REGULATION OF HYPOXIA RESPONSE GENES BY NEW TRANSCRIPTION FACTOR

缺氧诱导因子（I-HF-1）的活化及其与缺氧反应元件（I-IRE）的结合调节生物体的缺氧反应，该元件存在于各种缺氧氧反应基因的转录调控区。我们发现，一氧化氮（NO），这是在生活中产生的，除了缺氧反应上调血管内皮生长因子（VEGF）基因表达的机制与缺氧相同。进一步阐明了新的转录因子与缺氧或NO诱导的缺氧反应基因启动子区I-IRE下游的HIF-1辅助排列（HAS）结合，结合蛋白分子量分别为100 Kd和45 Kd。通过从HeLa细胞cDNA文库中克隆HAS结合蛋白，鉴定出核酸酶敏感元件结合蛋白和STATX抑制蛋白两个克隆。最近的研究表明，在常氧条件下，HIF-1脯氨酰羟化酶（I-HF-PH）调节HIF-1的降解。缺氧条件下，由于氧是HIF-PH反应的辅助因子，HIF-PH活性受到抑制。同样清楚的是，铁离子作为酶反应的辅因子是必需的。我们阐明了NO通过形成亚硝酰铁络合物来抑制HTF-PH的酶促反应。本研究通过对低氧和NO诱导的HIF-1表达的研究，阐明了低氧和NO诱导HIF-1表达的不同机制。

The hypoxia response of a living body regulated by the activation of hypoxia inducible factor (I-HF-1), and its binding to hypoxia response element (I-IRE) which exists in the transcriptionally regulatory region of various hypoxia oxygen response genes. We found that nitric oxide (NO) which is generated in the living body in addition to hypoxic response up-regulate vascular endothelial growth factor (VEGF) gene expression by the same mechanism as hypoxia. Furthermore, we clarified that new transcriptional factor bind to HIF-1 ancillary arrangement (HAS) which is located in the lower stream of I-IRE existed in promoter region of the hypoxia response genes by hypoxia or NO. The binding proteins had the molecular weight of 100Kd and 45Kd. By molecular cloning of HAS binding protein from HeLa cell cDNA library, we identified two clones which are nuclease sensitive element binding protein and protein inhibitor of activated STAT X. Recently, it has shown that HIF-1 proryl hydroxylase (I-HF-PH) regulated HIF-1 degradation under normoxic condition. Under hypoxic condition, HIF-PH activity was inhibited because oxygen is a cofactor of HIF-PH reaction. It is also clear that the iron ion is required as cofactor of the enzyme reaction. We clarified that NO inhibits enzymatic reaction of HTF-PH by forming a nitrosyl iron complex. In this study, we demonstrated that different mechanism of the activation of HIF-1 by low oxygen and NO.