Preferred Label : Hypoxia-Inducible Factor Pathway;
CISMeF synonym : HIF pathway;
NCIt related terms : Hypoxia-Inducible Factor in the Cardiovascular System;
Alternative definition : BIOCARTA: Hypoxia (or low O2 levels) affects various pathologies. First, tissue ischemia,
a variation in O2 tension caused by hypoxia/reoxygenation, can lead to endothelial
cell changes. For example, long periods of ischemia result in endothelial changes,
such as vascular leakage, resulting in varicose veins. In more severe situations,
ischemia can lead to myocardial or cerebral infarction and retinal vessel occlusion.
Of interest, HIF-1 is stabilized prior to induction of vascular endothelial growth
factor (VEGF) expression during acute ischemia in the human heart. Second, pulmonary
hypertension associated with chronic respiratory disorders results from persistent
vasoconstriction and vascular remodeling. Third, hypoxic gradients created in enlarging
solid tumors trigger expression of genes containing hypoxia response elements (HREs)
such as those involved in angiogenesis. This allows subsequent delivery of O2, nutrients,
and further tumor growth. Vascular remodeling is an important component to tumorigenesis;
without proper blood supply, delivery of oxygen may occur by diffusion, but becomes
inefficient in tumors greater than 1 mm in diameter. Short-term hypoxia can also elevate
platelet numbers, while prolonged exposure may cause some degree of thrombocytopenia
in response to increased levels of erythropoietin (EPO). Another disorder involving
inadequate responses to hypoxia is preeclampsia, a pathology of pregnancy thought
to be caused by improper differentiation of placental trophoblast cells due to poorly
controlled O2 tension or improper hypoxia-inducible factor (HIF)-mediated responses.
The primary molecular mechanism of gene activation during hypoxia is through HIF-1.
Several genes involved in cellular differentiation are directly or indirectly regulated
by hypoxia. These include EPO, LDH-A, ET-1, transferrin, transferrin receptor, VEGF,
Flk-1, Flt-1, platelet-derived growth factor-beta (PDGF-b), basic fibroblast growth
factor (bFGF), and others genes affecting glycolysis. HIF-1 is a member of the basic
helix-loop-helix (bHLH)-PAS family of transcription factors known to induce gene expression
by binding to a 50-bp HRE containing a core 5'-ACGTG-3' sequence. bHLH-PAS proteins
heterodimerize to form transcription complexes that regulate O2 homeostasis, circadian
rhythms, neurogenesis, and toxin metabolism. Three bHLH-PAS proteins in vertebrates
respond to hypoxia: HIF-1, EPAS (HIF-2), and HIF-3. These dimerize with ARNT (aryl
hydrocarbon receptor nuclear translocator protein), ARNT-2, or ARNT-3. HIF-1 is ubiquitinated
and subsequently degraded in less than 5 minutes under normoxic conditions. Although
several candidate O2-sensing molecules have emerged in the literature, the molecular
basis of how cells sense O2 levels is poorly characterized. pVHL, the protein product
of a tumor-suppressor gene responsible for von Hippel Lindau disease, is implicated
in this O2-sensing system by its association with HIF-1, targeting it for ubiquitin-mediated
degradation. Similarly, F-box-containing proteins recognize substrates of the ubiquitin
ligases, targeting them for phosphorylation-dependent ubiquitination and proteasomal
degradation. In addition to F-boxes, most of these proteins also contain a WD40 or
a leucine-rich repeat (LLR) domain that presumably functions as a Ser/Thr binding
module. A second family of proteins assisting the ubiquitin ligases share a region
designated SOCS-box (originally from the suppressor of cytokine signaling proteins
SOCS). Under low O2 ( 5% O2) HIF-1 is stabilized leading to the formation of a functional
transcription factor complex with ARNT. This complex is the master regulator of O2
homeostasis and induces a network of genes involved in angiogenesis, erythropoiesis,
and glucose metabolism. (This definition may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_hifPathway;
Origin ID : C39105;
UMLS CUI : C1512574;
- Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element