Regulation of erythropoietin production
Regulation of erythropoietin production
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DOI：
10.1111/j.1365-2362.2005.01525.x
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发表时间：
2005-12-01
影响因子：
5.5
通讯作者：
Kurtz, A
中科院分区：
文献类型：
--
作者：
Eckardt, KU;Kurtz, A
糖蛋白激素促红细胞生成素（EPO）是红系祖细胞的必需生长和存活因子，并且红细胞产生的速率通常由血清EPO浓度决定。EPO的产生与氧的可用性呈负相关，因此建立了有效的反馈回路，其控制红细胞生成。自从重组EPO成为一种有效的治疗剂以来，在理解这种反馈控制的基础方面也取得了重大进展。EPO合成的主要决定因素是其基因在肝脏和肾脏中的转录活性，这与局部氧张力有关。这种控制是通过低氧诱导转录因子（HIF）实现的，所述HIF由组成性β亚基和两种可选的氧调节HIF α亚基（HIF-1 α和HIF-2 α）之一组成。在氧存在下（常氧），HIF α亚基被羟基化，这使它们靶向蛋白酶体降解。在缺氧条件下，由于缺乏分子氧，HIF不能被羟基化，从而被稳定。虽然HIF-1 α是通过其与EPO基因的增强子序列结合的能力而鉴定的第一个转录因子，但最近的证据表明HIF-2 α负责EPO的调节。虽然EPO是氧调节基因的一个主要例子，但HIF系统的作用远远超出EPO的调节，因为它在几乎所有细胞中广泛发挥作用，并控制对缺氧的广泛转录反应，包括参与细胞代谢，血管生成和血管张力的基因。进一步的证据表明，除了作为红细胞生成激素的作用外，EPO还在大脑中以及可能在其他器官中充当旁分泌、组织保护蛋白。
The glycoprotein hormone erythropoietin (EPO) is an essential growth and survival factor for erythroid progenitor cells, and the rate of red blood cell production is normally determined by the serum EPO concentration. EPO production is inversely related to oxygen availability, so that an effective feedback loop is established, which controls erythropoiesis. Since recombinant EPO became available as an effective therapeutic agent, significant progress has also been made in understanding the basis of this feedback control. The main determinant of EPO synthesis is the transcriptional activity of its gene in liver and kidneys, which is related to local oxygen tensions. This control is achieved by hypoxia-inducible transcription factors (HIF), consisting of a constitutive beta-subunit and one of two alternative oxygen-regulated HIF alpha subunits (HIF-1 alpha and HIF-2 alpha). In the presence of oxygen (normoxia) the HIF alpha subunits are hydroxylated, which targets them for proteasomal degradation. Under hypoxia, because of the lack of molecular oxygen, HIF cannot be hydroxylated and is thereby stabilized. Although HIF-1 alpha was the first transcription factor identified through its ability to bind to an enhancer sequence of the EPO gene, more recent evidence suggests that HIF-2 alpha is responsible for the regulation of EPO. Although EPO is a prime example for an oxygen-regulated gene, the role of the HIF system goes far beyond the regulation of EPO, because it operates widely in almost all cells and controls a broad transcriptional response to hypoxia, including genes involved in cell metabolism, angiogenesis and vascular tone. Further evidence suggests that apart from its effect as an erythropoietic hormone EPO acts as a paracrine, tissue-protective protein in the brain and possibly also in other organs.