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首页> 外文期刊>Nucleic Acids Research >A functional genome-wide RNAi screen identifies TAF1 as a regulator for apoptosis in response to genotoxic stress.
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A functional genome-wide RNAi screen identifies TAF1 as a regulator for apoptosis in response to genotoxic stress.

机译：功能性全基因组RNAi筛选可确定TAF1是对遗传毒性应激的凋亡调控因子。

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摘要

Evasion from apoptotic cell death is a characteristic of cancer; genes that modulate this process may be optimal for therapeutic attack. Identifying key regulators of apoptosis is thus a central goal in cancer therapy. Here, we describe a loss-of-function screen that uses RNA interference libraries to identify genes required for induction of apoptosis. We used a short-hairpin RNA expressing vector with high gene-expression silencing activity that contained fetal brain cDNAs. Survived cells from genotoxic stress were isolated to determine knock-down of molecules that are crucial for induction of apoptosis. We identified TBP-associated factor 1 (TAF1), a gene previously implicated as an essential component of transcription machinery. Depletion of TAF1 was associated with substantial attenuation of apoptosis induced by oxidative as well as genotoxic stress. Microarray analysis further demonstrated that a number of genes were transcriptionally declined in cells silenced for TAF1. Surprisingly, knocking down TAF1 exhibited a marked decrease in p27Kipp# expression, allowing cells resistant from oxidative stress-induced apoptosis. These results suggest that TAF1 regulates apoptosis by controlling p27Kipp# expression. Our system provides a novel approach to identifying candidate genes that modulate apoptosis.
机译：避免凋亡细胞死亡是癌症的特征。调节此过程的基因可能是治疗攻击的最佳选择。因此，鉴定凋亡的关键调节剂是癌症治疗的主要目标。在这里，我们描述了一个功能丧失屏幕，该屏幕使用RNA干扰库来识别诱导凋亡的基因。我们使用了具有高基因表达沉默活性的短发夹RNA表达载体，其中包含胎儿脑cDNA。分离出来自遗传毒性应激的存活细胞，以确定对诱导细胞凋亡至关重要的分子的敲低。我们鉴定了TBP相关因子1（TAF1），该基因先前被认为是转录机制的重要组成部分。 TAF1的消耗与氧化和遗传毒性应激诱导的凋亡的显着减弱有关。微阵列分析进一步证明，在针对TAF1沉默的细胞中，许多基因转录下降。出人意料的是，敲低TAF1表现出p27Kipp＃表达的显着降低，从而使细胞抵抗氧化应激诱导的细胞凋亡。这些结果表明TAF1通过控制p27Kipp＃表达来调节细胞凋亡。我们的系统提供了一种新颖的方法来鉴定调节细胞凋亡的候选基因。

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