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      Iron regulatory proteins and their role in controlling iron metabolism.

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      Metallomics : integrated biometal science

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          Abstract

          Cellular iron homeostasis is regulated by post-transcriptional feedback mechanisms, which control the expression of proteins involved in iron uptake, release and storage. Two cytoplasmic proteins with mRNA-binding properties, iron regulatory proteins 1 and 2 (IRP1 and IRP2) play a central role in this regulation. Foremost, IRPs regulate ferritin H and ferritin L translation and thus iron storage, as well as transferrin receptor 1 (TfR1) mRNA stability, thereby adjusting receptor expression and iron uptake via receptor-mediated endocytosis of iron-loaded transferrin. In addition splice variants of iron transporters for import and export at the plasma-membrane, divalent metal transporter 1 (DMT1) and ferroportin are regulated by IRPs. These mechanisms have probably evolved to maintain the cytoplasmic labile iron pool (LIP) at an appropriate level. In certain tissues, the regulation exerted by IRPs influences iron homeostasis and utilization of the entire organism. In intestine, the control of ferritin expression limits intestinal iron absorption and, thus, whole body iron levels. In bone marrow, erythroid heme biosynthesis is coordinated with iron availability through IRP-mediated translational control of erythroid 5-aminolevulinate synthase mRNA. Moreover, the translational control of HIF2α mRNA in kidney by IRP1 coordinates erythropoietin synthesis with iron and oxygen supply. Besides IRPs, body iron absorption is negatively regulated by hepcidin. This peptide hormone, synthesized and secreted by the liver in response to high serum iron, downregulates ferroportin at the protein level and thereby limits iron absorption from the diet. Hepcidin will not be discussed in further detail here.

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          Author and article information

          Journal
          Metallomics
          Metallomics : integrated biometal science
          1756-591X
          1756-5901
          Feb 2015
          : 7
          : 2
          Affiliations
          [1 ] Ecole Polytechnique Fédérale de Lausanne (EPFL), ISREC - Swiss Institute for Experimental Cancer Research, EPFL_SV_ISREC, Room SV2516, Station 19, CH-1015 Lausanne, Switzerland. lukas.kuehn@epfl.ch.
          Article
          10.1039/c4mt00164h
          25306858

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