在人类癌症中对eIF4F复杂功能和结构的计算推断
bioRxiv : the preprint server for biology
|August 23, 2023
概括
癌细胞可以切换翻译启动机制,有利于独立于cap的途径. 像EIF4G1和EIF3E这样的转化启动因子的基因放大支持癌症生存,并提供潜在的治疗点.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 遗传学 遗传学 是一个
背景情况:
- 欧核细胞翻译启动因子4F (eIF4F) 复合体对于依赖翻译至关重要.
- 通过内部核糖体进入部位 (IRES) 进行的独立于的翻译可以在压力下在癌细胞中激活.
- 人类癌症中翻译启动选择的精确机制尚未完全理解.
研究的目的:
- 为了研究人类癌症中翻译启动基因中的基因复制数变异 (CNVs).
- 阐明癌症中依赖和独立转化启动的分子机制.
- 确定与翻译启动相关的潜在治疗漏洞.
主要方法:
- 对TCGA瘤样本CNVs的分析.
- 对基因表达与癌细胞生存途径的相关性分析.
- 蛋白质共同调节分析.
- 基于AlphaFold的eIF4F复合体的结构建模.
主要成果:
- 在人类癌症中观察到翻译启动基因的频繁放大,包括EIF4G1和EIF3E的同时发生的增长.
- EIF4G1放大与癌症生存基因 (细胞循环,脂质生成) 的过度表达相关.
- 对于eIF4G1/eIF4A1与eIF4E的不同蛋白质共同调节模式表明,朝着无限度独立启动的转变.
- AlphaFold模型说明了eIF4F的结构性适应,既适用于上限依赖的机制,也适用于上限独立的机制.
结论:
- 翻译启动的调节失调,特别是有利于独立于帽子的途径,在人类癌症中很普遍.
- 扩大EIF4G1和EIF3E可能会给癌细胞带来生存优势.
- 了解这些机制对于开发针对癌症细胞依赖转化启动的向疗法至关重要.
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