Regulatory mechanisms for liver-selective transcription of genes for ornithine cycle enzymes

为了阐明组织特异性转录的控制机制，我们研究了肝脏特异性表达鸟氨酸循环酶基因的调控区域。乍一看，精氨酸酶（周期的最后一种酶）的启动子受到类固醇受体超家族COUP-TF的普遍成员的刺激，而它受到肝脏选择性成员HNF-4的抑制。一种诱人的推测是，HNF-4参与了精氨酸酶基因的抑制，特别是在小肠和肾脏等组织中，HNF-4表达而精氨酸酶不表达。在这里，我研究了精氨酸酶启动子中的一个COUP-TF/ hnf -4响应元件。利用肝癌细胞系HepG2的瞬时转染系统，在转录起始位点- 50bp附近的区域鉴定出一个coup - tf响应元件。然而，该区域不与COUP-TF和HNF-4结合。另一方面，该区域确实与C/EBP家族成员结合，并作为成员激活启动子的元件发挥作用。一种可能性是，COUP-TF和HNF-4通过与C/EBPbeta等因子相互作用调节精氨酸酶启动子，而不直接与精氨酸酶启动子结合。

To clarify control mechanisms of tissue-specific transcription, we have investigated regulatory regions of genes for ornithine cycle enzymens that are expressed liver-specifically. Peculiarly at a glance, the promoter of arginase, the last enzyme of the cycle, was stimulated by a ubiquitous member of the steroid receptor superfamily COUP-TF,while it was repressed by a liver-selective member HNF-4. A tempting speculation is that HNF-4 is involved in repression of the arginase gene specifically in tissues such as the small intestine and kidney where HNF-4 is expressed but arginase is not expressed. Here, I investigated a COUP-TF/HNF-4-responsive element(s) in the arginase promoter. Using transient transfection system with a hepatoma cell line HepG2, a COUP-TF-responsive element was identified in the region around the position -50 bp of the trascription start site. However, this region did not bind with COUP-TF nor HNF-4.On the other hand, this region did bind with members of the C/EBP family, and functioned as an element responsible for activation of the promoter by the members. One posibility is that COUP-TF and HNF-4 regulate the arginase promoter through interaction with factors such as C/EBPbeta without directly binding to the arginase promoter.