REGULATION OF HYPOXIA RESPONSE GENES BY NEW TRANSCRIPTION FACTOR

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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.