| First Author | Anderson SA | Year | 2013 |
| Journal | Cell Metab | Volume | 17 |
| Issue | 2 | Pages | 282-90 |
| PubMed ID | 23395174 | Mgi Jnum | J:198049 |
| Mgi Id | MGI:5495338 | Doi | 10.1016/j.cmet.2013.01.007 |
| Citation | Anderson SA, et al. (2013) The IRP1-HIF-2alpha axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab 17(2):282-90 |
| abstractText | 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 2alpha (HIF-2alpha) synthesis by iron regulatory protein 1 (IRP1) is critical for controlling erythrocyte number. IRP1-null (Irp1(-/-)) mice display a marked transient polycythemia. HIF-2alpha 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-2alpha targets, is enhanced in Irp1(-/-) duodenum. Analysis of mRNA translation state in the liver revealed IRP1-dependent dysregulation of HIF-2alpha 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-2alpha action in hematologic, oncologic, and other disorders. |
