Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2.
Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2.
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DOI：
10.1093/nar/gks1454
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发表时间：
2013-02-01
影响因子：
14.9
通讯作者：
Grossman LI
中科院分区：
文献类型：
--
作者：
Aras S;Pak O;Sommer N;Finley R Jr;Hüttemann M;Weissmann N;Grossman LI
细胞色素c氧化酶（考克斯）是电子传递链的末端酶，由线粒体和核DNA编码的13个亚基组成。亚基4（COX 4）是一种关键的调节亚基，以两种亚型存在，即普遍存在的亚型1和组织特异性（主要是肺）亚型2（COX 4 I2）。与缺乏COX 4 I2的肝脏考克斯相比，COX 4 I2使肺考克斯的活性高约2倍。我们以前确定了一个高度保守的13-bp序列的近端启动子的COX 4 I2的功能作为一个氧响应元件（ORE），最大活性在4%的氧浓度。在此，我们已经确定了三个转录因子，即重组信号序列结合蛋白Jκ（RBPJ），卷曲螺旋结构域2（CHCHD 2）和CXXC指蛋白5（CXXC 5）。我们证明RBPJ和CHCHD 2在4%的氧气下激活ORE，而CXXC 5作为抑制剂发挥作用。为了验证来自培养细胞的结果，我们使用RNA干扰显示了这些转录因子在原代肺动脉平滑肌细胞中COX 4 I2基因调控中的类似作用。依赖于氧张力，三个转录因子的协同作用调节COX 4 I 2的表达，正如我们所讨论的，可以增强考克斯活性及其科普细胞能量需求变化的能力。
Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain, made up of 13 subunits encoded by both mitochondrial and nuclear DNA. Subunit 4 (COX4), a key regulatory subunit, exists as two isoforms, the ubiquitous isoform 1 and the tissue-specific (predominantly lung) isoform 2 (COX4I2). COX4I2 renders lung COX about 2-fold more active compared with liver COX, which lacks COX4I2. We previously identified a highly conserved 13-bp sequence in the proximal promoter of COX4I2 that functions as an oxygen responsive element (ORE), maximally active at a 4% oxygen concentration. Here, we have identified three transcription factors that bind this conserved ORE, namely recombination signal sequence–binding protein Jκ (RBPJ), coiled-coil-helix-coiled-coil-helix domain 2 (CHCHD2) and CXXC finger protein 5 (CXXC5). We demonstrate that RBPJ and CHCHD2 function towards activating the ORE at 4% oxygen, whereas CXXC5 functions as an inhibitor. To validate results derived from cultured cells, we show using RNA interference a similar effect of these transcription factors in the gene regulation of COX4I2 in primary pulmonary arterial smooth muscle cells. Depending on the oxygen tension, a concerted action of the three transcription factors regulates the expression of COX4I2 that, as we discuss, could augment both COX activity and its ability to cope with altered cellular energy requirements.
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