ecome limiting is to diminish ROS production. A master regulator of oxygen homeostasis is the hypoxia inducible factor (Hif) pathway. Hif is a heterodimer composed of a constitutively expressed subunit beta also known as the aryl-hydrocarbon receptor (Arnt) with roles in several transcription pathways and the alpha subunit whose protein levels are highly regulated by oxygen and also in an oxygen-independent manner. Both subunits are members of the bHLH (basic helix-loop-helix) and PAS (PER-ARNT-SIM) domain-containing family of transcription factors; the two domains are important for DNA binding and dimerization. The alpha subunit contains an oxygen-dependent degradation (ODD) domain and N- and C-terminal activation domains within the transactivation domain (TAD). There are three alpha genes of which 1(Hif1a) and 2 (Epas1) have overlapping yet distinct functions; the 3alpha gene is not well characterized - a splice variant appears to exert inhibitory roles. Hif1a is broadly expressed while the expression of Epas1 has a more restrictive pattern. A second beta subunit Arnt2 has been identified with possibly overlapping functions. Under normoxic conditions two prolines and one asparagine in Hif1a and Epas1 are hydroxylated by prolyl and asparagyl hydroxylases, respectively. The enzymes require oxygen, iron, and 2-oxoglutarate for enzymatic activity. Of the three modifying prolyl hydrolases, Egln1 known as Phd2 appears to be essential for the hypoxic response. Os9 binds the alpha subunit and Egln1 to promote hydroxylation. The modified prolines are recognized by von Hippel-Lindau (Vhl) which interacts with Tceb1 (elongin C) to recruit a ubiquitin ligase complex and target the alpha subunit for proteosomal degradation The interaction of Vhl with the hydroxylated alpha subunit is three orders of magnitude tighter than the one with the non-hydroxylated protein. Sat2 interacts with the alpha subunit, Vhl and Tceb1 to stabilize Vhl-Tceb1 interaction and promote ubiquitination. The hydroxylated asparagine on the other hand, blocks the interaction of alpha subunit with transcriptional activators such as Ep300 and Crebbp. In an oxygen-independent manner, Gnb2l1 (Rack1) interacts with alpha subunit and Tceb1 and can substitute for Vhl in promoting ubiquitination; the interaction is stabilized by Sat1. While hydroxylation of key residues is a major regulatory mechanism, the alpha subunit is subject to diverse post-translational modification as well as control by non-coding RNAs such as micro- and anti-sense RNAs. Under hypoxic conditions the hydroxylase activity is reduced and the stability of the Hif alpha is increased, the protein can now translocate to the nucleus to interact with the beta subunit and regulate the expression of many genes. Besides Ep300 and Crebbp, other co-activators are believed to play a role; the repression of genes is believed to be due to expression of transcriptional repressors and microRNA. Target genes are involved in glucose and energy homeostasis, iron homeostasis, erythropoiesis and angiogenesis, among others. To see the ontology report for annotations, GViewer and download, click here...(less)