Applied cell biology of novel functions of erythropoietin.

促红细胞生成素（EPO）是一种由肾脏以氧依赖的方式产生的糖蛋白；缺氧会显著激活EPO的产生。EPO被认为只作用于红细胞前体细胞，刺激红细胞的形成。然而，我们发现EPO在组织特异性调节EPO产生的其他位点产生，EPO在这些位点表现出意想不到的新生理功能，总结如下1。EPO是在中枢神经系统产生的。脑EPO作用于神经元中表达的EPO受体，防止神经元缺血损伤。促红细胞生成素的产生是缺氧诱导的，因为它在肾脏中。EPO也在女性生殖器官（子宫和输卵管）中产生。子宫促生成素刺激子宫血管生成，在动情周期周期性发生，但促生成素的输卵管功能仍有待研究。雌激素是两个器官中促生成素的主要诱导剂，尽管氧也有助于调节促生成素的产生。有趣的是，子宫中EPO基因表达的缺氧激活需要雌激素的存在。氧气供应是培养动物细胞生产有用蛋白质的主要问题之一，因此设计一种在低氧浓度下保持或提高重组蛋白高产率的系统是很重要的。在动物细胞中发现了许多缺氧诱导基因。在这些基因中存在一个负责缺氧激活的一致序列（HRE=缺氧反应增强子）。我们提供了一种新的系统，即使在低氧浓度下，通过使用基于缺氧诱导基因转录的生物学策略，也能保证高生产力。

Erythropoietin (EPO) is a glycoprotein produced by the kidney in an oxygen-dependent manner; hypoxia activates EPO production dramatically. EPO has been believed to act exclusively on erythroid precursor cells, stimulating red blood cell formation. However, we found that EPO is produced in other sites where EPO production is regulated in tissue-specific manner and that EPO manifests unexpected new physiological functions in these sites as summarized below.1.EPO is produced in the central nervous system. The brain EPO acts on EPO receptor expressed in neurons, preventing the neuronal damage from ischemic insult. EPO production is hypoxia-inducible as it is in the kidney.2.EPO is also produced in female reproductive organs (uterus and oviduct). The uterine EPO stimulates uterine angiogenesis that occurs periodically in the estrous cycle but the oviductal function of EPO remains to be studied. Estrogen is a major inducer of EPO in both organs, although oxygen also contributes the regulation of EPO production. Interestingly, the hypoxic activation of the EPO gene expression in the uterus requires the presence of estrogen.3.Oxygen supply is one of the major problems in the production of useful proteins by cultured animal cells and therefore it is of importance to devise a system by which a high productivity of recombinant proteins can be maintained or enhanced under low oxygen concentrations. A number of hypoxia-inducible genes have been found in animal cells. A consensus sequence (HRE=hypoxia-response enhancer) responsible for the hypoxic activation exists in these genes. We provided a novel system which guarantees a high productivity even under low oxygen concentrations by the use of the biological strategy based on the hypoxic induction of gene transcription.