HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation
HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation
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DOI：
10.1093/nar/27.21.4223
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发表时间：
1999-11-01
影响因子：
14.9
通讯作者：
Cairo, G
中科院分区：
文献类型：
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作者：
Bianchi, L;Tacchini, L;Cairo, G
铁螯合剂可以模拟缺氧诱导的缺氧诱导因子（HIF-1）， HIF-1通过结合缺氧反应元件（HRE）激活转录。我们研究了HIF-1是否参与转铁蛋白受体（TfR）的转录激活，TfR是一种介导细胞铁摄取的膜蛋白，以响应铁剥夺。用铁螯合剂去铁胺（DFO）处理Hep3B人肝癌细胞后，分离细胞核中TfR基因的转录率上调，HIF-1在TfR激活中的作用通过以下观察结果表明：(i)转染Hep3B细胞中荧光素酶报告基因的DFO依赖性激活是由含有推测的HRE序列的人TfR启动子片段介导的；（ii）该序列的突变阻止了荧光素酶活性的刺激；（iii）通过竞争实验和超移实验鉴定的HIF-1 α序列被DFO诱导结合。此外，在无法组装功能性HIF-1的小鼠肝癌细胞中，DFO失去了对TfR转录的诱导作用，TfR mRNA上调率降低。这些结果显示了HIF-1在铁缺乏条件下控制TfR基因表达的作用，从而深入了解了转录调控的机制，这些机制与众所周知的TfR表达的转录后控制一致，以扩大对铁缺乏的反应程度。
Treatment with iron chelators mimics hypoxic induction of the hypoxia inducible factor (HIF-1) which activates transcription by binding to hypoxia responsive elements (HRE), We investigated whether HIF-1 is involved in transcriptional activation of the transferrin receptor (TfR), a membrane protein which mediates cellular iron uptake, in response to iron deprivation, The transcription rate of the TfR gene in isolated nuclei was up-regulated by treatment of Hep3B human hepatoma cells with the iron chelator desferrioxamine (DFO), The role of HIF-1 in the activation of TfR was indicated by the following observations: (i) DFO-dependent activation of a luciferase reporter gene in transfected Hep3B cells was mediated by a fragment of the human TfR promoter containing a putative HRE sequence; (ii) mutation of this sequence prevented stimulation of luciferase activity; (iii) binding to this sequence of HIF-1 alpha identified by competition experiments and supershift assays, was induced by DFO, Furthermore, in mouse hepatoma cells unable to assemble functional HIF-1, inducibility of TfR transcription by DFO was lost and TfR mRNA up-regulation was reduced. These results, which show the role of HIF-1 in the control of TfR gene expression in conditions of iron depletion, give insights into the mechanisms of transcriptional regulation which concur with the well-characterized post-transcriptional control of TfR expression to expand the extent of response to iron deficiency.