Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis.
Red blood cells deliver O(2) from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O(2)-regulated alpha subunit and a constitutively expressed beta subunit. Hydroxylation of HIF-1alpha or HIF-2alpha by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1alpha or HIF-2alpha by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2alpha have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.
Semenza
Gregg L
GL
Vascular Program, Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA. gsemenza@jhmi.edu
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active / Q000235:genetics; D004920:Erythropoiesis; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006900:Hydroxylation / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008168:Lung / Q000378:metabolism / Q000473:pathology; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010100:Oxygen / Q000378:metabolism*; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D006899:Mixed Function Oxygenases; D010100:Oxygen; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C490190:EGLN1 protein, human; C497446:VHL protein, human