Protein-DNA array-based identification of transcription factor activities differentially regulated in skeletal muscle of normal and dystrophin-deficient mdx mice
Protein-DNA array-based identification of transcription factor activities differentially regulated in skeletal muscle of normal and dystrophin-deficient mdx mice
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DOI：
10.1007/s11010-008-9716-6
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发表时间：
2008-05-01
影响因子：
4.3
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
--
作者：
Dogra, Charu;Srivastava, Daya Shankar;Kumar, Ashok
肌营养不良蛋白基因失活是人类和mdx小鼠杜氏肌营养不良症（DMD）的主要原因。然而，控制肌营养不良蛋白缺乏的骨骼肌发病机制的基本机制仍然知之甚少。我们之前报道了mdx小鼠膈肌中丝裂原活化蛋白激酶（MAPK）、核因子κ B （nf - κ B）和磷脂酰肌醇3-激酶/Akt （PI3K/Akt）信号通路的激活。在这项研究中，我们使用基于蛋白质- dna阵列的方法，研究了6周龄正常和肌营养不良蛋白缺陷mdx小鼠膈肌中345个转录因子的激活。我们的数据表明，许多核转录因子的激活增加，包括AP1、hhh -3、PPAR α、c.myb BP、ETF、Fra-1/JUN、kBF-A、N-rasBP、乳铁蛋白BP、Myb(2)、EBP40_45、EKLF(1)、p53(2)、TFEB、Myc-Max；:;E2, ISRE;NF-kB;与正常小鼠比较，mdx小鼠膈肌中Stat1 p84/p91、抗氧化RE、EVI-1、Stat3、AP3、p53、Stat4、AP4、hhh -1、FAST-1、Pax-5、β -RE。在所有研究的转录因子中，p53的激活水平最高。此外，mdx小鼠膈肌中p53的高活化与其磷酸化和核易位增加有关。总的来说，我们的数据表明，肌营养不良蛋白的原发性缺乏导致核转录因子的异常激活，这可能进一步促进mdx小鼠的肌肉发病。
Inactivation of dystrophin gene is the primary cause of Duchenne muscular dystrophy (DMD) in humans and mdx mice. However, the underpinning mechanisms, which govern the pathogenesis of dystrophin-deficient skeletal muscle, remain poorly understood. We have previously reported activation of mitogen-activated protein kinases (MAPK), nuclear factor-kappa B (NF-kappa B), and phosphatidyl-inositol 3-kinase/Akt (PI3K/Akt) signaling pathways in diaphragm muscle of mdx mice. In this study, using a protein-DNA array-based approach, we have investigated the activation of 345 transcription factors in diaphragm muscle of 6-week old normal and dystrophin-deficient mdx mice. Our data demonstrate increased activation of a number nuclear transcription factors including AP1, HFH-3, PPAR alpha, c.myb BP, ETF, Fra-1/JUN, kBF-A, N-rasBP, lactoferrin BP, Myb(2), EBP40_45, EKLF(1), p53(2), TFEB, Myc-Max; c-Rel; E2, ISRE; NF-kB; Stat1 p84/p91, Antioxidant RE, EVI-1, Stat3, AP3, p53, Stat4, AP4, HFH-1, FAST-1, Pax-5, and Beta-RE in the diaphragm muscle of mdx mice compared to corresponding normal mice. The level of activation for p53 was highest among all the transcription factors studied. Furthermore, higher activation of p53 in diaphragm muscle of mdx mice was associated with its increased phosphorylation and nuclear translocation. Collectively, our data suggest that the primary deficiency of dystrophin leads to the aberrant activation of nuclear transcription factors which might further contribute to muscle pathogenesis in mdx mice.