USP39通过与SRSF6/HNRNPC合作调节替代拼接来促进肝细胞致癌
Jingyi Zheng1, Shasha Wu1, Mao Tang1
1Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
Cell death & disease
|October 11, 2023
概括
拼接体因子USP39通过改变基因拼接来驱动肝癌. USP39与RBP相互作用以控制替代拼接 (AS),提供潜在的癌症生物标志物和治疗点.
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 是一个遗传学.
背景情况:
- 替代拼接 (AS) 失调,由拼接体因子改变驱动,与癌症的发展有关.
- 目前的模型强调在结合部位选择中早期的结合体组件 (U1,U2 snRNP).
- 中/晚起作用的结合体蛋白质 (如USP39) 在瘤发生和结合部位选择中的作用尚不清楚.
研究的目的:
- 研究USP39在肝癌发生中的作用及其调节替代拼接的机制.
- 为了确定USP39是否调节瘤性拼接部位选择.
- 为了确定参与USP39介导的拼接控制的相互作用蛋白质和途径.
主要方法:
- 利用具有肝细胞特异性USP39过度表达的转基因小鼠来研究其在体内的影响.
- 使用人类肝癌细胞来评估USP39对瘤增殖和拼接的影响.
- 开发并应用了一种新的RBP-motif缩分析,以确定USP39的交互伙伴和监管机制.
- 分析了全球替代拼接事件的USP39耗尽效应.
主要成果:
- 肝细胞特异性USP39过度表达促进了肝癌发生和改变了小鼠的拼接部位选择.
- USP39以一种依赖于结合体细胞的方式增强了肝癌细胞增殖.
- USP39的耗尽导致了数百种替代拼接事件的放松管制,包括KANK2.2的瘤性拼接.
- 在人类和小鼠模型中,USP39通过与SRSF6和HNRNPC的相互作用来调节外子纳入/排除.
结论:
- 中/晚起作用的结合体蛋白质,如USP39所示,在控制结合部位选择方面发挥着重要作用.
- USP39与特定RBP (SRSF6,HNRNPC) 的相互作用为其在替代拼接中的功能提供了机制基础.
- USP39和潜在的其他中/晚起作用的结合体蛋白质代表了有希望的预后生物标志物和癌症治疗的治疗点,特别是肝癌.
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