Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element
Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element
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DOI：
10.1111/j.1742-4658.2007.06093.x
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发表时间：
2007-11-01
期刊：
影响因子：
5.4
通讯作者：
Grossman, Lawrence I.
中科院分区：
文献类型：
--
作者：
Huettemann, Maik;Lee, Icksoo;Grossman, Lawrence I.
细胞色素c氧化酶（CcO）亚基4是线粒体电子传递链末端复合物的核编码调节亚基。我们最近发现了一种CcO-4亚型（CcO-4 -2），它特异于肺和气管，并在出生后诱导。CcO作为主要的细胞氧消耗者的作用，以及CcO 4 -2的肺特异性表达，使我们研究CcO 4 -2基因调控。我们克隆了牛、大鼠和小鼠的CcO_4 -2启动子区，并与人的启动子区进行了比较。启动子活性定位在人类启动子的118 bp近端区域内，并受到缺氧的刺激，与常氧相比，在4%氧下达到最大值（三倍）。通过诱变将CcO 4 -2氧响应性分配给一个新的启动子元件（5 '-GGACGTTCCCACG-3'），该元件位于所有四个物种中79%保守的24-bp区域内。该元件能够结合蛋白质，竞争实验表明，在该元件内，4个核心碱基5 '-TCNCA-3'是转录因子结合的必需碱基。从肺中分离的CcO表现出2.5倍增加的最大营业额相比，肝CcO。我们建议，CcO 4 -2在高氧肺和气管的表达保护这些组织的氧化损伤，通过加速电子传递链的最后一步，导致自由基形成的可用电子减少。
Subunit 4 of cytochrome c oxidase (CcO) is a nuclear-encoded regulatory subunit of the terminal complex of the mitochondrial electron transport chain. We have recently discovered an isoform of CcO 4 (CcO4-2) which is specific to lung and trachea, and is induced after birth. The role of CcO as the major cellular oxygen consumer, and the lung-specific expression of CcO4-2, led us to investigate CcO4-2 gene regulation. We cloned the CcO4-2 promoter regions of cow, rat and mouse and compared them with the human promoter. Promoter activity is localized within a 118-bp proximal region of the human promoter and is stimulated by hypoxia, reaching a maximum (threefold) under 4% oxygen compared with normoxia. CcO4-2 oxygen responsiveness was assigned by mutagenesis to a novel promoter element (5'-GGACGTTCCCACG-3') that lies within a 24-bp region that is 79% conserved in all four species. This element is able to bind protein, and competition experiments revealed that, within the element, the four core bases 5'-TCNCA-3' are obligatory for transcription factor binding. CcO isolated from lung showed a 2.5-fold increased maximal turnover compared with liver CcO. We propose that CcO4-2 expression in highly oxygenated lung and trachea protects these tissues from oxidative damage by accelerating the last step in the electron transport chain, leading to a decrease in available electrons for free radical formation.