Hypoxia-inducible factors: details create a picture. Part II. HIF-2

Abstract

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.