Interferons and IRF-1 induce expression of the survival motor neuron (SMN) genes
Interferons and IRF-1 induce expression of the survival motor neuron (SMN) genes
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DOI：
10.1007/bf03401830
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发表时间：
2000-11-01
影响因子：
5.7
通讯作者：
Beretta, L
中科院分区：
文献类型：
--
作者：
Baron-Delage, S;Abadie, A;Beretta, L
背景：脊髓性肌萎缩症（SMA）是一种常见的隐性遗传性疾病，以脊髓运动神经元变性为特征。运动神经元存活基因（SMN）的缺失、转换或突变是SMA的原因。SMA患者中SMN基因（SMNc）的高度同源着丝粒拷贝保持完整。然而，SMNc基因产物的量与疾病的临床严重程度之间呈负相关。SMN和SMNc基因调控的理解，因此，对治疗SMA的重要一步。结果：我们确定了一个候选人干扰素刺激的反应元件（ISRE），与干扰素调节因子结合基序（IRF-E）在SMN和SMNc基因的启动子区域重叠。ISRE和IRF-E基序都参与介导干扰素刺激的基因表达的转录诱导。因此，我们研究了SMN和SMNc基因是否受干扰素（IFN）的调控。在这里，我们表明，IFN-β和IFN-γ快速诱导SMN和SMNc mRNA和蛋白质表达在各种细胞系。转录因子IRF-1在体外与SMN和SMNc基因的候选ISRE/IRF-E序列结合，并且在转染测定中IRF-1的过表达诱导这两个基因的表达。因此，IRF-1至少部分负责IFN诱导SMN和SMNc。在SMA患者成纤维细胞的原代培养中，IFN-β和IFN-γ诱导SMNc基因表达并修复蛋白质缺陷。
Background: Spinal muscular atrophy (SMA) is a common recessive disorder, characterized by degeneration of motor neurons of the spinal cord. Deletions, conversions, or mutations of the survival motor neuron gene (SMN) are responsible for SMA. A highly homologous centromeric copy of the SMN gene (SMNc) remains intact in SMA patients. However, the-re is an inverse correlation between the amount of the SMNc gene product and the clinical severity of the disease. An understanding of SMN and SMNc gene regulation is, therefore, an important step towards therapy for SMA.Results: We identified a candidate Interferon-stimulated Response Element (ISRE), overlapping with an Interferon Regulatory Factors binding motif (IRF-E) in the promoter region of SMN and SMNc genes. Both ISRE and IRF-E motifs are involved in mediating transcriptional induction of interferon-stimulated gene expression. We, therefore, investigated whether SMN and SMNc genes were regulated by interferons (IFN). Here we show that both IFN-beta and IFN-gamma rapidly induced SMN and SMNc mRNA and protein expression in various cell lines. The transcription factor IRF-1 bound to the candidate ISRE/IRF-E sequence of SMN and SMNc genes in vitro and overexpression of IRF-1 induced expression of both genes in transfection assays. IRF-1 is, therefore, at least in part responsible for the induction of SMN and SMNc by IFNs. In primary culture of fibroblasts from SMA patients, IFN-beta and IFN-gamma induced SMNc gene expression and restored protein defect.