The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption

被引：179

作者：

Anderson, Sheila A. ^{[1
]}

Nizzi, Christopher P. ^{[1
]}

Chang, Yuan-I. ^{[2
]}

Deck, Kathryn M. ^{[1
]}

Schmidt, Paul J. ^{[5
,6
]}

Galy, Bruno ^{[4
]}

Damnernsawad, Alisa ^{[2
]}

Broman, Aimee T. ^{[3
]}

Kendziorski, Christina ^{[3
]}

Hentze, Matthias W. ^{[4
]}

Fleming, Mark D. ^{[5
,6
]}

Zhang, Jing ^{[2
]}

Eisenstein, Richard S. ^{[1
]}

机构：

[1] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA

[2] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA

[3] Univ Wisconsin, Madison, WI 53706 USA

[4] European Mol Biol Lab, D-69117 Heidelberg, Germany

[5] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Boston, MA 02115 USA

来源：

CELL METABOLISM | 2013年 / 17卷 / 02期

基金：

美国国家卫生研究院;

关键词：

HYPOXIA-INDUCIBLE FACTOR-2-ALPHA; REGULATORY PROTEIN-2; RESPONSIVE ELEMENT; DEPENDENT MANNER; MICE; ANEMIA; TRANSLATION; HIF-2-ALPHA; DEFICIENCY; METABOLISM;

D O I：

10.1016/j.cmet.2013.01.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 2 alpha (HIF-2 alpha) synthesis by iron regulatory protein 1 (IRP1) is critical for controlling erythrocyte number. IRP1-null (Irp1(-/-)) mice display a marked transient polycythemia. HIF-2 alpha 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-2 alpha targets, is enhanced in Irp1(-/-) duodenum. Analysis of mRNA translation state in the liver revealed IRP1-dependent dysregulation of HIF-2 alpha 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-2 alpha action in hematologic, oncologic, and other disorders.

引用

页码：282 / 290

页数：9

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