Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts
Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts
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DOI：
10.1016/s0006-291x(03)00728-9
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发表时间：
2003-05-30
影响因子：
3.1
通讯作者：
Ishii, T
中科院分区：
文献类型：
--
作者：
Aono, J;Yanagawa, T;Ishii, T
亚致死水平的砷会诱导应激蛋白上调。我们在这里首次报道无机砷激活转录因子 Nrf2，该因子控制氧化应激诱导蛋白的表达。用亚砷酸盐或砷酸盐处理培养的 MC3T3-E1 成骨细胞，诱导 Nrf2 增加，随后编码 HO-1、Prx 1 和 A 170 的靶基因转录激活。我们发现砷酸盐 (200-800 muM) 仅略微增加正常的 60 kDa A 170 蛋白，但显着增加出现的较高分子量形式的 A 170 (HMM-A170)作为涂抹带。砷酸盐还显着增加泛素结合的细胞蛋白，表明 HMM-A170 是多聚泛素化蛋白之一。亚砷酸盐 (50100 muM) 还诱导 HMM-A170 和泛素缀合蛋白的积累。这些结果提供了第一个直接证据，证明有毒砷会损害 A 170 的正常功能。我们的研究结果为监测细胞和组织对砷化合物的生物毒性提供了潜在的诊断工具。 (C) 2003 年爱思唯尔科学（美国）。版权所有。
Sub-lethal levels of arsenic induce upregulation of stress proteins. We here report for the first time that inorganic arsenic activates the transcription factor Nrf2, which controls the expression of oxidative stress-induced proteins. Treatment of cultured MC3T3-E1 osteoblasts with arsenite or arsenate induced increase of Nrf2, followed by transcriptional activation of target genes encoding HO-1, Prx 1, and A 170. We found that arsenate (200-800 muM) only slightly increased the normal 60 kDa A 170 protein but markedly increased higher molecular mass forms of A 170 (HMM-A170) that appeared as smeared bands. Arsenate also markedly increased ubiquitin-conjugated cellular proteins, suggesting that HMM-A170 was one of the poly-ubiquitinated proteins. Arsenite (50100 muM) also induced accumulation of HMM-A170 and ubiquitin-conjugated proteins. These results provide the first direct evidence that toxic arsenics impair the normal function of A 170. Our findings provide a potential diagnostic tool for monitoring biotoxicity in cells and tissues in response to arsenic compounds. (C) 2003 Elsevier Science (USA). All rights reserved.