Regulation of metallothionein gene expression by oxidative stress and metal ions
Regulation of metallothionein gene expression by oxidative stress and metal ions
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DOI：
10.1016/s0006-2952(99)00301-9
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发表时间：
2000-01-01
影响因子：
5.8
通讯作者：
Andrews, GK
中科院分区：
文献类型：
--
作者：
Andrews, GK
金属硫蛋白（MT）是一种富含半胱氨酸的小分子重金属结合蛋白，参与一系列保护性应激反应。虽然MT的单一基本功能尚未得到证实，但高等真核生物的MT进化为调节细胞和生物体内锌水平和分布的机制。这些蛋白质还可以防止一些有毒金属和氧化应激诱导剂。在小鼠中，在四种已知的MT基因中，MT-I和MT-II基因表达最广泛。这些基因的转录响应于锌和镉以及响应于引起氧化应激和/或炎症的试剂而快速且显著地上调。六个锌指金属响应转录因子MTF-1在MT-I基因的转录激活中起核心作用，以响应金属和氧化应激。MTF-1基因的突变消除了这些反应，并且在用锌处理的细胞中或在氧化应激期间，MTF-1被诱导与近端MT启动子中的金属反应元件结合。MTF-1的确切分子作用机制尚未完全了解。我们的研究表明，MTF-1在体内和体外的DNA结合活性是可逆激活锌的相互作用与：inc指结构域。这反映了六个锌指结构和功能的异质性。我们假设MTF-1作为细胞中游离锌池的传感器发挥作用。游离锌的变化可能会发生在响应不同的化学诱导剂。MTF-1还对MT-I基因转录产生影响，其独立于MTF-1 DNA结合活性的大幅增加。例如，在体内或体外对MTF-1的DNA结合活性几乎没有影响的镉是比锌更有效的MT基因表达诱导剂。（上游刺激因子家族），在镉或H2 O2诱导的小鼠MT-1基因转录调控中也起作用。1或从近端启动子缺失其结合位点减弱小鼠MT-1基因的诱导。USF显然在这种情况下，通过与尚未鉴定的蛋白质相互作用发挥作用，这些蛋白质结合到与USF结合位点重叠的抗氧化反应元件（USF/ARE）。有趣的是，这种复合元素不参与锌或氧化还原循环醌类诱导MT-I基因转录。因此，金属和氧化应激对小鼠MT-I基因的调节涉及多种信号传导途径，这取决于金属离子的种类和氧化应激的性质。生物化学制药59;1：95-104，2000. (C)1999 Elsevier Science Inc.
The metallothioneins (MT) are small, cysteine-rich heavy metal binding proteins which participate in an array of protective stress responses. Although a single essential function of MT has not been demonstrated, MT of higher eukaryotes evolved as a mechanism to regulate zinc levels and distribution within cells and organisms. These proteins can also protect against some toxic metals and oxidative stress-inducing agents. In mice, among the four known MT genes, the MT-I and -II genes are most widely expressed. Transcription of these genes is rapidly and dramatically up-regulated in response to zinc and cadmium, as well as in response to agents which cause oxidative stress and/or inflammation. The six zinc-finger metal-responsive transcription factor MTF-1 plays a central role in transcriptional activation of the MT-I gene in response to metals and oxidative stress. Mutation of the MTF-1 gene abolishes these responses, and MTF-1 is induced to bind to the metal response elements in proximal MT promoter in cells treated with zinc or during oxidative stress. The exact molecular mechanisms of action of MTF-1 are not fully understood. Our studies suggest that the DNA-binding activity of MTF-1 in vivo and in vitro is reversibly activated by zinc interactions with the :inc finger domain. This reflects heterogeneity in the structure and function of the six zinc fingers. We hypothesize that MTF-1 functions as a sensor of free zinc pools in the cell. Changes in free zinc may occur in response to chemically diverse inducers. MTF-1 also exerts effects on MT-I gene transcription which are independent of a large increase in MTF-1 DNA-binding activity. For example, cadmium, which has little effect on the DNA-binding activity of MTF-1 in vivo or in vitro, is a more potent inducer of MT gene expression than is zinc, The basic helix-loop-helix-leucine zipper protein, USF (upstream stimulatory factor family), also plays a role in regulating transcription of the mouse MT- gene in response to cadmium or H2O2 Expression of dominant negative USF-1 or deletion of its binding site from the proximal promoter attenuates induction of the mouse MT-I gene. USF apparently functions in this context by interacting with as yet unidentified proteins which bind to an antioxidant response element which overlaps the USF binding site (USF/ARE). Interestingly, this composite element does not participate in the induction of MT-I gene transcription by zinc or redox-cycling quinones. Thus, regulation of the mouse MT-I gene by metals and oxidative stress involves multiple signaling pathways which depend on the species of metal ion and the nature of the oxidative stress. BIOCHEM PHARMACOL 59;1:95-104, 2000. (C) 1999 Elsevier Science Inc.