id: PW:0000360
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000360
title: hypoxia inducible factor pathway
description: Maintaining adequate levels of oxygen is crucial for the proper functioning of cells and
  tissues as either excess or deficiency of oxygen can have profound pathological consequences. Oxygen
  is the terminal electron acceptor of the respiratory chain - the electron transport pathway (ETC) whose
  resulting electrochemical proton gradient drives the synthesis of ATP. ETC also produces reactive oxygen
  species (ROS) and it is thought that the switch to glycolysis for ATP production when oxygen levels
  become 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.
diagram_image: https://rgd.mcw.edu/pathway/PW0000360/hypoxia%20inducible%20factor%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000360/hypoxia%20inducible%20factor%20pathway/hypoxia%20inducible%20factor%20pathway.gpp
diagram_pathway_links: []
diagram_gene_links:
- id: RGD:2153
  label: Arnt
- id: RGD:2154
  label: Arnt2
- id: RGD:2401
  label: Crebbp
- id: RGD:631375
  label: Egln1
- id: RGD:631376
  label: Egln2
- id: RGD:71019
  label: Egln3
- id: RGD:620036
  label: EP300
- id: RGD:68404
  label: Epas1
- id: RGD:69229
  label: Gnb2l1
- id: RGD:61928
  label: Hif1a+O2
- id: RGD:1308281
  label: Hif1an
- id: RGD:70332
  label: Hif3a
- id: RGD:1359574
  label: Os9
- id: RGD:1586174
  label: Sat1
- id: RGD:1307869
  label: Sat2
- id: RGD:620658
  label: Tceb1
- id: RGD:3960
  label: Vhl
diagram_chemicals: []
diagram_edges:
- source: Egln1
  relation: associated_with
  target: Os9
- source: Egln1
  relation: positively_affects
  target: Hif1a+O2
- source: Gnb2l1
  relation: associated_with
  target: Hif1a+O2
- source: Gnb2l1
  relation: associated_with
  target: Sat1
- source: Gnb2l1
  relation: associated_with
  target: Tceb1
- source: Hif1a+O2
  relation: associated_with
  target: Os9
- source: Hif1a+O2
  relation: associated_with
  target: Sat1
- source: Hif1a+O2
  relation: associated_with
  target: Sat2
- source: Hif1a+O2
  relation: associated_with
  target: Vhl
- source: Hif1a+O2
  relation: negatively_affects
  target: Crebbp
- source: Hif1a+O2
  relation: negatively_affects
  target: EP300
- source: Hif1a-O2
  relation: positively_affects
  target: Hif target genes
- source: Hif1an
  relation: positively_affects
  target: Hif1a+O2
- source: Sat2
  relation: associated_with
  target: Tceb1
- source: Sat2
  relation: associated_with
  target: Vhl
- source: Tceb1
  relation: associated_with
  target: Tceb1 recruited complex
- source: Tceb1
  relation: associated_with
  target: Vhl
diagram_labels:
- Hif-alpha ubiquitination, proteasomal degradation
- N-OH
- P-OH
diagram_other_links:
- href: /wg/home/pathway2/molecular-pathways2/hif-target-genes
  label: Hif target genes
- href: /wg/home/pathway2/molecular-pathways2/tceb1-recruited-complex
  label: Tceb1 recruited complex
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