Breakthrough science: hypoxia-inducible factors, oxygen sensing, and disorders of hematopoiesis
Gregg L. Semenza
Abstract
Hypoxia-inducible factors (HIFs) were discovered as activators of erythropoietin gene transcription in response to reduced oxygen (O2) availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcriptional activity, respectively. Mutations in genes encoding components of the O2-sensing pathway cause familial erythrocytosis. Several small-molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis-stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcomes in these disorders.
Topics & Concepts
ErythropoiesisTranscription factorErythropoietinHypoxia-inducible factorsHaematopoiesisHypoxia (environmental)HydroxylationCancer researchBiologyAsparagineGeneBone marrowCell biologyChemistryGeneticsBiochemistryInternal medicineMedicineStem cellImmunologyAnemiaEnzymeOxygenOrganic chemistryCancer, Hypoxia, and MetabolismErythrocyte Function and PathophysiologyMetabolism, Diabetes, and Cancer