Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN
Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN
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DOI：
10.3892/ijo_00000451
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发表时间：
2009-12-01
影响因子：
5.2
通讯作者：
Ariga, Hiroyoshi
中科院分区：
文献类型：
--
作者：
Kim, Yun-Chul;Kitaura, Hirotake;Ariga, Hiroyoshi
DJ-1是一种致癌基因，也是一种家族性帕金森病的致病基因。DJ-1具有多种功能，包括抗氧化应激反应，而DJ-1的半胱氨酸106（C106）都是DJ-1发挥其功能的必需氨基酸。虽然已经报道了在患有各种癌症的患者中DJ-1的表达和分泌增加到血清中以及DJ-1对p53和PTEN的调节，但是对DJ-1致癌性的分子机制知之甚少。在此，我们分析了DJ-1在氧化应激条件下P13 'K信号通路中的功能，重点是DJ-1与PTEN的相互作用。我们发现，野生型（wt）和C106 S-DJ-1，DJ-1的取代突变体，直接结合到PTEN和抑制PTEN磷酸酶活性，但C106 S-DJ-1更强烈地抑制活性比wt-DJ-1。H_2O_2处理NIH 3 T3细胞后，wt-DJ-1的C106被氧化，与PTEN的结合增加，PTEN活性降低，AKT磷酸化增加。C106 S-DJ-1比wt-DJ-1更强地转化细胞，并且DJ-1的转化活性通过H2 O2处理细胞而增强，其中观察到DJ-1与PTEN的结合增加和PTEN活性降低。此外，C106的氧化状态的TOF-MS分析表明DJ-1活性需要C106的还原形式的存在，其占总形式的>50%。这些结果表明DJ-1的氧化状态调节PTEN活性，导致细胞增殖和转化。
DJ-1 is all oncogene and also a causative gene for a familial form of Parkinson's disease. DJ-1 has multiple functions, including anti-oxidative stress reaction and cysteine 106 (C106) of DJ-1 is all essential amino acid for DJ-1 to exert its function. While increased expression and secretion of DJ-1 into serum in patients with various cancers and regulation of p53 and PTEN by DJ-1 have been reported, the molecular mechanism underlying oncogenicity of DJ-I is poorly understood. Here, we analyzed the function of DJ-1 in the P13'K signaling pathway under an oxidative stress condition, focusing on the interaction of DJ-1 with PTEN. We found that both wild-type (wt) and C106S-DJ-1, a substitution mutant of DJ-1, directly bound to PTEN and inhibited PTEN phosphatase activity but that C106S-DJ-1 more strongly inhibited the activity than did wt-DJ-1. When NIH3T3 cells were treated with H2O2, oxidation of C106 of wt-DJ-1 occurred, accompanied by increased binding, of wt-DJ-1 to PTEN, decreased PTEN activity and increased phosphorylation of AKT. C106S-DJ-1 transformed cells more strongly than did wt-DJ-1 and the transforming activity of DJ-1 was enhanced by H2O2 treatment of cells in which increased binding of DJ-1 to PTEN and decreased PTEN activity were observed. Furthermore, TOF-MS analysis of the oxidative status of C106 suggested that DJ-1 activity requires the presence of the reduced form of C106, which accounts for >50% of the total form. These results suggest that the oxidative status of DJ-1 regulates PTEN activity, leading to cell proliferation and transformation.