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Copper-inducible transcription: regulation by metal- and oxidative stress-responsive pathways.

机译:铜诱导的转录:通过金属和氧化应激反应途径的调控。

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Although copper is an essential metal, it is capable of catalyzing the formation of reactive oxygen species that can cause intracellular oxidative damage. We investigated the hypothesis that metal- and oxidative stress-responsive signal transduction pathways mediate the cellular and molecular responses associated with copper exposure. Transient transfection assays using COS-7 cells and mouse metallothionein-I (MT-I) or rat NAD(P)H:oxidoreductase 1-based reporter genes demonstrate that copper activates transcription via metal and antioxidant response elements. Concomitant with copper exposures is a decrease in the level of total glutathione and an increase in oxidized glutathione. Depletion of glutathione, before copper exposure, increases metal- and oxidative stress-inducible transcription and cytotoxicity. Pretreatment with the reactive oxygen scavengers aspirin or vitamin E provides partial protection against copper toxicity and reduces inducible transcription. Experiments using signal transduction inhibitors and a metal transcription factor (MTF)-1 null cell line demonstrate that copper-inducible MT-I transcription is regulated by protein kinase C and mitogen-activated protein kinase signaling pathways and requires MTF-1. The results of these studies indicate that copper activates transcription through both metal- and oxidative stress-responsive signal transduction pathways.
机译:尽管铜是必不可少的金属,但它能够催化活性氧的形成,从而引起细胞内的氧化损伤。我们调查了金属和氧化应激反应信号转导通路介导与铜暴露有关的细胞和分子反应的假说。使用COS-7细胞和小鼠金属硫蛋白-I(MT-1)或基于大鼠NAD(P)H:氧化还原酶1的报告基因进行的瞬时转染测定表明,铜通过金属和抗氧化剂响应元件激活转录。与铜接触的同时是总谷胱甘肽水平的降低和氧化型谷胱甘肽的升高。在暴露于铜之前,谷胱甘肽的消耗会增加金属和氧化应激诱导的转录和细胞毒性。用活性氧清除剂阿司匹林或维生素E进行的预处理可部分保护铜免受毒性,并减少诱导型转录。使用信号转导抑制剂和金属转录因子(MTF)-1空细胞系进行的实验表明,铜诱导的MT-1转录受蛋白激酶C和有丝分裂原激活的蛋白激酶信号通路调节,并且需要MTF-1。这些研究的结果表明,铜通过金属和氧化应激响应信号转导途径激活转录。

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