Translational regulation of utrophin by miRNAs.
Translational regulation of utrophin by miRNAs.
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DOI：
10.1371/journal.pone.0029376
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Khurana TS
中科院分区：
文献类型：
--
作者：
Basu U;Lozynska O;Moorwood C;Patel G;Wilton SD;Khurana TS
肌营养不良蛋白是肌营养不良蛋白的常染色体同系物，是杜氏肌营养不良（DMD）基因座的产物。它的调节具有治疗意义，因为它的过表达可以弥补DMD动物模型中肌营养不良蛋白的缺失。肌营养蛋白的组织分布和转录调控已经被广泛地表征，最近，其复杂表达模式背后的翻译控制机制已经开始被确定。利用多种生物信息学、分子和细胞生物学技术，我们发现肌异构体肌营养蛋白a在C2C12成肌细胞的翻译水平上主要受到抑制。在C2C12细胞中，翻译抑制的程度估计为~ 99%，并由utrophin-A mRNA的5 ' -和3 ' - utr介导。在本研究中，我们鉴定了介导这种抑制的5种mirna (let-7c、miR-150、miR-196b、miR-296-5p、miR-133b)，并证实了先前鉴定的miR-206的抑制作用。我们证明这种翻译抑制可以通过阻断mirna的作用来克服，从而导致C2C12细胞中肌营养蛋白水平的增加。本研究已经确定了以调节肌营养因子表达的mirna为特征的关键抑制机制，并证明这些机制可以靶向增加培养肌肉细胞中内源性肌营养因子的表达。我们建议mirna介导的抑制机制可以通过类似于本文所述的方法作为一种新的策略来增加富营养蛋白的表达，作为治疗DMD的一种方法。
Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne Muscular Dystrophy (DMD) locus. Its regulation is of therapeutic interest as its overexpression can compensate for dystrophin's absence in animal models of DMD. The tissue distribution and transcriptional regulation of utrophin have been characterized extensively, and more recently translational control mechanisms that may underlie its complex expression patterns have begun to be identified. Using a variety of bioinformatic, molecular and cell biology techniques, we show that the muscle isoform utrophin-A is predominantly suppressed at the translational level in C2C12 myoblasts. The extent of translational inhibition is estimated to be ∼99% in C2C12 cells and is mediated by both the 5′- and 3′-UTRs of the utrophin-A mRNA. In this study we identify five miRNAs (let-7c, miR-150, miR-196b, miR-296-5p, miR-133b) that mediate the repression, and confirm repression by the previously identified miR-206. We demonstrate that this translational repression can be overcome by blocking the actions of miRNAs, resulting in an increased level of utrophin protein in C2C12 cells. The present study has identified key inhibitory mechanisms featuring miRNAs that regulate utrophin expression, and demonstrated that these mechanisms can be targeted to increase endogenous utrophin expression in cultured muscle cells. We suggest that miRNA-mediated inhibitory mechanisms could be targeted by methods similar to those described here as a novel strategy to increase utrophin expression as a therapy for DMD.
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DOI：
10.1083/jcb.200603039
发表时间：
2006-10-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rosenberg MI;Georges SA;Asawachaicharn A;Analau E;Tapscott SJ
通讯作者：
Tapscott SJ
影响因子：
3.5
作者：
Di Certo, Maria Grazia;Corbi, Nicoletta;Passananti, Claudio
通讯作者：
Passananti, Claudio
影响因子：
14.9
作者：
Perkins, KJ;Burton, EA;Davies, KE
通讯作者：
Davies, KE
DOI：
10.1073/pnas.96.6.3223
发表时间：
1999-03-16
影响因子：
11.1
作者：
Gramolini, AO;Angus, LM;Jasmin, BJ
通讯作者：
Jasmin, BJ
影响因子：
4.8
作者：
Miura, P;Thompson, J;Jasmin, BJ
通讯作者：
Jasmin, BJ