Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene.
Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene.
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DOI：
10.1074/jbc.m110.137034
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发表时间：
2010-12-17
期刊：
影响因子：
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通讯作者：
Iguchi-Ariga SM
中科院分区：
文献类型：
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作者：
Ishikawa S;Taira T;Takahashi-Niki K;Niki T;Ariga H;Iguchi-Ariga SM
DJ-1 基因的功能丧失突变会导致一部分家族性帕金森病。然而，多巴胺能通路中 DJ-1 相关选择性脆弱性的潜在机制尚不清楚。 DJ-1具有转录调控等多种功能，DJ-1的转录靶基因之一是酪氨酸羟化酶(TH)基因，其产物是多巴胺生物合成的关键酶。据报道，DJ-1 是一种神经保护性转录共激活剂，可从 TH 基因启动子中隔离转录共阻遏物聚嘧啶束结合蛋白相关剪接因子 (PSF)。在这项研究中，我们发现在人多巴胺能细胞系中通过小干扰RNA敲低人DJ-1会减弱TH基因表达和4-二羟基-L-苯丙氨酸的产生，但在小鼠细胞系或小鼠中敲低或敲除小鼠DJ-1并不影响这种表达和TH活性。在使用与荧光素酶基因连接的人类 TH 基因启动子的报告基因检测中，在用 DJ-1 转染的人类细胞中观察到 TH 启动子活性的刺激，但在小鼠细胞中未观察到。尽管人DJ-1和小鼠DJ-1与人或小鼠PSF相关，但被PSF抑制的TH启动子活性被人DJ-1恢复，但不能被小鼠DJ-1恢复。染色质免疫沉淀分析表明，PSF 与 DJ-1 的复合物与人类 TH 基因启动子结合，但不与小鼠 TH 基因启动子结合。这些结果表明 DJ-1 对 TH 启动子进行新的物种特异性转录调节，也是 DJ-1 敲除小鼠中 TH 不减少的机制之一。
Loss-of-function mutation in the DJ-1 gene causes a subset of familial Parkinson disease. The mechanism underlying DJ-1-related selective vulnerability in the dopaminergic pathway is, however, not known. DJ-1 has multiple functions, including transcriptional regulation, and one of transcriptional target genes for DJ-1 is the tyrosine hydroxylase (TH) gene, the product of which is a key enzyme for dopamine biosynthesis. It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter. In this study, we found that knockdown of human DJ-1 by small interference RNA in human dopaminergic cell lines attenuated TH gene expression and 4-dihydroxy-l-phenylalanine production but that knockdown or knock-out of mouse DJ-1 in mouse cell lines or in mice did not affect such expression and TH activity. In reporter assays using the human TH gene promoter linked to the luciferase gene, stimulation of TH promoter activity was observed in human cells, but not mouse cells, that had been transfected with DJ-1. Although human DJ-1 and mouse DJ-1 were associated either with human or with mouse PSF, TH promoter activity inhibited by PSF was restored by human DJ-1 but not by mouse DJ-1. Chromatin immunoprecipitation assays revealed that the complex of PSF with DJ-1 bound to the human but not the mouse TH gene promoter. These results suggest a novel species-specific transcriptional regulation of the TH promoter by DJ-1 and one of the mechanisms for no reduction of TH in DJ-1-knock-out mice.