miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR.
miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR.
复制标题
DOI：
10.1126/scisignal.2004177
复制
发表时间：
2013-07-30
影响因子：
7.3
通讯作者：
Guttridge DC
中科院分区：
文献类型：
--
作者：
Balkhi MY;Iwenofu OH;Bakkar N;Ladner KJ;Chandler DS;Houghton PJ;London CA;Kraybill W;Perrotti D;Croce CM;Keller C;Guttridge DC
在肉瘤中，NF-κB（核因子κB）的活性降低了microRNA (miRNA) miR-29的丰度。肿瘤抑制因子A20[也称为TNFAIP3（肿瘤坏死因子- α -诱导蛋白3）]抑制NF-κB的上游激活因子，常在淋巴瘤中发生突变。在一组人肉瘤细胞系中，我们发现NF-κB的激活增加，尽管A20蛋白和mRNA的丰度降低，但编码A20的基因很少发生突变。A20 mRNA的3 '非翻译区（UTR）对miR-29和miR-125都有保守的结合位点。miR-125在人肉瘤组织中的表达升高，而miR-29在大多数样本中的表达降低。过表达miR-125降低了A20 mRNA的丰度，而在肉瘤细胞系中重组miR-29增加了A20 mRNA和蛋白质的丰度。通过直接与RNA结合蛋白HuR（人抗原R，也称为ELAVL1）相互作用，miR-29阻止HuR与A20 3'UTR结合并招募RNA降解复合体RISC （RNA诱导沉默复合体），这表明miR-29可以作为HuR的诱饵，从而保护A20转录本。肉瘤中miR-29和A20丰度的降低与NF-κB活性的增加和分化相关基因表达的降低相关。总之，这些发现揭示了miR-29的独特作用，并表明其缺失可能有助于肉瘤的发生。
In sarcoma, the activity of NF-κB (nuclear factor κB) reduces the abundance of the microRNA (miRNA) miR-29. The tumor suppressor A20 [also known as TNFAIP3 (tumor necrosis factor–α–induced protein 3)] inhibits an upstream activator of NF-κB and is often mutated in lymphomas. In a panel of human sarcoma cell lines, we found that the activation of NF-κB was increased and, although the abundance of A20 protein and mRNA was decreased, the gene encoding A20 was rarely mutated. The 3′ untranslated region (UTR) of A20 mRNA has conserved binding sites for both of the miRNAs miR-29 and miR-125. Whereas the expression of miR-125 was increased in human sarcoma tissue, that of miR-29 was decreased in most samples. Overexpression of miR-125 decreased the abundance of A20 mRNA, whereas reconstituting miR-29 in sarcoma cell lines increased the abundance of A20 mRNA and protein. By interacting directly with the RNA binding protein HuR (human antigen R; also known as ELAVL1), miR-29 prevented HuR from binding to the A20 3′UTR and recruiting the RNA degradation complex RISC (RNA-induced silencing complex), suggesting that miR-29 can act as a decoy for HuR, thus protecting A20 transcripts. Decreased miR-29 and A20 abundance in sarcomas correlated with increased activity of NF-κB and decreased expression of genes associated with differentiation. Together, the findings reveal a unique role of miR-29 and suggest that its absence may contribute to sarcoma tumorigenesis.
登录
查看更多内容
影响因子：
14.9
作者：
Cook KB;Kazan H;Zuberi K;Morris Q;Hughes TR
通讯作者：
Hughes TR
影响因子：
16
作者：
Ea, CK;Deng, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
影响因子：
14.9
作者：
Leandersson K;Riesbeck K;Andersson T
通讯作者：
Andersson T
影响因子：
64.8
作者：
Compagno, Mara;Lim, Wei Keat;Grunn, Adina;Nandula, Subhadra V.;Brahmachary, Manisha;Shen, Qiong;Bertoni, Francesco;Ponzoni, Maurilio;Scandurra, Marta;Califano, Andrea;Bhagat, Govind;Chadburn, Amy;Dalla-Favera, Riccardo;Pasqualucci, Laura
通讯作者：
Pasqualucci, Laura