Regulation of the human protein S gene promoter by liver enriched transcription factors
Regulation of the human protein S gene promoter by liver enriched transcription factors
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DOI：
10.1111/j.1365-2141.2006.06327.x
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发表时间：
2006-11-01
影响因子：
6.5
通讯作者：
Winship, Peter R.
中科院分区：
文献类型：
--
作者：
Hall, Adrian J.;Peake, Ian R.;Winship, Peter R.
蛋白质S在许多组织类型中表达，其中最生理相关的是肝脏。然而，蛋白S基因表达的转录控制知之甚少。我们已经表征了人蛋白S基因的5'侧翼区域中的638 bp区域，跨越了所有10个先前报道的转录起始位点，这证明了人肝源性细胞系HepG 2中的启动子活性。该区域的更精细的报告基因分析使得能够鉴定三个转录起始位点，其缺失与显著降低的启动子活性相关，以及许多正性和负性作用的转录调控元件。与这些发现一致，DNA酶I足迹分析从这638 bp区域内鉴定出11个位点（I-XI），这些位点显示出结合核蛋白的证据。我们目前的证据表明，肝脏特异性因子肝细胞核因子1（HNF 1）和HNF 4结合的蛋白S启动子，这是在确定的蛋白结合位点V和VIII，分别位于区域，和HNF 4激活蛋白S启动子。报告基因分析表明，CCAAT/增强子结合蛋白（C/EBP）家族转录因子的成员是HepG 2细胞中蛋白S基因转录的有效激活剂。
Protein S is expressed in a number of tissue types, one of the most physiologically relevant being the liver. However, transcriptional control of protein S gene expression is poorly understood. We have characterised a 638 bp area in the 5' flanking region of the human protein S gene, spanning all 10 previously reported transcription initiation sites, which demonstrates promoter activity in the human liver-derived cell line HepG2. More refined reporter gene analysis of this region enabled the identification of three transcription initiation sites whose absence is associated with significantly reduced promoter activity, together with a number of positively and negatively acting transcriptional regulatory elements. Consistent with these findings, DNaseI footprinting analysis identified eleven sites (I-XI) from within this 638 bp region that show evidence of binding nuclear proteins. We present evidence to show that the liver-specific factors hepatocyte nuclear factor 1 (HNF1) and HNF4 bind regions of the protein S promoter, which lie within the identified protein binding sites V and VIII, respectively, and that HNF4 activates the protein S promoter. Reporter gene analysis suggests that members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors are potent activators of protein S gene transcription in HepG2 cells.