缺氧诱导因子:细节决定成败。第二部分:HIF-2HIF-2

G. A. Ignatenko, N. Bondarenko, A. Dubovaya, T. S. Ignatenko, Ya. S. Valigun, E. A. Belyaeva, V. G. Gavrilyak
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摘要

本综述介绍了缺氧诱导因子-2(HIF-2)在生理组织缺氧和病理缺氧条件下的作用。文章介绍了 HIF-2 亚基(HIF-2α 和 HIF-β)的结构和功能特征,以及在正常缺氧和缺氧条件下调节它们的方法。表达 HIF-2α 的细胞种类繁多:血管内皮细胞、肾成纤维细胞、肝细胞、胰腺间质细胞(端细胞)、肠粘膜上皮细胞、II 型肺泡细胞、神经胶质细胞、神经嵴细胞的衍生物(肾上腺嗜铬细胞)。依赖于 HIF-2α 的转录效应具有高度的位点特异性,仅在特定情况下才会发生。两类调节分子(RNA 结合蛋白和 mR-NAs)可通过与特定靶标 mRNA 的 3' 或 5' 非翻译区(3' 或 5' UTR)结合而改变翻译速率,从而实现对 HIF-2α 翻译的调节。HIF-2α 的活性主要在翻译后水平上受到 mRNA 表达、mRNA 翻译、蛋白质稳定性和转录活性水平上各种信号机制的调控。在常氧条件下,HIF-2α 活性的规范调控由依赖氧的机制决定,而在缺氧条件下,则由非规范(不依赖氧)机制决定,通过磷酸化、SUMOlyated、乙酰化、甲基化等,产生积极和消极的影响。目前已经确定,HIF 影响着影响胚胎发育、新陈代谢、炎症和功能系统生理的信号通路,还在慢性缺氧的长期反应中起作用,在此期间,它调节血管生成、葡萄糖、铁、脂代谢、细胞周期、转移和其他过程。研究细胞内 HIF-2α 含量的变化和 HIF-2 的转录活性,将使我们能够开发出有效的方法来纠正伴随全身和局部缺氧的各种疾病。
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Hypoxia-inducible factors: details create a picture. Part II. HIF-2
This review presents current information on the role of hypoxia-inducible factor-2 (HIF-2) under conditions of physiological tissue hypoxia and pathological hypoxic conditions. The structural and functional features of HIF-2 subunits (HIF-2α and HIF-β) and methods of their regulation under conditions of normoxia and hypoxia are described. The spectrum of cells expressing HIF-2α is quite diverse: endothelial cells of blood vessels, kidney fibroblasts, hepatocytes, interstitial cells (telocytes) of the pancreas, epithelial cells lining the intestinal mucosa, type II alveolocytes, glial cells, derivatives of neural crest cells (chromaffinocytes of the adrenal gland). HIF-2α -dependent transcriptional effects are highly locus specific and occur only under certain circumstances. Regulation of HIF-2α translation can be accomplished by two classes of regulatory molecules (RNA-binding proteins and mR-NAs) by altering the rate of translation due to binding to the 3' or 5' untranslated region of mRNA (3' or 5' UTR) of specific targets. HIF-2α activity is regulated primarily at the post-translational level by various signaling mechanisms at the level of mRNA expression, mRNA translation, protein stability, and transcriptional activity. Under normoxia, the canonical regulation of HIF-2α activity is determined by oxygen-dependent mechanisms, and under hypoxia conditions - by non-canonical (oxygen-independent) mechanisms, through phosphorylation, SUMOlyated, acetylation, methylation, etc., causing positive and negative effects. It has been established that HIF influences signaling pathways affecting embryonic development, metabolism, inflammation and the physiology of functional systems, and also works in long-term responses to chronic hypoxia, during which it regulates angiogenesis, glucose, iron, lipid metabolism, cell cycle, metastasis and other processes. Studying changes in the intracellular content of HIF-2α and the transcriptional activity of HIF-2 will allow us to develop effective methods for correcting various diseases accompanied by systemic and local oxygen deficiency.
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