Hypoxia-inducible factor 1 (HIF-1) pathway.
Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix-PAS domain transcription factor that is expressed in all metazoan organisms and is composed of HIF-1alpha and HIF-1beta subunits. Under hypoxic conditions, HIF-1 regulates the transcription of hundreds of genes in a cell type-specific manner. The HIF-1alpha subunit is regulated by O2-dependent hydroxylation of proline residue 402, 564, or both, by prolyl hydroxylase domain protein 2 (PHD2), which promotes binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation; and O2-dependent hydroxylation of asparagine residue 803 by factor inhibiting HIF-1 (FIH-1), which blocks the binding of the 300-kilodalton coactivator protein (p300) and CREB binding protein (CBP). The hydroxylation reactions, which utilize O2 and alpha-ketoglutarate as substrates and generate CO2 and succinate as by-products, provide a mechanism by which changes in cellular oxygenation are transduced to the nucleus as changes in HIF-1 activity. Hydroxylase activity is inhibited in the presence of low concentrations of O2, high concentrations of tricarboxylic acid cycle intermediates (isocitrate, oxaloacetate, succinate, or fumarate), or chelators of Fe(II). Receptor for activated C kinase 1 (RACK1) competes with heat shock protein 90 (HSP90) for binding to HIF-1alpha and mediates O2-independent ubiquitination and proteasomal degradation. A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1alpha.
Semenza
Gregg L
GL
Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Broadway Research Building, Suite 671, 733 North Broadway, Baltimore, MD 21205, USA. gsemenza@jhmi.edu
D000818:Animals; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D018841:HSP90 Heat-Shock Proteins; D051793:Hypoxia-Inducible Factor 1; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D014157:Transcription Factors; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D010100:Oxygen