Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis
Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis
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p53 对 miR-17-92 簇的抑制在缺氧诱导的细胞凋亡中具有重要作用
DOI：
10.1038/emboj.2009.214
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发表时间：
2009-09-16
期刊：
影响因子：
11.4
通讯作者：
Sun, Shu-han
中科院分区：
文献类型：
--
作者：
Yan, Hong-li;Xue, Geng;Sun, Shu-han
我们在这里报告，miR-17-92簇是一个新的目标p53介导的转录抑制缺氧。我们发现，在缺氧处理的含有野生型p53的细胞中，miR-17-92簇的表达水平降低，但在缺氧处理的p53缺陷细胞中，miR-17-92簇的表达水平不变。缺氧条件下miR-17-92簇的抑制不依赖于c-Myc。荧光素酶报告基因分析将对p53介导的抑制反应的区域映射到miR-17-92启动子近端区域中的p53结合位点。染色质免疫沉淀（ChIP）、Re-ChIP和凝胶阻滞试验显示，p53和TATA结合蛋白（TBP）的结合位点在miR-17-92启动子内重叠;发现这些蛋白竞争结合。最后，我们发现pri-miR-17-92的表达与结直肠癌中p53的状态密切相关。过表达miR-17-92簇可显著抑制缺氧诱导的细胞凋亡，而阻断miR-17- 5 p和miR-20 a则可使细胞对缺氧诱导的细胞凋亡敏感。这些数据表明，p53介导的miR-17-92表达抑制可能在缺氧诱导的细胞凋亡中具有重要作用，从而进一步加深了我们对p53肿瘤抑制功能的理解。The EMBO Journal（2009）28，2719-2732. doi：10.1038/doj.2009.214; 2009年8月20日在线发布
We here report that miR-17-92 cluster is a novel target for p53-mediated transcriptional repression under hypoxia. We found the expression levels of miR-17-92 cluster were reduced in hypoxia-treated cells containing wild-type p53, but were unchanged in hypoxia-treated p53-deficient cells. The repression of miR-17-92 cluster under hypoxia is independent of c-Myc. Luciferase reporter assays mapped the region responding to p53-mediated repression to a p53-binding site in the proximal region of the miR-17-92 promoter. Chromatin immunoprecipitation (ChIP), Re-ChIP and gel retardation assays revealed that the binding sites for p53- and the TATA-binding protein (TBP) overlap within the miR-17-92 promoter; these proteins were found to compete for binding. Finally, we show that pri-miR-17-92 expression correlated well with p53 status in colorectal carcinomas. Over-express miR-17-92 cluster markedly inhibits hypoxia-induced apoptosis, whereas blocked miR-17-5p and miR-20a sensitize the cells to hypoxia-induced apoptosis. These data indicated that p53- mediated repression of miR-17-92 expression likely has an important function in hypoxia-induced apoptosis, and thus further our understanding of the tumour suppressive function of p53. The EMBO Journal (2009) 28, 2719-2732. doi: 10.1038/emboj.2009.214; Published online 20 August 2009