DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2
DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2
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DOI：
10.1073/pnas.0607260103
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发表时间：
2006-10-10
影响因子：
11.1
通讯作者：
Ting, Jenny P-Y.
中科院分区：
文献类型：
--
作者：
Clements, Casey M.;McNally, Richard S.;Ting, Jenny P-Y.
DJ-1/PARK7是一种癌症和帕金森病（PD）相关蛋白，可保护细胞免受毒性应激。然而，这种保护的功能基础仍然难以捉摸。我们发现，DJ-1的缺失导致解毒酶NQO1 [NAD(P)H醌氧化还原酶1]的缺失。这种缺陷归因于Nrf2（核因子红系2相关因子）的缺失，Nrf2是抗氧化转录反应的主要调节因子。DJ-1通过阻止Nrf2与其抑制剂蛋白Keap1的结合以及Nrf2随后的泛素化来稳定Nrf2。没有完整的DJ-1， Nrf2蛋白是不稳定的，因此在基础上和诱导后转录反应都降低。DJ-1对Nrf2的影响存在于人类和小鼠的转化系和原代细胞中。DJ-1对Nrf2的影响以及随后对抗氧化反应的影响可能解释了DJ-1如何影响癌症和PD的病因学，这两种疾病看起来完全不同。此外，这个DJ-1/Nrf2功能轴在癌症治疗中提供了一个治疗靶点，并证明DJ-1是肿瘤生物标志物。
DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-l's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.