Hif Transcription Factors Proteins


 Creative BioMart Hif Transcription Factors Proteins Product List
 Hif Transcription Factors Proteins Background

The primary transcriptional regulator of both cellular and systemic hypoxic responses is the heterodimeric transcription factor hypoxia inducible factor (HIF). HIF heterodimers consist of an alpha subunit (HIFα) and a beta subunit (HIFβ also known as ARNT [aryl hydrocarbon nuclear translocator]). Both subunits contain basic helix-loop-helix (bHLH) and PER-ARNT-SIM homology (PAS) domains that mediate dimerization. HIF dimerization is essential for HIF transcriptional activity.
The HIF protein family is complex in that three genes encode HIFα subunits (HIF-lα, -2α, and -3α) and three genes encode HIFβ subunits (ARNT/HIF-1β, ARNT2, and ARNT3). However, not all family members are involved in activating transcription in the response to hypoxia and dimerization between different subunits can be limited by expression. Of the different β subunits, only ARNT and ARNT2 can form functional HIF complexes to regulate hypoxia responsive genes. ARNT3/MOP3 does not form HIF complexes nor can it restore HIF target gene expression in response to low Oz when expressed in Arnf-/- ES cells. Whereas HIF-lα and HIF-2α can directly activate transcription of target genes, HIF-3α lacks a transcriptional activation domain and appears to repress O2-regulated gene expression.
ARNT and HIF-lα are expressed ubiquitously, whereas the other subunits exhibit a more tissue-restricted pattern of expression. For example, HIF-2α mRNA is expressed in endothelial cells, mesenchyme of the lung, and neural crest derivatives during development. Postnatally, under conditions of hypoxia, HIF-2α is expressed in other tissues and cell types, such as bone marrow macrophages, kidney epithelial cells, liver parenchyma, cardiac myoctyes, uterine decidua, and pancreatic parenchyma.

HIF Target Genes
Under hypoxic conditions (<6% O2), HIF induces the expression of at least 150 genes involved in metabolism, cell survival, erythropoiesis, and vascular remodeling. HIF activates gene expression by binding to a cis-acting hypoxia response element (HRE) located in the enhancer and promoter regions of genes. The list of target genes activated by HIF continues to increase and includes angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor-β (PDGF-β).

HIF Regulation
The ability of HIF to activate transcription is regulated by the stability of the HIFα subunit. Under normal O2 conditions or “normoxia” (21%), HIFα subunits are ubiquitinated and degraded via the 26S proteasome pathway through interaction with an E3 ubiquitin ligase complex containing the von Hippel-Lindau tumor suppressor protein (pVHL). The mechanisms and factors involved in the HIF regulatory pathway have been intensely investigated. HIFα subunits are hydroxylated on key proline residues by an oxygen dependent family of prolyl hydroxylases (PHDs). The HIF-PHDs are evolutionarily conserved from nematodes to mammals. To date, three HIF-PHD homologs with different activities, specificities, and expression patterns have been identified. The hydroxylation reaction is O2-, 2-oxoglutarate-, Fe2+-, and ascorbate- dependent. The high efficiency of the hydroxylation and subsequent degradation reactions results in HIFα instability that exhibits a half-life of minutes under normoxic conditions.
However, under hypoxic conditions, the HIF-PHDs are not active. Therefore, pVHL cannot interact with HIFα subunits and, as a result, the HIFα subunits are stabilized, translocate into the nucleus, and heterodimerize with a HIFβ subunit to form a HIF complex. HIF transactivation is then achieved by the recruitment of coactivators, such as p300/CBP. Under normoxia, HIF and p300 interaction is blocked by an additional hydroxylation reaction that is mediated by a HIF asparaginyl hydroxylase known as FIH (factor inhibiting HIF). In summary, this regulation ensures that decreases in O2 lead to a finely tuned and proportional increase in the accumulation of HIFα subunits.