Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.
Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.
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DOI：
10.1038/ncb2443
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发表时间：
2012-02-26
影响因子：
21.3
通讯作者：
Bischof O
中科院分区：
文献类型：
--
作者：
Benhamed M;Herbig U;Ye T;Dejean A;Bischof O
细胞衰老是由哺乳动物细胞中的癌症引发或促进事件触发的肿瘤抑制机制。这种稳定停滞的分子基础涉及由视网膜母细胞瘤（Rb）/E2 F阻遏物复合物调节的增殖促进基因的转录抑制。在这里，我们证明，AGO 2，Rb和microRNA（miR），这里举例说明让-7，物理和功能相互作用，抑制Rb/E2 F靶基因在衰老，一个过程，我们称之为衰老相关的转录基因沉默（SA-TGS）。在本文中，AGO 2作为效应蛋白，用于miR-let 7指导的靶启动子处沉默状态染色质修饰的实施，并且let-7-AGO 2效应复合物的抑制扰乱衰老的及时执行。因此，我们将细胞衰老鉴定为人细胞中miR-AGO 2介导的TGS的内源性信号。我们的研究结果表明，miR-AGO 2介导的SA-TGS可能有助于稳定抑制癌前癌细胞中的增殖促进基因的肿瘤抑制。
Cellular senescence is a tumour suppressor mechanism that is triggered by cancer-initiating or promoting events in mammalian cells. The molecular underpinnings for this stable arrest involve transcriptional repression of proliferation-promoting genes regulated by the retinoblastoma (Rb)/E2F repressor complex. Here, we demonstrate that AGO2, Rb and microRNAs (miRs), as exemplified here by let-7, physically and functionally interact to repress Rb/E2F target genes in senescence, a process that we refer to as senescence-associated transcriptional gene silencing (SA-TGS). Herein, AGO2 acts as the effector protein for miR-let7-directed implementation of silent state chromatin modifications at target promoters and inhibition of the let-7-AGO2 effector complex perturbs the timely execution of senescence. Thus, we identify cellular senescence as the an endogenous signal of miR-AGO2-mediated TGS in human cells. Our results suggest that miR-AGO2-mediated SA-TGS may contribute to tumour suppression by stably repressing proliferation-promoting genes in pre-malignant cancer cells.