Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs.
Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs.
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DOI：
10.1371/journal.pgen.1002242
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发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Lim B
中科院分区：
文献类型：
--
作者：
Le MT;Shyh-Chang N;Khaw SL;Chin L;Teh C;Tay J;O'Day E;Korzh V;Yang H;Lal A;Lieberman J;Lodish HF;Lim B
MicroRNAs调节基因网络以协调细胞功能。Mir-125b是秀丽线虫microRNA lin-4的脊椎动物同源物，参与调节神经和造血干细胞的动态平衡，类似于Lin-4调节秀丽线虫干细胞的方式。根据细胞环境的不同，miR-125b被认为既可以调节细胞凋亡，也可以调节细胞增殖。由于P53网络是细胞凋亡和增殖的中枢调节因子，miR-125b的双重作用引发了P53网络中哪些基因可能受miR-125b调控的问题。通过在人类、小鼠和斑马鱼中使用miR-125b靶标的获得和功能丧失筛选，并通过荧光素酶试验和一种新的miRNA下拉试验验证这些靶标，我们证明miR-125b直接抑制p53网络中的20个新靶标。这些靶点既包括Bak1、IGFBP3、Itch、Puma、Prkra、Tp53inp1、TP53、Zac1等细胞周期调节因子，也包括p53网络中的细胞周期调节因子如Cyclin C、CDc25c、CDKN2c、Edn1、Ppp1ca、Sel11。我们发现，虽然每个miRNA-靶点对很少是保守的，但miR-125b对p53通路的调节在网络水平上是保守的。我们的结果导致我们提出miR-125b通过调节增殖和凋亡调节剂的剂量来缓冲和微调p53网络的活性，这意味着组织干细胞的动态平衡和肿瘤发生。MicroRNAs(MiRNAs)是一种微小的内源RNA，可以同时调节数百个基因的表达，从而协调基因网络的变化，调节植物和动物的细胞功能。尽管识别miRNAs的单个靶标具有重要意义，但到目前为止，很少有研究试图揭示基因网络水平上的miRNA靶标和网络水平上miRNA调控的一般原理。在这里，我们描述了miR-125b如何靶向p53网络中的20个凋亡和增殖基因。我们发现，虽然每个miRNA-靶点对在脊椎动物中进化迅速，但miR-125b对p53通路的调节在网络水平上是保守的。MiR-125b调控网络的结构表明miR-125b对p53网络活动进行缓冲和微调。MiR-125b的这一缓冲功能对于我们理解miR-125b如何调控肿瘤发生和组织干细胞动态平衡具有重要意义。我们认为，关于miR-125b的这些发现支持了miRNAs如何调控基因网络的一个新的基本原则。
MicroRNAs regulate networks of genes to orchestrate cellular functions. MiR-125b, the vertebrate homologue of the Caenorhabditis elegans microRNA lin-4, has been implicated in the regulation of neural and hematopoietic stem cell homeostasis, analogous to how lin-4 regulates stem cells in C. elegans. Depending on the cell context, miR-125b has been proposed to regulate both apoptosis and proliferation. Because the p53 network is a central regulator of both apoptosis and proliferation, the dual roles of miR-125b raise the question of what genes in the p53 network might be regulated by miR-125b. By using a gain- and loss-of-function screen for miR-125b targets in humans, mice, and zebrafish and by validating these targets with the luciferase assay and a novel miRNA pull-down assay, we demonstrate that miR-125b directly represses 20 novel targets in the p53 network. These targets include both apoptosis regulators like Bak1, Igfbp3, Itch, Puma, Prkra, Tp53inp1, Tp53, Zac1, and also cell-cycle regulators like cyclin C, Cdc25c, Cdkn2c, Edn1, Ppp1ca, Sel1l, in the p53 network. We found that, although each miRNA–target pair was seldom conserved, miR-125b regulation of the p53 pathway is conserved at the network level. Our results lead us to propose that miR-125b buffers and fine-tunes p53 network activity by regulating the dose of both proliferative and apoptotic regulators, with implications for tissue stem cell homeostasis and oncogenesis. MicroRNAs (miRNAs) are tiny endogenous RNAs that can regulate the expression of hundreds of genes simultaneously, thus orchestrating changes in gene networks and mediating cellular functions in both plants and animals. Although the identification of individual targets of miRNAs is of major importance, to date few studies have sought to uncover miRNA targets at the gene network level and general principles of miRNA regulation at the network level. Here we describe how miR-125b targets 20 apoptosis and proliferation genes in the p53 network. We found that, although each miRNA-target pair evolves rapidly across vertebrates, regulation of the p53 pathway by miR-125b is conserved at the network level. The structure of the miR-125b regulatory network suggests that miR-125b buffers and fine-tunes p53 network activity. This buffering feature of miR-125b has implications for our understanding of how miR-125b regulates oncogenesis and tissue stem cell homeostasis. We believe these findings on miR-125b support a new fundamental principle for how miRNAs regulate gene networks in general.
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影响因子：
64.5
作者：
CHALFIE, M;HORVITZ, HR;SULSTON, JE
通讯作者：
SULSTON, JE
影响因子：
56.9
作者：
Milo, R;Shen-Orr, S;Alon, U
通讯作者：
Alon, U
Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.
DOI：
10.1084/jem.20080285
发表时间：
2008-10-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bousquet M;Quelen C;Rosati R;Mansat-De Mas V;La Starza R;Bastard C;Lippert E;Talmant P;Lafage-Pochitaloff M;Leroux D;Gervais C;Viguié F;Lai JL;Terre C;Beverlo B;Sambani C;Hagemeijer A;Marynen P;Delsol G;Dastugue N;Mecucci C;Brousset P
通讯作者：
Brousset P
DOI：
10.1073/pnas.1016611107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Bousquet, Marina;Harris, Marian H.;Lodish, Harvey F.
通讯作者：
Lodish, Harvey F.