Upregulation of Cyclin B1 by miRNA and its implications in cancer.
Upregulation of Cyclin B1 by miRNA and its implications in cancer.
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DOI：
10.1093/nar/gkr934
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发表时间：
2012-02
影响因子：
14.9
通讯作者：
Li LC
中科院分区：
文献类型：
--
作者：
Huang V;Place RF;Portnoy V;Wang J;Qi Z;Jia Z;Yu A;Shuman M;Yu J;Li LC
人们普遍认识到，微小RNA（miRNA）通过靶向3′非翻译区（3′UTR）来沉默基因表达。然而，也有研究表明miRNA可通过靶向启动子元件正向调控基因表达，这种现象被称为RNA激活（RNAa）。在本研究中，我们发现小鼠细胞周期蛋白B1（Ccnb1）的表达依赖于参与miRNA生物发生和功能的关键因子（即Dicer、Drosha、Ago1和Ago2）。通过计算机分析，在Ccnb1启动子中鉴定出21种miRNA的高度互补位点。实验验证确定了三种miRNA（miR - 744、miR - 1186和miR - 466d - 3p）可诱导小鼠细胞系中Ccnb1的表达。相反，内源性miR - 744的敲低导致Ccnb1水平下降。染色质免疫沉淀（ChIP）分析显示，Ago1与Ccnb1启动子选择性结合，并且miR - 744增加了Ccnb1转录起始位点处RNA聚合酶II（RNAP II）的富集以及组蛋白3赖氨酸4位点的三甲基化（H3K4me3）。在功能上，miR - 744和miR - 1186的短期过表达导致细胞增殖增强，而长期表达则导致染色体不稳定和体内肿瘤抑制。Ccnb1的过表达也重现了这些表型。我们的研究结果揭示了一种内源性系统，通过该系统miRNA在小鼠细胞中激活Ccnb1的表达并调控体内肿瘤的发生/生长。
It is largely recognized that microRNAs (miRNAs) function to silence gene expression by targeting 3′UTR regions. However, miRNAs have also been implicated to positively-regulate gene expression by targeting promoter elements, a phenomenon known as RNA activation (RNAa). In the present study, we show that expression of mouse Cyclin B1 (Ccnb1) is dependent on key factors involved in miRNA biogenesis and function (i.e. Dicer, Drosha, Ago1 and Ago2). In silico analysis identifies highly-complementary sites for 21 miRNAs in the Ccnb1 promoter. Experimental validation identified three miRNAs (miR-744, miR-1186 and miR-466d-3p) that induce Ccnb1 expression in mouse cell lines. Conversely, knockdown of endogenous miR-744 led to decreased Ccnb1 levels. Chromatin immunoprecipitation (ChIP) analysis revealed that Ago1 was selectively associated with the Ccnb1 promoter and miR-744 increased enrichment of RNA polymerase II (RNAP II) and trimethylation of histone 3 at lysine 4 (H3K4me3) at the Ccnb1 transcription start site. Functionally, short-term overexpression of miR-744 and miR-1186 resulted in enhanced cell proliferation, while prolonged expression caused chromosomal instability and in vivo tumor suppression. Such phenotypes were recapitulated by overexpression of Ccnb1. Our findings reveal an endogenous system by which miRNA functions to activate Ccnb1 expression in mouse cells and manipulate in vivo tumor development/growth.
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影响因子：
3.7
作者：
Liao JY;Ma LM;Guo YH;Zhang YC;Zhou H;Shao P;Chen YQ;Qu LH
通讯作者：
Qu LH
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-08-3293
发表时间：
2009-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Agarwal R;Gonzalez-Angulo AM;Myhre S;Carey M;Lee JS;Overgaard J;Alsner J;Stemke-Hale K;Lluch A;Neve RM;Kuo WL;Sorlie T;Sahin A;Valero V;Keyomarsi K;Gray JW;Borresen-Dale AL;Mills GB;Hennessy BT
通讯作者：
Hennessy BT
DOI：
10.1073/pnas.0808830105
发表时间：
2008-10-21
影响因子：
11.1
作者：
Kim, Daniel H.;Saetrom, Pal;Rossi, John J.
通讯作者：
Rossi, John J.
影响因子：
7
作者：
Lee, Inhan;Ajay, Subramanian S.;Athey, Brian D.
通讯作者：
Athey, Brian D.