イベントは,メラノーマの形成に極めて重要です.
- DHODHはニューラルクライストの発達とメラノーマの成長の重要なレギュラーです.
- DHODH阻害は,メラノーマに対する有望な治療戦略であり,潜在的にBRAF (V600E) 阻害剤と組み合わせることができます.
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