Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction.
Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction.
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DOI：
10.1182/blood.v82.12.3610.bloodjournal82123610
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发表时间：
1993-12
期刊：
影响因子：
20.3
通讯作者：
Guang-lei Wang;G. Semenza
中科院分区：
文献类型：
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作者：
Guang-lei Wang;G. Semenza
促红细胞生成素（EPO）基因转录在体内肾细胞和暴露于缺氧或氯化钴的Hep 3B细胞中被激活。缺氧诱导因子1（HIF-1）是一种核因子，其在转录激活所需的位点与EPO基因的缺氧诱导增强子结合。缺氧或氯化钴处理Hep 3B细胞可诱导HIF-1 DNA结合活性。我们报告说，去铁胺（DFX）治疗的Hep 3B细胞诱导HIF-1活性和EPO RNA表达的动力学类似的诱导HIF-1缺氧或氯化钴。这些刺激的诱导抑制放线菌酮，表明从头蛋白质合成的要求。DFX似乎通过螯合铁诱导HIF-1，因为硫酸亚铁铵的共同给药抑制了诱导。对小鼠施用DFX瞬时增加了肾脏中的EPO RNA水平。如前所述，缺氧和钴治疗，DFX也诱导HIF-1活性在非EPO生产细胞，表明存在一个共同的缺氧信号转导途径，导致HIF-1诱导在不同的细胞类型。
Erythropoietin (EPO) gene transcription is activated in kidney cells in vivo and in Hep3B cells exposed to hypoxia or cobalt chloride. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor that binds to the hypoxia-inducible enhancer of the EPO gene at a site that is required for transcriptional activation. HIF-1 DNA-binding activity is induced by hypoxia or cobalt chloride treatment of Hep3B cells. We report that treatment of Hep3B cells with desferrioxamine (DFX) induced HIF-1 activity and EPO RNA expression with kinetics similar to the induction of HIF-1 by hypoxia or cobalt chloride. Induction by each of these stimuli was inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. DFX appears to induce HIF-1 by chelating iron as induction was inhibited by coadministration of ferrous ammonium sulfate. DFX administration to mice transiently increased EPO RNA levels in the kidney. As previously shown for hypoxia and cobalt treatment, DFX also induced HIF-1 activity in non-EPO-producing cells, suggesting the existence of a common hypoxia signal-transduction pathway leading to HIF-1 induction in different cell types.