@article{74e6b28e1ee548adb43ec61847e4338d,
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.",
author = "Anderson, {Sheila A.} and Nizzi, {Christopher P.} and Chang, {Yuan I.} and Deck, {Kathryn M.} and Schmidt, {Paul J.} and Bruno Galy and Alisa Damnernsawad and Broman, {Aimee T.} and Christina Kendziorski and Hentze, {Matthias W.} and Fleming, {Mark D.} and Jing Zhang and Eisenstein, {Richard S.}",
note = "Funding Information: This study was supported by the National Institutes of Health (NIH; R01 DK66600), the Iron Metabolism Research Fund, and the University of Wisconsin-Madison Graduate School and Hatch Project (WIS01324) to R.E.; NIH R01CA152108, a Shaw Scientist Award from the Greater Milwaukee Foundation, a V Scholar Award from the V Foundation for Cancer Research, and an Investigator Initiated Grant from the University of Wisconsin Comprehensive Cancer Center Support (UWCCC) to J.Z.; NIH R01 DK 080011 to M.D.F.; NIH R01 GM102756 to C.K.; and a grant from the Clinical and Translational Science Award program of the National Center for Research Resources, NIH (1UL1RR025011). We thank UWCCC for use of its flow cytometry and experimental pathology units. Partial support from NIH and National Cancer Institute (P30 CA014520) was also given to the UWCCC. ",
year = "2013",
month = feb,
day = "5",
doi = "10.1016/j.cmet.2013.01.007",
language = "English",
volume = "17",
pages = "282--290",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",
}