title: The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption.
abstract: Red blood cell production is a finely tuned process that requires coordinated oxygen- and iron-dependent regulation of cell differentiation and iron metabolism. Here, we show that translational regulation of hypoxia-inducible factor 2α (HIF-2α) synthesis by iron regulatory protein 1 (IRP1) is critical for controlling erythrocyte number. IRP1-null (Irp1(-/-)) mice display a marked transient polycythemia. HIF-2α messenger RNA (mRNA) is derepressed in kidneys of Irp1(-/-) mice but not in kidneys of Irp2(-/-) mice, leading to increased renal erythropoietin (Epo) mRNA and inappropriately elevated serum Epo levels. Expression of the iron transport genes DCytb, Dmt1, and ferroportin, as well as other HIF-2α targets, is enhanced in Irp1(-/-) duodenum. Analysis of mRNA translation state in the liver revealed IRP1-dependent dysregulation of HIF-2α mRNA translation, whereas IRP2 deficiency derepressed translation of all other known 5' iron response element (IRE)-containing mRNAs expressed in the liver. These results uncover separable physiological roles of each IRP and identify IRP1 as a therapeutic target for manipulating HIF-2α action in hematologic, oncologic, and other disorders.
authors: Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Sheila A
authors: SA
authors: Anderson
authors: Christopher P
authors: CP
authors: Nizzi
authors: Yuan-I
authors: YI
authors: Chang
authors: Kathryn M
authors: KM
authors: Deck
authors: Paul J
authors: PJ
authors: Schmidt
authors: Bruno
authors: B
authors: Galy
authors: Alisa
authors: A
authors: Damnernsawad
authors: Aimee T
authors: AT
authors: Broman
authors: Christina
authors: C
authors: Kendziorski
authors: Matthias W
authors: MW
authors: Hentze
authors: Mark D
authors: MD
authors: Fleming
authors: Jing
authors: J
authors: Zhang
authors: Richard S
authors: RS
authors: Eisenstein
mesh_terms: D000042:Absorption; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D041905:Erythroid Cells / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000097:blood; D005786:Gene Expression Regulation; D006411:Hematopoiesis, Extramedullary; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D011086:Polycythemia / Q000097:blood / Q000473:pathology; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D007501:Iron; D035941:Iron Regulatory Protein 1; D010100:Oxygen; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1
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