A: the structural domains of HIF-1α are shown. The basic helix-loop-helix (bHLH) and Per-ARNT-Sim homology (PAS) domains mediate dimerization with HIF-1β (ARNT) and DNA binding; the oxygen-dependent degradation domain (ODD) encompasses the sites of prolyl hydroxylation (POH) that are required for VHL binding; and the transactivation domain (TAD) encompasses the site of asparaginyl hydroxylation (NOH) that blocks binding of the coactivators p300 and CBP. The prolyl (PHD2) and asparaginyl (FIH-1) hydroxylases utilize O2 and α-ketoglutarate (α-KG) as substrates. Protein-protein interactions are indicated by double-sided arrows. B: the signal transduction pathways by which intermittent hypoxia induces HIF-1α protein synthesis (red), protein stability (green), and transactivation (blue) are shown.
Oxygen-independent regulation of HIF-1α protein levels
A: the regulation of HIF-1α protein stability by RACK1 is shown. RACK1 binding is increased by treatment with the heat shock protein 90 (HSP90) inhibitor 17-allylaminogeldanamycin (17-AAG) or by the calcineurin inhibitor cyclosporine A (CsA). Binding of Ca2+ to calmodulin (Cam) activates cal-cineurin phosphatase activity, which inhibits RACK1 dimerization. B: the regulation of HIF-1α protein synthesis by the PI3K-AKT-mTOR (purple) and MAP kinase (orange) pathways, which mediate phosphorylation of key regulators of translation (red), is shown. Arrow and blocked arrow indicate activation and inhibition, respectively.
A: the regulation of erythropoiesis is shown. Direct HIF-1 target genes are indicated in blue. Arrow and blocked arrow indicate activation and repression, respectively. B: the regulation of angiogenesis is shown. Direct HIF-1 target genes are indicated in blue, whereas genes that may be either direct or indirect (secondary) targets of HIF-1 are indicated in maroon. The combination arrow/blocked arrows indicate that the genes encoding angiopoietin (ANGPT) 1 and 2 may be activated or repressed by HIF-1 in response to hypoxia depending on the cell type. C: the regulation of glucose and energy metabolism is shown. Green numerals indicate processes that are stimulated by HIF-1: 1) COX4-1 to COX4-2 subunit switch; 2) expression of glucose transporters GLUT1 and GLUT3; 3) expression of glycolytic enzymes; 4) expression of lactate dehydrogenase A; and 6) mitochondrial autophagy. Red numeral indicates process that is inhibited by HIF-1: 5) pyruvate dehydrogenase activity. AcCoA, acetyl coenzyme A; ETC, electron transport chain; TCA, tricarboxylic acid cycle.
A: the role of HIF-1 in the pathogenesis of pulmonary hypertension induced in response to chronic continuous hypoxia is shown. B: the role of HIF-1 in the pathogenesis of systemic hypertension induced in response to chronic intermittent hypoxia is shown. EDN1, endothelin 1; Kv1.5, voltage-gated potassium channel 1.5; NHE1, sodium-hydrogen exchanger 1; TRPC1, transient receptor potential protein C1.