Cloning and characterization of the rat cytochrome P450 4F5 (CYP4F5) gene.
Cloning and characterization of the rat cytochrome P450 4F5 (CYP4F5) gene.
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大鼠细胞色素 P450 4F5 (CYP4F5) 基因的克隆和表征。
DOI：
10.1016/s0378-1119(02)00885-5
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发表时间：
2002
期刊：
影响因子：
3.5
通讯作者：
Strobel,HenryW
中科院分区：
文献类型：
--
作者：
Cui,Xiaoming;Strobel,HenryW
细胞色素P450 4F是代谢花生四烯酸衍生物（例如脂氧素、前列腺素、羟基二十碳四烯酸，最重要的是，白三烯B4，一种参与白细胞吸引和血管渗透性调节的炎症介质）所需的。CYP 4F 5是大鼠4F亚家族成员之一，在肝、肾和脑中表达。为了了解CYP 4F 5的基因调控机制，分离并表征了CYP 4F 5的基因组克隆。CYP 4F 5基因全长15.5kb，由13个外显子组成，长度为54 ~ 964 bp。内含子-外显子连接的位置与人类4F基因的位置相似。转录起始位点通过5′快速扩增与RNA互补的DNA（cDNA）末端-聚合酶链反应确定，并且位于最初由Kawashima和Strobel（Biochem.Biophys.Biophys.2002）鉴定的cDNA的第一个核苷酸的上游10 bp。Res. Commun. 217（1995）1137），得到了83 bp的5′端非翻译区。对4kb的5′侧翼区进行测序，并利用TRANSFAC程序分析潜在的转录因子结合位点。未观察到TATA盒，但鉴定出CCAAT盒，CCAAT盒两侧各有一个Sp1位点。在4kb的分析区域内，未发现过氧化物酶体聚合物激活受体（peroxisomepoliferator-activatedreceptor）的结合位点，也发现了核受体维甲酸受体（retinoicacidreceptor）、维甲酸X受体（retinoicacidXreceptor）、肝细胞核因子3（hepatocellularnuclearfactor 3）、糖皮质激素受体（glucocorticoidreceptor）、核因子κB和激活蛋白1（activatorprotein 1）的可能结合位点。转染CYP 4F 5/荧光素酶报告基因5′侧翼区的缺失构建体，鉴定侧翼区的前134 bp含有CYP 4F 5基因组成型表达所必需的启动子序列。还鉴定了两个负调控区域。这些研究为深入了解CYP 4F亚家族基因调控机制提供了新的思路。
Cytochrome P450 4Fs are required for metabolizing arachidonic acid derivatives such as lipoxins, prostaglandins, hydroxyeicosatetraenoic acids and, most importantly, leukotriene B4, an inflammatory mediator involved in leukocyte attraction and blood vessel permeability regulation. CYP4F5 is one of the rat 4F subfamily members expressed in liver, kidney and brain. To understand the mechanism of gene regulation of CYP4F5, genomic clones for CYP4F5 were isolated and characterized. The gene organization reveals that CYP4F5 gene spans 15.5 kb, and contains 13 exons ranging from 54 to 964 bp. The positions of intron-exon junctions are similar to those of human 4F genes. The transcription start site was determined by 5′ rapid amplification of DNA complementary to RNA (cDNA) end-polymerase chain reaction, and is located 10 bp upstream of the first nucleotide of cDNA identified originally by Kawashima and Strobel (Biochem. Biophys. Res. Commun. 217 (1995) 1137), and results in 83 bp of 5′ untranslated region. The 4 kb 5′ flanking region was sequenced and analyzed using TRANSFAC program for potential transcription factor binding sites. No TATA box was observed, but a CCAAT box was identified, and one Sp1 site is located on each side of the CCAAT box. The elements likely for nuclear receptors retinoic acid receptor, retinoic acid X receptor, hepatocyte nuclear factor-3, glucocorticoid receptor, nuclear factor-κB and activator protein-1 were also found. However no binding site for peroxisome poliferator-activated receptor was present in the 4 kb region analyzed. Transfection of deletion constructs of the 5′ flanking region of CYP4F5/luciferase reporter gene identified that the first 134 bp of flanking region contained essential promoter sequences for constitutive expression of the CYP4F5 gene. Two negative regulatory regions were also identified. These studies provide insight into the mechanism of CYP4F subfamily gene regulation.
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