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Cell Metab. 2013 Feb 5;17(2):282-90. doi: 10.1016/j.cmet.2013.01.007.

The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption.

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1
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.

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.

PMID:
23395174
PMCID:
PMC3612289
DOI:
10.1016/j.cmet.2013.01.007
[Indexed for MEDLINE]
Free PMC Article
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