Role of hepatocyte nuclear factor 3γ in the expression of human CYP2C genes
Role of hepatocyte nuclear factor 3γ in the expression of human CYP2C genes
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DOI：
10.1016/j.abb.2004.03.032
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发表时间：
2004-06-01
影响因子：
3.9
通讯作者：
Jover, R
中科院分区：
文献类型：
--
作者：
Bort, R;Gómez-Lechón, MJ;Jover, R
肝细胞核因子3gamma（HNF-3gamma）是维持特定肝功能的重要转录因子。然而，其与人类细胞色素 P450 (CYP) 基因表达的相关性尚未被探索。可以在人 CYP2C 5' 侧翼区域中鉴定出几个 HNF3 推定结合位点。使用近端启动子的基因报告实验表明，HNF-3gamma 反式激活 CYP2C8、CYP2C9 和 CYP2C19（分别为 25、4 和 4 倍），但它不会反式激活 CYP2C18。然而，通过重组腺病毒在肝癌细胞中过表达 HNF-3gamma 会诱导 CYP2C9、CYP2C18 和 CYP2C19 mRNA（分别是 4.5 倍、20 倍和 50 倍），但不会激活内源性 CYP2C8。 HNF-3gamma 对内源性 CYP2C8 缺乏影响可以通过用脱乙酰酶抑制剂曲古抑菌 A 处理细胞来逆转，这表明该基因中功能性 HNF3 元件周围存在染色质浓缩。我们得出结论，HNF3gamma 是人类 CYP2C 基因肝脏特异性表达的重要转录因子。我们的结果还证明，有效的转染工具（例如腺病毒载体）对于评估转录因子对染色质组织基因的作用可能具有决定性作用。 (C) 2004 Elsevier Inc. 保留所有权利。
Hepatocyte nuclear factor 3gamma (HNF-3gamma) is an important transcription factor for the maintenance of specific liver functions. However, its relevance in the expression of human cytochrome P450 (CYP) genes has not yet been explored. Several HNF3 putative binding sites can be identified in human CYP2C 5'-flanking regions. Gene reporter experiments with proximal promoters revealed that HNF-3gamma transactivated CYP2C8, CYP2C9, and CYP2C19 (25-, 4-, and 4-fold, respectively), but it did not transactivate CYP2C18. However, overexpression of HNF-3gamma in hepatoma cells by means of a recombinant adenovirus induced CYP2C9, CYP2C18, and CYP2C19 mRNA (4.5-, 20-, and 50-fold, respectively) but did not activate endogenous CYP2C8. The lack of effect of HNF-3gamma on endogenous CYP2C8 could be reversed by treating cells with the deacetylase inhibitor, trichostatin A, suggesting the existence of chromatin condensation around functional HNF3 elements in this gene. We conclude that HNF3gamma is an important transcription factor for the hepatic-specific expression of human CYP2C genes. Our results also evidence that efficient transfection tools, such as adenoviral vectors, may be decisive for assessing the role of transcription factor on chromatin organized genes. (C) 2004 Elsevier Inc. All rights reserved.