赫赛汀诱导的肌动蛋白相关蛋白-A启动子的表观遗传调控。
Heregulin-induced epigenetic regulation of the utrophin-A promoter.
作者信息
Basu Utpal, Gyrd-Hansen Mads, Baby Santhosh M, Lozynska Olga, Krag Thomas O B, Jensen Claus J, Frödin Morten, Khurana Tejvir S
机构信息
Department of Physiology & Pennsylvania Muscle Institute, 3700 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104-6085, USA.
出版信息
FEBS Lett. 2007 Sep 4;581(22):4153-8. doi: 10.1016/j.febslet.2007.07.021. Epub 2007 Jul 23.
Abstract
Utrophin is the autosomal homolog of dystrophin, the product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin is of therapeutic interest since its over-expression can compensate dystrophin's absence. Utrophin is enriched at neuromuscular junctions due to heregulin-mediated utrophin-A promoter activation. We demonstrate that heregulin activated MSK1/2 and phosphorylated histone H3 at serine 10 in cultured C2C12 muscle cells, in an ERK-dependent manner. MSK1/2 inhibition suppressed heregulin-mediated utrophin-A activation. MSK1 over-expression potentiated heregulin-mediated utrophin-A activation and chromatin remodeling at the utrophin-A promoter. These results identify MSK1/2 as key effectors modulating utrophin-A expression as well as identify novel targets for DMD therapy.
摘要
肌养蛋白是抗肌萎缩蛋白的常染色体同源物，抗肌萎缩蛋白是杜氏肌营养不良症（DMD）基因座的产物。肌养蛋白具有治疗意义，因为其过表达可以补偿抗肌萎缩蛋白的缺失。由于神经调节蛋白介导的肌养蛋白-A启动子激活，肌养蛋白在神经肌肉接头处富集。我们证明，在培养的C2C12肌肉细胞中，神经调节蛋白以ERK依赖的方式激活MSK1/2并使组蛋白H3的丝氨酸10磷酸化。MSK1/2抑制可抑制神经调节蛋白介导的肌养蛋白-A激活。MSK1的过表达增强了神经调节蛋白介导的肌养蛋白-A激活以及肌养蛋白-A启动子处的染色质重塑。这些结果确定MSK1/2是调节肌养蛋白-A表达的关键效应因子，并确定了DMD治疗的新靶点。
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Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1{alpha}, drives utrophin gene expression at the neuromuscular junction.钙调神经磷酸酶-NFAT信号通路，与GA结合蛋白和过氧化物酶体PGC-1α共同驱动神经肌肉接头处的抗肌萎缩蛋白基因表达。
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