DJ-1 upregulates tyrosine hydroxylase gene expression by activating its transcriptional factor Nurr1 via the ERK1/2 pathway
DJ-1 upregulates tyrosine hydroxylase gene expression by activating its transcriptional factor Nurr1 via the ERK1/2 pathway
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DJ-1 通过 ERK1/2 途径激活其转录因子 Nurr1，上调酪氨酸羟化酶基因表达
DOI：
10.1016/j.biocel.2011.09.007
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Yang, Hui
中科院分区：
文献类型：
--
作者：
Lu, Lingling;Sun, Xiaohong;Yang, Hui
DJ-1基因突变与常染色体隐性遗传早发性帕金森综合征有关。然而，DJ-1的假定功能尚未完全了解。先前的研究表明DJ-1过表达导致酪氨酸羟化酶基因的上调。DJ-1影响酪氨酸羟化酶表达的机制仍然难以捉摸。在本研究中，我们发现DJ-1过表达诱导ERK 1/2激活，沿着酪氨酸羟化酶表达增加。L166 P DJ-1突变体，已被确定为负责家族性帕金森症，没有这种效果。此外，药理学抑制剂U 0126抑制ERK 1/2磷酸化部分取消了DJ-1对酪氨酸羟化酶的调节作用。Nurr 1是酪氨酸羟化酶的转录因子，可被ERK 1/2磷酸化并移位到细胞核，在那里被激活。因此，我们测量了Nurr 1的核转位。共聚焦显微镜和蛋白质印迹显示，Nurr 1易位到细胞核，并激活野生型DJ-1的过表达，但不是其L166 P突变体。Nurr 1基因表达的敲除消除了DJ-1诱导的酪氨酸羟化酶的作用。综上所述，这些数据表明，DJ-1上调酪氨酸羟化酶的表达激活其转录因子Nurr 1通过ERK 1/2途径。(C)2011年由Elsevier Ltd.出版
Loss-of-function DJ-1 mutations have been linked to autosomal recessive early-onset Parikinsonism. However, the putative function of DJ-1 is not completely understood. Previous studies indicate that DJ-1 overexpression results in upregulation of the tyrosine hydroxylase gene. The mechanism by which DJ-1 affects tyrosine hydroxylase expression remains elusive. In the present study, we show that DJ-1 overexpression induces ERK1/2 activation, along with increased tyrosine hydroxylase expression. The L166P DJ-1 mutant, which has been identified as being responsible for familial Parkinsonism, did not have this effect. Moreover, suppression of ERK1/2 phosphorylation by the pharmacological inhibitor U0126 partially abolished the regulating effect of DJ-1 on tyrosine hydroxylase. Nurr1, a transcriptional factor for tyrosine hydroxylase, can be phosphorylated by ERK1/2 and translocate to the nucleus, where it is activated. Thus, we measured nuclear translocation of Nurr1. Confocal microscopy and Western blotting revealed that Nurr1 translocated to the nucleus and was activated by overexpression of wildtype DJ-1, but not of its L166P mutant. Knockdown of Nurr1 gene expression abolished the effect on tyrosine hydroxylase induced by DJ-1. Taken together, these data suggest that DJ-1 upregulates tyrosine hydroxylase expression by activating its transcription factor Nurr1 via the ERK1/2 pathway. (C) 2011 Published by Elsevier Ltd.