Species differences in the regulation mechanisms between human and mouse carboxylesterase genes

哺乳动物羧酸酯酶(CES)是一个多基因家族，其基因产物定位于内质网。我们最近描述了人类肝脏中主要形式的CES，称为CES HU1，属于CES1家族，被认为在药物和脂质代谢中发挥重要作用。由于CES HU1的表达水平可能会影响CHUG和血脂的水平，因此了解CES HU1基因表达的调控机制是很重要的。在本研究中，我们分离了两个编码人CES HU1的CES基因，暂时命名为CES HU1a和CES HU1b。这两个基因在16号染色体上以反向重复的形式存在。除了外显子1和推测的顺式元件外，这两个基因完全相似。在人体肝脏中，CES HU1a的转录水平明显高于CES HU1b。缺失分析和凝胶迁移率改变分析结果表明，-160-54区域包含两个基因启动子。但Sp1和GEBP与CES HU1a启动子相互作用，而不与CES HU1b启动子相互作用。结果表明，这两个基因很可能起源于早期的基因复制事件，它们高度保守的结构和转录水平上的调控差异有力地证明了每种基因产物在细胞代谢中的重要作用。

Mammalian carboxylesterase (CES) comprise a multigene family, which gene products are localized in the endoplasmic reticulum. We have recently described that major forms of CES in the human liver termed CES HU1 belongs to the CES1 family and that it is thought to play an important roles in drug and lipid metabolism. Since the expression level of CES HU1 may affect the level of chugs and lipid, it is important to understand the mechanism by which CES HU1 gene expression is regulated. In this study, we isolated the two CES genes encoding human CES HU1, which were tentatively designated as CES HU1a and CES HU1b. Both genes exist in inverted duplication on chromosome 16. These genes were completely similar, except for exon 1 and putative cis elements. The transcriptional level of CES HU1a was much higher than CES HU1b in human livers. Results of deletion assays and electrophoretic mobility shift assays suggested that the region from -160 to +54 consisted of the both gene promoters. However, Sp1 and GEBP interacted with the CES HU1a promoter, but not CES HU1b promoter. It was concluded that these two genes most probably arose from an early gene duplication event and that their highly conserved structures and difference in regulation at the transcriptional level argue strongly for a significant role for each gene product in cellular metabolism.