Cell Death , and Senescence miR-15 and miR-16 Are Direct Transcriptional Targets of E 2 F 1 that Limit E 2 F-Induced Proliferation by Targeting Cyclin E
Cell Death , and Senescence miR-15 and miR-16 Are Direct Transcriptional Targets of E 2 F 1 that Limit E 2 F-Induced Proliferation by Targeting Cyclin E
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发表时间：
2011
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通讯作者：
Matan Ofir;Dalia Hacohen;D. Ginsberg
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作者：
Matan Ofir;Dalia Hacohen;D. Ginsberg
MicroRNAs(MiR)是一种小的非编码RNA分子，最近作为基因表达的关键调节因子出现，在癌症中经常被解除调控。特别是，由miR-15a、miR-16-1簇编码的miR似乎具有肿瘤抑制作用。在这里，我们证明miR-15a，miR-16-1簇和相关的miR-15b，miR-16-2簇由E2F1调控的miR组成，E2F1是一种关键的转录因子，可以诱导细胞增殖和死亡。E2F1是肿瘤抑制因子视网膜母细胞瘤(RB)的关键下游靶点。在人类肿瘤中，Rb通路经常失活，导致E2F活性失控。我们发现，异位E2F1激活后，4个成熟的miR，miR-15a，miR-16-1和miR-15b，miR-16-2及其前体原生RNA的表达水平上升。此外，内源性E2F的激活上调了这些miRs的表达，内源性E2F1结合了它们各自的启动子。重要的是，我们证实miR-15a/b抑制了细胞周期蛋白E的表达，后者是E2F的一个关键的直接转录靶点，在G1/S的转变中起关键作用，这增加了E2F1、miR-15和细胞周期蛋白E组成一个前馈环调控E2F活性和细胞周期进展的可能性。支持这一点的是，miR-15的异位表达抑制了G1/S的转变，反过来，抑制miR-15的表达增强了E2F1诱导的细胞周期蛋白E1水平的上调。此外，抑制miR-15和miR-16可增强E2F1诱导的G1/S转变。综上所述，我们的数据确定miR-15和miR-16家族是E2F的新转录靶点，而E2F反过来又调节E2F的活性。摩尔癌症资源；9(4)；440-7。2011年AACR。
microRNAs (miR) are small noncoding RNAmolecules that have recently emerged as critical regulators of gene expression and are often deregulated in cancer. In particular, miRs encoded by the miR-15a, miR-16-1 cluster seem to act as tumor suppressors. Here, we evidence that the miR-15a, miR-16-1 cluster and related miR-15b, miR-16-2 cluster comprise miRs regulated by E2F1, a pivotal transcription factor that can induce both proliferation and cell death. E2F1 is a critical downstream target of the tumor suppressor retinoblastoma (RB). The RB pathway is often inactivated in human tumors resulting in deregulated E2F activity. We show that expression levels of the 4 mature miRs, miR-15a, miR-16-1 and miR-15b, miR-16-2, as well as their precursor primiRNAs, are elevated upon activation of ectopic E2F1. Moreover, activation of endogenous E2Fs upregulates expression of these miRs and endogenous E2F1 binds their respective promoters. Importantly, we corroborate that miR-15a/b inhibits expression of cyclin E, the latter a key direct transcriptional target of E2F pivotal for the G1/S transition, raising the possibility that E2F1, miR-15, and cyclin E constitute a feed-forward loop that modulates E2F activity and cell-cycle progression. In support of this, ectopic expression of miR-15 inhibits the G1/S transition, and, conversely, inhibition of miR-15 expression enhances E2F1-induced upregulation of cyclin E1 levels. Furthermore, inhibition of both miR-15 and miR-16 enhances E2F1-induced G1/S transition. In summary, our data identify the miR-15 and miR-16 families as novel transcriptional targets of E2F, which, in turn, modulates E2F activity. Mol Cancer Res; 9(4); 440–7. 2011 AACR.