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DHODH调节神经和黑色素瘤中的转录延长
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
概括
BRAF ((V600E) 在神经细胞中的基因激活通过破坏发育驱动黑色素瘤. 用诸如莱夫卢诺米德之类的化合物抑制二罗酸脱酶 (DHODH) 抑制了神经的发育和黑色素瘤的生长.
科学领域:
- 发育生物学 发展生物学
- 癌症生物学 癌症生物学
- 遗传学 是一个遗传学.
背景情况:
- 黑色素瘤是由转变的黑色素细胞引起的,这些黑色素细胞起源于胚胎神经细胞.
- 神经发育途径与黑色素瘤中BRAF瘤基因突变之间的相互作用尚未完全理解.
- BRAF (V600E) 是人类黑色素瘤中最常发生突变的基因.
研究的目的:
- 使用斑马鱼识别神经谱系中BRAF (V600E) 激活的发起转录事件.
- 研究这些早期转录事件在黑色素瘤发病过程中的作用.
- 通过对神经发展的小分子抑制剂进行查,识别黑色素瘤的潜在治疗点.
主要方法:
- 使用的斑马鱼胚胎转基因为mitfa:BRAF ((V600E) 并缺乏p53.
- 进行了化学基因选,以确定神经谱系的小分子抑制剂.
- 在实验室和老鼠异种移植中测试了它们对黑色素瘤发展的影响的已识别的化合物.
主要成果:
- 在神经细胞中的BRAF (V600E) 激活导致了为多能神经标记物和受损终端分化丰富的基因特征.
- 双基酸脱酶 (DHODH) 抑制剂,如莱夫卢诺米德,在斑马鱼中废除了神经的发育,并减少了哺乳动物神经干细胞的自我更新.
- DHODH抑制抑制了神经发育和黑色素瘤生长的关键基因的转录延长,在体外和体内显著减少了黑色素瘤的生长.
结论:
- 神经发育中的早期转录事件对于黑色素瘤的形成至关重要.
- DHODH是神经发展和黑色素瘤生长的关键调节者.
- DHODH抑制代表了黑色素瘤的一个有前途的治疗策略,可能与BRAF (V600E) 抑制剂结合使用.
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