Regulation of DMD pathology by an ankyrin-encoded miRNA.
Regulation of DMD pathology by an ankyrin-encoded miRNA.
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DOI：
10.1186/2044-5040-1-27
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发表时间：
2011-08-08
期刊：
影响因子：
4.9
通讯作者：
Kunkel LM
中科院分区：
文献类型：
--
作者：
Alexander MS;Casar JC;Motohashi N;Myers JA;Eisenberg I;Gonzalez RT;Estrella EA;Kang PB;Kawahara G;Kunkel LM
杜氏肌营养不良症（DMD）是一种X-连锁的肌病，由非功能性肌营养不良蛋白的产生引起。microRNA（miRNA）是一种21 - 24个核苷酸的小RNA，可以调节单个基因和整个细胞信号通路。以前，我们确定了几种mRNA，肌肉富集和炎症诱导，在DMD患者的骨骼肌失调。一种特别富含肌肉的miRNA，miR-486，在肌营养不良蛋白缺陷的小鼠和人类骨骼肌中显著下调。miR-486嵌入ANKYRIN1（ANK1）基因座内，根据细胞和组织类型，其转录为长（红细胞富集）或短（心肌和骨骼肌富集）同种型。正常肌肉成肌细胞中miR-486的抑制导致原代成肌细胞培养物中迁移受抑制和伤口修复失败。相反，原代成肌细胞培养物中miR-486的过表达导致增殖增加，而细胞凋亡没有变化。使用生物信息学和miRNA报告基因分析，我们已经鉴定了血小板衍生生长因子受体β，沿着与10号染色体上缺失的磷酸酶和张力蛋白同源物/AKT（PTEN/AKT）途径的几个其他下游靶点，其被miR-486调节。过表达miR-486的肌肉特异性转基因小鼠的产生表明，miR-486改变了体内再生肌纤维的细胞周期动力学，因为这些小鼠的肌肉再生受损。这些研究证明了miR-486作为肌营养不良蛋白缺陷肌肉中PTEN/AKT通路的调节剂和DMD肌肉病理学调节中的重要因素的联系。
Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting from the production of a nonfunctional dystrophin protein. MicroRNA (miRNA) are small 21- to 24-nucleotide RNA that can regulate both individual genes and entire cell signaling pathways. Previously, we identified several mRNA, both muscle-enriched and inflammation-induced, that are dysregulated in the skeletal muscles of DMD patients. One particularly muscle-enriched miRNA, miR-486, is significantly downregulated in dystrophin-deficient mouse and human skeletal muscles. miR-486 is embedded within the ANKYRIN1(ANK1) gene locus, which is transcribed as either a long (erythroid-enriched) or a short (heart muscle- and skeletal muscle-enriched) isoform, depending on the cell and tissue types. Inhibition of miR-486 in normal muscle myoblasts results in inhibited migration and failure to repair a wound in primary myoblast cell cultures. Conversely, overexpression of miR-486 in primary myoblast cell cultures results in increased proliferation with no changes in cellular apoptosis. Using bioinformatics and miRNA reporter assays, we have identified platelet-derived growth factor receptor β, along with several other downstream targets of the phosphatase and tensin homolog deleted on chromosome 10/AKT (PTEN/AKT) pathway, as being modulated by miR-486. The generation of muscle-specific transgenic mice that overexpress miR-486 revealed that miR-486 alters the cell cycle kinetics of regenerated myofibers in vivo, as these mice had impaired muscle regeneration. These studies demonstrate a link for miR-486 as a regulator of the PTEN/AKT pathway in dystrophin-deficient muscle and an important factor in the regulation of DMD muscle pathology.
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影响因子：
--
作者：
Jiang, Bing-Hua;Liu, Ling-Zhi
通讯作者：
Liu, Ling-Zhi
DOI：
10.1016/j.bbrc.2008.08.107
发表时间：
2008-11-07
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Kahn, CR