title: HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal.
abstract: With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance erythroid colony-forming unit (CFU-E) production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using erythroid burst-forming unit (BFU-E) and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1α (HIF1α) binding sites. This suggests activation of HIF1α may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1α activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Because PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating erythropoietin-resistant anemia.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Johan
authors.initials: J
authors.lastname: Flygare
authors.forename: Violeta
authors.initials: V
authors.lastname: Rayon Estrada
authors.forename: Chanseok
authors.initials: C
authors.lastname: Shin
authors.forename: Sumeet
authors.initials: S
authors.lastname: Gupta
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002469:Cell Separation; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000502:physiology*; D005333:Fetus / Q000166:cytology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists* / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D020218:Response Elements / Q000187:drug effects / Q000235:genetics
chemical_list: D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; C040947:oxalylglycine