核呼吸因子1调控HIF-1α表达对细胞低氧适应的影响

低氧是许多疾病共有的病理过程，也是特殊环境最常见的医学问题之一。核呼吸因子1（NRF-1）是调控线粒体呼吸链蛋白表达的核转录因子，最新研究显示在二千余种基因的启动子区含有NRF-1结合共有序列，提示NRF-1有更多的潜在功能。低氧诱导因子1（HIF-1）是研究低氧适应最受关注的热点，但是对HIF-1α转录水平调控的了解还非常有限。我们前期研究在HEK293T细胞中首次发现NRF-1功能性结合于人HIF-1α基因5'-调控区，对HIF-1α基因表达具有负调控作用。低氧对正常组织细胞和肿瘤细胞的NRF-1具有不同影响，且NRF-1蛋白水平与HIF-1α mRNA 水平负相关。故本项目拟系统研究NRF-1对HIF-1α基因表达的调控作用，探讨该调控作用对细胞低氧适应的影响。该研究将提出细胞低氧适应的新机制，并为研究正常与肿瘤细胞在低氧适应中的不同反应提供新的切入点。

Hypoxia is a common pathological process for mamy diseases, and one of the most frequent medical problem in specific environment. The nuclear respiratory factor-1 (NRF-1)serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits.Recent research identified the existence of the NRF-1 binding consensus sequence in the proximal promoter regions of more than two thousand genes, suggesting more potential function of NRF-1 might be discovered. Hypoxia-inducible factor 1 (HIF-1), a most important transcription factor regulating more than one hundred target genes under hypoxic conditon, has long been a research focus to study hypoxic adaptation.However,the regulation of HIF-1α in transcriptional level has not been fully elucidated. We first discovered the functional binding sites in the 5'-regulator region of HIF-1α and the negtive regulation of HIF-1α by NRF-1 in HEK293T cell line. We also observed the different expression of NRF-1 between normal tissue and carcinoma cells under hypoxia, which negtively correlated to HIF-1α mRNA levels. The project will focus on the regulation of HIF-1α expression by NRF-1 and the effect on cellular adaptation to hypoxia. This work will suggest a novel mechanism for hypoxic adaptation,supplying a new suitable solution to study the various response to hypoxia between normal and cancer cells.