STUDIES ON FUNCTIONS OF THIOREDOXIN REDUCTASE IN DETOXIFICATION OF HEAVY METALS

硫氧还蛋白还原酶重金属解毒作用的研究

基本信息

项目摘要

The mammalian thioredoxin reductase (TrxR) is a selenocysteine-containing flavoprotein that regulates the thioredoxin system, one of the major systems that maintain the intracellular redox balance. To date, three TrxR isozymes, TrxR1, TrxR2 and TrxR3, have been identified. We previously reported that TrxR1 was induced by heavy metals such as cadmium (Cd) and arsenite (As). In this study, the functions of TrxR1 in detoxification of heavy metals were investigated as follows :(1)Transcriptional regulation of Cd-induced TrxR1 expression-Treatment of bovine arterial endothelial cells with Cd enhanced the promoter activity of the 5'-flanking region of human TrxR1 gene (nucleotides -1692 to +49). Deletion and site-directed mutation of antioxidant responsive element (ARE) (nucleotide -62 to -48) in this region abolished the response to Cd. Overexpression of NF-E2-related factor-2 (Nrf2) augmented the TrxR1 promoter activity. These results indicated that Cd-induced TrxR1 gene expression is mediated by the activation of Nrf2 and its binding to ARE in the TrxR1 gene promoter. We further found that in addition to Cd, the activators of Nrf2, such as diethyl maleate (DEM) and As, induced both TrxR1 and Trx gene expression. Nrf2 might play an important role in the regulation of the cellular Trx system consisting of Trx and TrxR.(2)Involvement of TrxR1 in cellular defense against heavy metals-We silenced the expression of TrxR1 in HeLa cells by using short-interfering RNA and found that the gene silencing of TrxR1 had a dual effect on Cd- and As-induced celldeath, depending on the concentration of heavy metals. The TrxR1 silencing increased the sensitivity toward a low dose of heavy metals but decreased the sensitivity toward a high dose of heavy metals. These results suggested that TrxR1 might play an important role in the cellular defense system against heavy metals in two ways.
哺乳动物硫氧还蛋白还原酶(TrxR)是一种含硒半胱氨酸的黄素蛋白,其调节硫氧还蛋白系统,该系统是维持细胞内氧化还原平衡的主要系统之一。迄今为止,已鉴定出三种TrxR同工酶,TrxR 1、TrxR 2和TrxR 3。我们以前报道过TrxR 1被重金属如镉(Cd)和砷(As)诱导。本研究对TrxR 1在重金属解毒中的作用进行了如下研究:(1)镉诱导TrxR 1表达的转录调控--镉处理牛动脉内皮细胞后,人TrxR 1基因5 '侧翼区(核苷酸-1692 ~+49)的启动子活性增强。抗氧化反应元件(ARE)(-62 ~-48位核苷酸)的缺失和定点突变可使镉胁迫的反应消失。过表达NF-E2相关因子-2(Nrf 2)增强了TrxR 1启动子活性。这些结果表明,镉诱导的TrxR 1基因的表达是通过激活Nrf 2和它的结合在TrxR 1基因启动子ARE介导的。我们进一步发现,除了镉,Nrf 2的激活剂,如马来酸二乙酯(DEM)和砷,诱导TrxR 1和Trx基因的表达。Nrf 2可能在由Trx和TrxR组成的细胞Trx系统的调节中起重要作用。(2)TrxR 1参与细胞对重金属的防御--我们利用短干扰RNA(Short interfering RNA,shRNA)沉默HeLa细胞中TrxR 1的表达,发现TrxR 1基因沉默对Cd和As诱导的细胞死亡具有双重效应,并依赖于重金属的浓度。TrxR 1沉默增加了对低剂量重金属的敏感性,但降低了对高剂量重金属的敏感性。这些结果表明,TrxR 1可能通过两种途径在重金属的细胞防御系统中发挥重要作用。

项目成果

期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Short-interfering RNA-mediated Silencing of Thioredoxin Reductase 1 Alters the Sensitivity of HeLa Cells toward Cadmium
短干扰 RNA 介导的硫氧还蛋白还原酶 1 沉默改变了 HeLa 细胞对镉的敏感性
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    C.Cuiping;R.Tanaka;Y.Okuda;N.Ikota;H.Yamamoto;S.Urano;T.Ozawa;K.Anzai;西本 理恵 ほか
  • 通讯作者:
    西本 理恵 ほか
Transcriptional regulation of thioredoxin reductase 1 expression by cadmium in vascular endothelial cells: Role of NF-E2-related factor-2
  • DOI:
    10.1002/jcp.20246
  • 发表时间:
    2005-06-01
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Sakurai, A;Nishimoto, M;Hara, S
  • 通讯作者:
    Hara, S
Transcriptional Regulation of Thioredoxin Reductase 1 Expression by Cadmium in Vascular Endothelial Cells
血管内皮细胞中镉对硫氧还蛋白还原酶 1 表达的转录调节
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hashimoto Y;Kaneko Y;Tsukamoto E;Frankowski H;Kouyama K;Kita Y;Niikura T;Aiso S;Bredesen DE;Matsuoka M;Nishimoto I;Kitamura et al.分担(R.C.Gupta編集);Tetsushi Watanabe;櫻井貴子ほか
  • 通讯作者:
    櫻井貴子ほか
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HARA Shuntaro其他文献

HARA Shuntaro的其他文献

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{{ truncateString('HARA Shuntaro', 18)}}的其他基金

Studies on novel mechanisms of environmental chemicals-induced toxicity using arachidonate-metabolizing enzyme genetically modified mice
利用花生四烯酸代谢酶转基因小鼠研究环境化学物质诱导毒性的新机制
  • 批准号:
    21390036
  • 财政年份:
    2009
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Functional analysis of phospholipase A2 by genetically modified mice and its biopharmaceutical application
转基因小鼠磷脂酶A2的功能分析及其生物制药应用
  • 批准号:
    18209004
  • 财政年份:
    2006
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
CHARACTERIZATION OF ENDOGENOUS HYPDXIA-INDUCED TRANSCRIPTIONAL REPRESSOR HIF-3ALPHA
内源性缺氧诱导的转录抑制子 HIF-3ALPHA 的表征
  • 批准号:
    18590071
  • 财政年份:
    2006
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Studies on Induction and Functions of Thioredoxin Reductase in Stress Responses
硫氧还蛋白还原酶应激反应的诱导及功能研究
  • 批准号:
    13672345
  • 财政年份:
    2001
  • 资助金额:
    $ 2.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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