Fig. 1.
Hypoxia-inducible factor (HIF)-1α regulation and signaling under normoxic, hypoxic, and inflammatory conditions. HIF-1α subunits are constantly produced but rapidly degraded under normoxic conditions. Several pathways of HIF-1α regulation have been described. First, under normoxic conditions, HIF-1α subunits are rapidly hydroxylated by oxygen-dependent prolyl hydroxylase domain enzymes (PHDs), which are subsequently captured by the ubiquitin ligase Von Hippel–Lindau (VHL) protein and degraded by the proteasome. Second, the oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF (FIH) hydroxylates a conserved asparaginyl residue, preventing the recruitment of coactivators P300 and cAMP-response element–binding protein (CBP), in turn inhibiting dimerization with HIFβ. During oxygen deficiency, PHD and FIH activities decrease, resulting in accumulation of HIF-1α subunits in the cytosol. The receptor for activated C kinase 1 (RACK1) and heat shock protein 90 (HSP90) regulate HIF-1α in an oxygen-independent manner: RACK facilitates oxygen-independent proteasomal degradation of HIF-1α, while HSP90 competes with RACK, thereby stabilizing HIF-1α, and facilitates its transactivation. Upon accumulation, HIF-1α is coactivated by P300/CBP and dimerizes with HIFβ to form stable HIF-1αβ dimers. These dimers translocate to the nucleus and bind to hypoxia response elements (HREs) in promoter enhancer regions of genes, resulting in transcriptional activity. HIF-1α stabilization results in transcription of many (greater than 100) hypoxia responsive genes. As FIH remains active at lower oxygen concentrations than PHDs, FIH suppresses the activity of HIF-1α proteins that escape destruction during moderate hypoxia. Not only hypoxia but also exposure to bacteria and bacterial products such as lipopolysaccharide (LPS) results in HIF-1α accumulation. NF-κB = nuclear factor of kappa-light-chain-enhancer of activated B cells; TLR = toll-like receptor.