Ting Chen-Hung, Lin Chiao-Wei, Wen Shin-Lan, Hsieh-Li Hsiu-Mei, Li Hung
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
Hum Mol Genet. 2007 Mar 1;16(5):499-514. doi: 10.1093/hmg/ddl482. Epub 2007 Jan 12.
Proximal spinal muscular atrophy (SMA) is a motor neuron degeneration disorder for which there is currently no effective treatment. Here, we report three compounds (sodium vanadate, trichostatin A and aclarubicin) that effectively enhance SMN2 expression by inducing Stat5 activation in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. We found that Stat5 activation enhanced SMN2 promoter activity with increase in both full-length and deletion exon 7 SMN transcripts in SMN2-NSC34 cells. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. In addition, constitutive activation of Stat5 mutant (Stat5A1*6) profoundly increased the number of nuclear gems in SMA-patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects. These results demonstrate that Stat5 signaling could be a possible pharmacological target for treating SMA.
近端脊髓性肌萎缩症（SMA）是一种运动神经元退行性疾病，目前尚无有效治疗方法。在此，我们报告三种化合物（钒酸钠、曲古抑菌素A和阿克拉霉素），它们通过在SMA样小鼠胚胎成纤维细胞和人SMN2转染的NSC34细胞中诱导Stat5激活，有效增强了SMN2的表达。我们发现，Stat5激活增强了SMN2启动子活性，同时增加了SMN2-NSC34细胞中全长和缺失外显子7的SMN转录本。敲低Stat5表达破坏了钒酸钠对SMN2激活的作用，但不影响SMN2剪接，这表明Stat5信号传导参与了SMN2的转录调控。此外，Stat5突变体（Stat5A1*6）的组成型激活显著增加了SMA患者淋巴细胞中核宝石的数量，并减少了SMA样运动神经元轴突生长缺陷。这些结果表明，Stat5信号传导可能是治疗SMA的一个潜在药理学靶点。
