MiR-24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism.
MiR-24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism.
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DOI：
10.1371/journal.pone.0008445
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发表时间：
2009-12-24
期刊：
影响因子：
3.7
通讯作者：
Bertino JR
中科院分区：
文献类型：
--
作者：
Mishra PJ;Song B;Mishra PJ;Wang Y;Humeniuk R;Banerjee D;Merlino G;Ju J;Bertino JR
据预测，microRNAs(MiRNAs)可以调控大约30%的人类基因；然而，只有少数miRNAs被赋予了它们的靶标和特定的功能。在这里，我们证明了miR-24，一种普遍表达的miRNA，具有独立于P53功能的抗增殖作用。以不同P53基因状态的细胞株为模型，研究miR-24对细胞增殖、细胞周期调控、基因调控和细胞转化的影响。在6种不同的细胞系中，miR-24的过表达独立于P53功能，抑制细胞增殖，并导致G2/S细胞周期停滞。在含有wt-p53的细胞中，miR-24过表达上调了TP53和p21蛋白；然而，在p53缺失的细胞中，miR-24仍然诱导细胞周期停滞，而不涉及p21。我们发现miR-24通过调节S相酶，二氢叶酸还原酶(DHFR)，化疗药物甲氨蝶呤(MTX)的靶点来调节非依赖于P53的细胞增殖。有趣的是，我们发现DHFR 3‘非编码区的miR-24靶点多态性导致miR-24功能丧失和细胞中高水平的DHFR赋予永生化细胞生长优势并诱导肿瘤转化。具有临床意义的是，我们发现miR-24在人类结直肠癌肿瘤中被解除调控，并且部分肿瘤的miR-24水平降低。提出了miR-24作为p53非依赖性细胞周期抑制因子miRNA的一种新功能。
MicroRNAs (miRNAs) are predicted to regulate approximately 30% of all human genes; however, only a few miRNAs have been assigned their targets and specific functions. Here we demonstrate that miR-24, a ubiquitously expressed miRNA, has an anti-proliferative effect independent of p53 function. Cell lines with differential p53 status were used as a model to study the effects of miR-24 on cell proliferation, cell cycle control, gene regulation and cellular transformation. Overexpression of miR-24 in six different cell lines, independent of p53 function, inhibited cell proliferation and resulted in G2/S cell cycle arrest. MiR-24 over expression in cells with wt-p53 upregulated TP53 and p21 protein; however, in p53-null cells miR-24 still induced cell cycle arrest without the involvement of p21. We show that miR-24 regulates p53-independent cellular proliferation by regulating an S-phase enzyme, dihydrofolate reductase (DHFR) a target of the chemotherapeutic drug methotrexate (MTX). Of interest, we found that a miR-24 target site polymorphism in DHFR 3′ UTR that results in loss of miR-24-function and high DHFR levels in the cell imparts a growth advantage to immortalized cells and induces neoplastic transformation. Of clinical significance, we found that miR-24 is deregulated in human colorectal cancer tumors and a subset of tumors has reduced levels of miR-24. A novel function for miR-24 as a p53-independent cell cycle inhibitory miRNA is proposed.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
56.9
作者：
Mayr, Christine;Hemann, Michael T.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
16
作者：
Lal A;Navarro F;Maher CA;Maliszewski LE;Yan N;O'Day E;Chowdhury D;Dykxhoorn DM;Tsai P;Hofmann O;Becker KG;Gorospe M;Hide W;Lieberman J
通讯作者：
Lieberman J
p16（ink4a）被miR-24抑制的翻译。
影响因子：
3.7
作者：
Lal A;Kim HH;Abdelmohsen K;Kuwano Y;Pullmann R Jr;Srikantan S;Subrahmanyam R;Martindale JL;Yang X;Ahmed F;Navarro F;Dykxhoorn D;Lieberman J;Gorospe M
通讯作者：
Gorospe M