REGULATION OF THE ERYTHROPOIETIN GENE - EVIDENCE THAT THE OXYGEN SENSOR IS A HEME PROTEIN
REGULATION OF THE ERYTHROPOIETIN GENE - EVIDENCE THAT THE OXYGEN SENSOR IS A HEME PROTEIN
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DOI：
10.1126/science.2849206
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发表时间：
1988-12-09
期刊：
影响因子：
56.9
通讯作者：
BUNN, HF
中科院分区：
文献类型：
--
作者：
GOLDBERG, MA;DUNNING, SP;BUNN, HF
促红细胞生成素（Epo）是一种刺激红细胞生成的激素，在肾脏和肝脏中合成以应对缺氧。人肝癌细胞系Hep3B以生理方式调节其Epo的产生。无论是缺氧还是氯化钴都能显著增加Epo mRNA的表达以及具有生物学活性和免疫学特性的Epo蛋白的产生。新的蛋白质的合成是必需的，然后才能诱导缺氧或钴诱导的Epo mRNA水平的增加。低氧、氯化钴和氯化镍似乎通过共同的途径刺激Epo产生。一氧化碳在低氧分压下抑制Epo产生提供了血红素蛋白整体参与氧传感机制的证据。这一假说进一步支持的发现，当血红素合成被阻断，缺氧，钴，镍诱导的Epo生产都显着抑制。提出了一种模型，其中血红素蛋白中的配体依赖性构象变化占缺氧以及钴和镍刺激Epo产生的机制。
Erythropoietin (Epo), the hormone that stimultes red blood cell production, is synthesized in the kidney and liver in response to hypoxia. The human hepatoma cell line Hep3B regulates its production of Epo in a physiologic manner. Either hypoxia or cobalt choloride markedly increases expression of Epo mRNA as well as production of biologically active and immunologically distinct Epo protien. New protein synthesis is required before the induction of increased levels of hypoxia- or cobalt-induced Epo mRNA. Hypoxia, cobalt chloride, and nickel chloride appear to stimulate Epo production through a common pathway. The inhibition of Epo production at low partial pressures of oxygen by carbon monoxide provides evidence that a heme protein is integrally involved in the oxygen-sensing mechanism. This hypothesis is further supported by the finding that when heme synthesis is blocked, hypoxia-, cobalt-, and nickel-induced Epo production are all markedly inhibited. A model is proposed in which a ligand-dependent conformational change in a heme protein accounts for the mechanism by which hypoxia as well as cobalt and nickel stimulate the production of Epo.