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Regulation of Rad51 promoter

机译：Rad51启动子的调控

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The DNA double-strand break repair and homologous recombination protein Rad51 is overexpressed in the majority of human cancers. This correlates with therapy resistance and decreased patient survival. We previously showed that constructs containing Rad51 promoter fused to a reporter gene are, on average, 850-fold more active in cancer cells than in normal cells. It is not well understood what factors and sequences regulate the Rad51 promoter and cause its high activity in cancerous cells. Here we characterized regulatory regions and examined genetic requirements for oncogenic stimulation of the Rad51 promoter. We identified specific regions responsible for up- and downregulation of the Rad51 promoter in cancerous cells. Furthermore, we show that Rad51 expression is positively regulated by EGR1 transcription factor. We then modeled the malignant transformation process by expressing a set of oncoproteins in normal human fibroblasts. Expression of different combinations of SV40 large T antigen, oncogenic Ras and SV40 small T antigen resulted in step-wise increase in Rad51 promoter activity, with all the 3 oncoproteins together leading to a 47-fold increase in expression. Cumulatively, these results suggest that Rad51 promoter is regulated by multiple factors, and that its expression is gradually activated as cells progress toward malignancy.
机译：DNA双链断裂修复和同源重组蛋白Rad51在大多数人类癌症中均过表达。这与治疗抵抗力和患者存活率降低相关。我们以前显示含有与报道基因融合的Rad51启动子的构建体在癌细胞中的活性平均比在正常细胞中高850倍。尚不清楚什么因子和序列调节Rad51启动子并导致其在癌细胞中的高活性。在这里，我们表征了调控区域并检查了Rad51启动子致癌性刺激的遗传要求。我们确定了特定区域负责癌细胞中Rad51启动子的上调和下调。此外，我们显示Rad51表达受EGR1转录因子正调控。然后，我们通过在正常人成纤维细胞中表达一组癌蛋白来模拟恶性转化过程。 SV40大T抗原，致癌性Ras和SV40小T抗原的不同组合的表达导致Rad51启动子活性逐步提高，所有3种癌蛋白一起导致表达增加47倍。累积地，这些结果表明，Rad51启动子受多种因素调节，并且其表达随着细胞向恶性进展而逐渐被激活。

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