MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.
MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein.
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MicroRNA-26a/b 及其宿主基因通过激活 pRb 蛋白合作抑制 G1/S 转变
DOI：
10.1093/nar/gkr1278
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发表时间：
2012-05
影响因子：
14.9
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
Zhu Y;Lu Y;Zhang Q;Liu JJ;Li TJ;Yang JR;Zeng C;Zhuang SM
内含子miRNAs与其宿主基因之间的功能关联在很大程度上仍不清楚。我们发现，产生miR-26a和miR-26b的3个基因座嵌入了编码小分子磷酸酶家族蛋白的基因内含子，包括CTDSP1、CTDSP2和CTDSP1。我们在原代成纤维细胞和小鼠三分之二肝部分切除模型中进行了血清饥饿刺激实验，结果表明miR-26a/b和CTDSP1/2/L在细胞周期过程中同时表达。具体地说，它们在静止细胞中增加，在细胞增殖过程中减少。此外，miR-26和CTDSP家族成员在肝细胞癌组织中经常下调。功能获得和功能丧失研究表明，miR-26a/b和CTDSP1/2/L协同降低pRb的磷酸化形式(PpRb)，并阻断G1/S期进程。进一步研究发现，miR-26a/b直接抑制CDK6和Cyclin E1的表达，从而降低了pRb的磷酸化。此外，在癌细胞中经常上调的c-Myc降低了miR-26和CTDSPs家族成员的表达，提高了ppRb水平，促进了G1/S期转变。我们的发现突出了miR-26a/b及其宿主基因的功能关联，并为G1/S相变的调控网络提供了新的见解。
The functional association between intronic miRNAs and their host genes is still largely unknown. We found that three gene loci, which produced miR-26a and miR-26b, were embedded within introns of genes coding for the proteins of carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase (CTDSP) family, including CTDSPL, CTDSP2 and CTDSP1. We conducted serum starvation-stimulation assays in primary fibroblasts and two-thirds partial-hepatectomies in mice, which revealed that miR-26a/b and CTDSP1/2/L were expressed concomitantly during the cell cycle process. Specifically, they were increased in quiescent cells and decreased during cell proliferation. Furthermore, both miR-26 and CTDSP family members were frequently downregulated in hepatocellular carcinoma (HCC) tissues. Gain- and loss-of-function studies showed that miR-26a/b and CTDSP1/2/L synergistically decreased the phosphorylated form of pRb (ppRb), and blocked G1/S-phase progression. Further investigation disclosed that miR-26a/b directly suppressed the expression of CDK6 and cyclin E1, which resulted in reduced phosphorylation of pRb. Moreover, c-Myc, which is often upregulated in cancer cells, diminished the expression of both miR-26 and CTDSP family members, enhanced the ppRb level and promoted the G1/S-phase transition. Our findings highlight the functional association of miR-26a/b and their host genes and provide new insight into the regulatory network of the G1/S-phase transition.
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DOI：
10.1126/science.1189123
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Najafi-Shoushtari SH;Kristo F;Li Y;Shioda T;Cohen DE;Gerszten RE;Näär AM
通讯作者：
Näär AM
影响因子：
4.8
作者：
Gerin, Isabelle;Clerbaux, Laure-Alix;Bommer, Guido T.
通讯作者：
Bommer, Guido T.
影响因子：
3.5
作者：
Wang, Wei-Zhang;Cheng, Jiasen;Zhuang, Shi-Mei
通讯作者：
Zhuang, Shi-Mei
DOI：
10.1126/science.1189862
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rayner KJ;Suárez Y;Dávalos A;Parathath S;Fitzgerald ML;Tamehiro N;Fisher EA;Moore KJ;Fernández-Hernando C
通讯作者：
Fernández-Hernando C
影响因子：
56.9
作者：
Matsuo, T;Yamaguchi, S;Okamura, H
通讯作者：
Okamura, H