Pumilio facilitates miRNA regulation of the E2F3 oncogene
Pumilio facilitates miRNA regulation of the E2F3 oncogene
复制标题
DOI：
10.1101/gad.182568.111
复制
发表时间：
2012-02-15
影响因子：
10.5
通讯作者：
Dyson, Nicholas J.
中科院分区：
文献类型：
--
作者：
Miles, Wayne O.;Tschoep, Katrin;Dyson, Nicholas J.
E2 F转录因子是细胞增殖的重要调节因子，并且在人类恶性肿瘤中经常失调。为了鉴定E2 F功能的新调节子，我们使用果蝇作为模型系统来筛选由dE 2F 1水平降低引起的修饰表型的突变。该筛选将Pumilio翻译阻遏物复合物的组分（Pumilio、Nanos和脑肿瘤）鉴定为dE 2F 1-RNAi表型的抑制物。随后的实验提供了证据表明，Pumilio复合物抑制dE 2F 1水平，这种转录后调控机制在人类细胞中是保守的。人Pumilio同源物Pum 1和Pum 2通过结合E2 F3 39非翻译区（UTR）来抑制E2 F3的翻译，并且还增强多个E2 F3靶向microRNA（miRNA）的活性。E2 F3是一种具有强增殖潜力的癌基因，在癌症中经常失调或过度表达。有趣的是，Pumilio/miRNA介导的E2 F3调节在癌细胞中以几种不同的方式被规避。膀胱癌选择性下调与Pumilio合作靶向E2 F3的miRNA，并且多种肿瘤细胞系缩短E2 F3 mRNA的39末端，去除Pumilio调节元件。这些研究表明，Pumilio-miRNA对E2 F3翻译的抑制提供了一个重要的E2 F调节水平，该水平在癌细胞中经常被废除。
E2F transcription factors are important regulators of cell proliferation and are frequently dysregulated in human malignancies. To identify novel regulators of E2F function, we used Drosophila as a model system to screen for mutations that modify phenotypes caused by reduced levels of dE2F1. This screen identified components of the Pumilio translational repressor complex (Pumilio, Nanos, and Brain tumor) as suppressors of dE2F1-RNAi phenotypes. Subsequent experiments provided evidence that Pumilio complexes repress dE2F1 levels and that this mechanism of post-transcriptional regulation is conserved in human cells. The human Pumilio homologs Pum 1 and Pum 2 repress the translation of E2F3 by binding to the E2F3 39 untranslated region (UTR) and also enhance the activity of multiple E2F3 targeting microRNAs (miRNAs). E2F3 is an oncogene with strong proliferative potential and is regularly dysregulated or overexpressed in cancer. Interestingly, Pumilio/miRNA-mediated regulation of E2F3 is circumvented in cancer cells in several different ways. Bladder carcinomas selectively downregulate miRNAs that cooperate with Pumilio to target E2F3, and multiple tumor cell lines shorten the 39 end of the E2F3 mRNA, removing the Pumilio regulatory elements. These studies suggest that Pumilio-miRNA repression of E2F3 translation provides an important level of E2F regulation that is frequently abrogated in cancer cells.