Cardiovascular Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota 57104, USA.
J Biol Chem. 2011 Nov 18;286(46):40296-306. doi: 10.1074/jbc.M111.241455. Epub 2011 Sep 26.
Myotonic dystrophy 1 (DM1) is a multisystemic disease caused by a triplet nucleotide repeat expansion in the 3' untranslated region of the gene coding for myotonic dystrophy protein kinase (DMPK). DMPK is a nuclear envelope (NE) protein that promotes myogenic gene expression in skeletal myoblasts. Muscular dystrophy research has revealed the NE to be a key determinant of nuclear structure, gene regulation, and muscle function. To investigate the role of DMPK in NE stability, we analyzed DMPK expression in epithelial and myoblast cells. We found that DMPK localizes to the NE and coimmunoprecipitates with Lamin-A/C. Overexpression of DMPK in HeLa cells or C2C12 myoblasts disrupts Lamin-A/C and Lamin-B1 localization and causes nuclear fragmentation. Depletion of DMPK also disrupts NE lamina, showing that DMPK is required for NE stability. Our data demonstrate for the first time that DMPK is a critical component of the NE. These novel findings suggest that reduced DMPK may contribute to NE instability, a common mechanism of skeletal muscle wasting in muscular dystrophies.
强直性肌营养不良 1 型（DM1）是一种多系统疾病，由编码肌强直性营养不良蛋白激酶（DMPK）的基因 3'非翻译区的三核苷酸重复扩展引起。DMPK 是核膜（NE）的一种蛋白，可促进成肌细胞中的肌生成基因表达。肌肉疾病研究揭示 NE 是核结构、基因调控和肌肉功能的关键决定因素。为了研究 DMPK 在 NE 稳定性中的作用，我们分析了上皮细胞和成肌细胞中 DMPK 的表达。我们发现 DMPK 定位于 NE 并与 Lamin-A/C 共免疫沉淀。在 HeLa 细胞或 C2C12 成肌细胞中过表达 DMPK 会破坏 Lamin-A/C 和 Lamin-B1 的定位，并导致核碎片化。DMPK 的耗竭也会破坏 NE 层，表明 DMPK 是 NE 稳定性所必需的。我们的数据首次证明 DMPK 是 NE 的关键组成部分。这些新发现表明，DMPK 的减少可能导致 NE 不稳定，这是肌肉疾病中骨骼肌减少的常见机制。
