通过METTL3-eIF3h的mRNA循环化增强翻译并促进瘤发生
Junho Choe1,2, Shuibin Lin1,2,3, Wencai Zhang4
1Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Nature
|September 21, 2018
概括
甲基转移酶类3 (METTL3) 蛋白通过循环机制增强mRNA转化,促进瘤转化. 针对METTL3-eIF3h相互作用可能提供一种新的癌症治疗策略.
科学领域:
- 分子生物学
- 基因表达的调节
- 癌症生物学
背景情况:
- N6甲基氨酸 (m6A) 修饰是癌症中关键的基因表达调节剂.
- METTL3催化了m6A的修饰,特别是在停止子附近,并且已知会影响翻译,尽管机制尚不清楚.
研究的目的:
- 阐明METTL3增强mRNA翻译的机制.
- 研究METTL3在癌症,特别是肺癌中的功能相关性.
- 根据METTL3功能确定癌症治疗的潜在治疗点.
主要方法:
- 报告器mRNA测定用于研究METTL3在绑定时对翻译的影响.
- 电子显微镜可视化多核糖体拓和蛋白质相互作用.
- 共同免疫沉以确定METTL3和转化因子之间的物理相互作用.
- 在人类肺部瘤中分析m6A修饰的瘤mRNA.
主要成果:
- METTL3通过mRNA循环增强转化,涉及与5'盖结合蛋白的相互作用.
- 确定了METTL3和真核转化启动因子3小单元h (eIF3h) 之间的直接物理和功能相互作用.
- 在肺瘤中,METTL3促进瘤性mRNA的转化,包括BRD4,从而推动瘤性转化.
- 抑制瘤生长并增加对BRD4抑制剂的敏感性.
结论:
- METTL3使用mRNA循环机制来控制翻译,涉及与eIF3h的相互作用.
- 这种METTL3-eIF3h通路对于致癌mRNA转换和转化至关重要.
- 在癌症治疗中,METTL3- eIF3h相互作用是一个有前途的治疗标.
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