Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 306 (5704): 2087-2090

Copyright © 2004 by the American Association for the Advancement of Science

Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo

Esther G. Meyron-Holtz, Manik C. Ghosh, Tracey A. Rouault*

Abstract: The iron-regulatory proteins (IRPs) posttranscriptionally regulate expression of transferrin receptor, ferritin, and other iron metabolism proteins. Although both IRPs can regulate expression of the same target genes, IRP2–/– mice significantly misregulate iron metabolism and develop neurodegeneration, whereas IRP1–/– mice are spared. We found that IRP2–/– cells misregulated iron metabolism when cultured in 3 to 6% oxygen, which is comparable to physiological tissue concentrations, but not in 21% oxygen, a concentration that activated IRP1 and allowed it to substitute for IRP2. Thus, IRP2 dominates regulation of mammalian iron homeostasis because it alone registers iron concentrations and modulates its RNA-binding activity at physiological oxygen tensions.

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.

* To whom correspondence should be addressed. E-mail: trou{at}

IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2{alpha} mRNA translation.
N. Wilkinson and K. Pantopoulos (2013)
Blood 122, 1658-1668
   Abstract »    Full Text »    PDF »
Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro.
Y. Gottlieb, O. Topaz, L. A. Cohen, L. D. Yakov, T. Haber, A. Morgenstern, A. Weiss, K. Chait Berman, E. Fibach, and E. G. Meyron-Holtz (2012)
Haematologica 97, 994-1002
   Abstract »    Full Text »    PDF »
Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload.
Y. Leichtmann-Bardoogo, L. A. Cohen, A. Weiss, B. Marohn, S. Schubert, A. Meinhardt, and E. G. Meyron-Holtz (2012)
Am J Physiol Endocrinol Metab 302, E1519-E1530
   Abstract »    Full Text »    PDF »
Iron sensing and signalling.
R. Evstatiev and C. Gasche (2012)
Gut 61, 933-952
   Abstract »    Full Text »    PDF »
Hypoxia Inducible Factor-2{alpha} Is Translationally Repressed in Response to Dietary Iron Deficiency in Sprague-Dawley Rats.
M. R. Davis, K. M. Shawron, E. Rendina, S. K. Peterson, E. A. Lucas, B. J. Smith, and S. L. Clarke (2011)
J. Nutr. 141, 1590-1596
   Abstract »    Full Text »    PDF »
Iron Regulatory Protein 1 Outcompetes Iron Regulatory Protein 2 in Regulating Cellular Iron Homeostasis in Response to Nitric Oxide.
A. Stys, B. Galy, R. R. Starzynski, E. Smuda, J.-C. Drapier, P. Lipinski, and C. Bouton (2011)
J. Biol. Chem. 286, 22846-22854
   Abstract »    Full Text »    PDF »
Mouse Knock-out of IOP1 Protein Reveals Its Essential Role in Mammalian Cytosolic Iron-Sulfur Protein Biogenesis.
D. Song and F. S. Lee (2011)
J. Biol. Chem. 286, 15797-15805
   Abstract »    Full Text »    PDF »
Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution.
G. Kovtunovych, M. A. Eckhaus, M. C. Ghosh, H. Ollivierre-Wilson, and T. A. Rouault (2010)
Blood 116, 6054-6062
   Abstract »    Full Text »    PDF »
Polarization dictates iron handling by inflammatory and alternatively activated macrophages.
G. Corna, L. Campana, E. Pignatti, A. Castiglioni, E. Tagliafico, L. Bosurgi, A. Campanella, S. Brunelli, A. A. Manfredi, P. Apostoli, et al. (2010)
Haematologica 95, 1814-1822
   Abstract »    Full Text »    PDF »
Selective Translational Control of the Alzheimer Amyloid Precursor Protein Transcript by Iron Regulatory Protein-1.
H.-H. Cho, C. M. Cahill, C. R. Vanderburg, C. R. Scherzer, B. Wang, X. Huang, and J. T. Rogers (2010)
J. Biol. Chem. 285, 31217-31232
   Abstract »    Full Text »    PDF »
Cytosolic Iron-Sulfur Cluster Assembly (CIA) System: Factors, Mechanism, and Relevance to Cellular Iron Regulation.
A. K. Sharma, L. J. Pallesen, R. J. Spang, and W. E. Walden (2010)
J. Biol. Chem. 285, 26745-26751
   Abstract »    Full Text »    PDF »
Iron control of erythroid development by a novel aconitase-associated regulatory pathway.
G. C. Bullock, L. L. Delehanty, A.-L. Talbot, S. L. Gonias, W.-H. Tong, T. A. Rouault, B. Dewar, J. M. Macdonald, J. J. Chruma, and A. N. Goldfarb (2010)
Blood 116, 97-108
   Abstract »    Full Text »    PDF »
Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.
D. R. Richardson, D. J. R. Lane, E. M. Becker, M. L.- H. Huang, M. Whitnall, Y. S. Rahmanto, A. D. Sheftel, and P. Ponka (2010)
PNAS 107, 10775-10782
   Abstract »    Full Text »    PDF »
Nitric oxide and frataxin: two players contributing to maintain cellular iron homeostasis.
L. Ramirez, E. J. Zabaleta, and L. Lamattina (2010)
Ann. Bot. 105, 801-810
   Abstract »    Full Text »    PDF »
Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase.
A. A. Vashisht, K. B. Zumbrennen, X. Huang, D. N. Powers, A. Durazo, D. Sun, N. Bhaskaran, A. Persson, M. Uhlen, O. Sangfelt, et al. (2009)
Science 326, 718-721
   Abstract »    Full Text »    PDF »
Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis.
Y. Shi, M. C. Ghosh, W.-H. Tong, and T. A. Rouault (2009)
Hum. Mol. Genet. 18, 3014-3025
   Abstract »    Full Text »    PDF »
Evidence That Phosphorylation of Iron Regulatory Protein 1 at Serine 138 Destabilizes the [4Fe-4S] Cluster in Cytosolic Aconitase by Enhancing 4Fe-3Fe Cycling.
K. M. Deck, A. Vasanthakumar, S. A. Anderson, J. B. Goforth, M. C. Kennedy, W. E. Antholine, and R. S. Eisenstein (2009)
J. Biol. Chem. 284, 12701-12709
   Abstract »    Full Text »    PDF »
Cysteine Oxidation Regulates the RNA-Binding Activity of Iron Regulatory Protein 2.
K. B. Zumbrennen, M. L. Wallander, S. J. Romney, and E. A. Leibold (2009)
Mol. Cell. Biol. 29, 2219-2229
   Abstract »    Full Text »    PDF »
Cell-autonomous and systemic context-dependent functions of iron regulatory protein 2 in mammalian iron metabolism.
D. Ferring-Appel, M. W. Hentze, and B. Galy (2009)
Blood 113, 679-687
   Abstract »    Full Text »    PDF »
Nitric Oxide-induced Conversion of Cellular Chelatable Iron into Macromolecule-bound Paramagnetic Dinitrosyliron Complexes.
J. C. Toledo Jr., C. A. Bosworth, S. W. Hennon, H. A. Mahtani, H. A. Bergonia, and J. R. Lancaster Jr. (2008)
J. Biol. Chem. 283, 28926-28933
   Abstract »    Full Text »    PDF »
Iron-independent Phosphorylation of Iron Regulatory Protein 2 Regulates Ferritin during the Cell Cycle.
M. L. Wallander, K. B. Zumbrennen, E. S. Rodansky, S. J. Romney, and E. A. Leibold (2008)
J. Biol. Chem. 283, 23589-23598
   Abstract »    Full Text »    PDF »
Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice.
M. C. Ghosh, W.-H. Tong, D. Zhang, H. Ollivierre-Wilson, A. Singh, M. C. Krishna, J. B. Mitchell, and T. A. Rouault (2008)
PNAS 105, 12028-12033
   Abstract »    Full Text »    PDF »
Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia.
K. Li, E. K. Besse, D. Ha, G. Kovtunovych, and T. A. Rouault (2008)
Hum. Mol. Genet. 17, 2265-2273
   Abstract »    Full Text »    PDF »
The MCK mouse heart model of Friedreich's ataxia: Alterations in iron-regulated proteins and cardiac hypertrophy are limited by iron chelation.
M. Whitnall, Y. S. Rahmanto, R. Sutak, X. Xu, E. M. Becker, M. R. Mikhael, P. Ponka, and D. R. Richardson (2008)
PNAS 105, 9757-9762
   Abstract »    Full Text »    PDF »
Forging a field: the golden age of iron biology.
N. C. Andrews (2008)
Blood 112, 219-230
   Full Text »    PDF »
Zinc Deficiency-induced Iron Accumulation, a Consequence of Alterations in Iron Regulatory Protein-binding Activity, Iron Transporters, and Iron Storage Proteins.
B. J. Niles, M. S. Clegg, L. A. Hanna, S. S. Chou, T. Y. Momma, H. Hong, and C. L. Keen (2008)
J. Biol. Chem. 283, 5168-5177
   Abstract »    Full Text »    PDF »
Ferritin L and H Subunits Are Differentially Regulated on a Post-transcriptional Level.
M. C. Sammarco, S. Ditch, A. Banerjee, and E. Grabczyk (2008)
J. Biol. Chem. 283, 4578-4587
   Abstract »    Full Text »    PDF »
Oxygen Levels and HIV-1 Transcription..
S. Nekhai, S. Charles, T. Ammosova, J. Cardenas, M. Jerebtsova, A. A. Ayodeji, X. Niu, P. E. Ray, F. Kashanchi, and V. R. Gordeuk (2007)
Blood (ASH Annual Meeting Abstracts) 110, 2280
   Abstract »
Excess Capacity of the Iron Regulatory Protein System.
W. Wang, X. Di, R. B. D'Agostino Jr., S. V. Torti, and F. M. Torti (2007)
J. Biol. Chem. 282, 24650-24659
   Abstract »    Full Text »    PDF »
Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts.
G. Chen, C. Fillebeen, J. Wang, and K. Pantopoulos (2007)
Carcinogenesis 28, 785-791
   Abstract »    Full Text »    PDF »
Renal Iron Metabolism: Transferrin Iron Delivery and the Role of Iron Regulatory Proteins.
D. Zhang, E. Meyron-Holtz, and T. A. Rouault (2007)
J. Am. Soc. Nephrol. 18, 401-406
   Full Text »    PDF »
Of Two Cytosolic Aconitases Expressed in Drosophila, Only One Functions as an Iron-regulatory Protein.
M. I. Lind, F. Missirlis, O. Melefors, H. Uhrigshardt, K. Kirby, J. P. Phillips, K. Soderhall, and T. A. Rouault (2006)
J. Biol. Chem. 281, 18707-18714
   Abstract »    Full Text »    PDF »
Sodium Nitroprusside Promotes IRP2 Degradation via an Increase in Intracellular Iron and in the Absence of S Nitrosylation at C178.
J. Wang, C. Fillebeen, G. Chen, B. Andriopoulos, and K. Pantopoulos (2006)
Mol. Cell. Biol. 26, 1948-1954
   Abstract »    Full Text »    PDF »
Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster.
S. L. Clarke, A. Vasanthakumar, S. A. Anderson, C. Pondarre, C. M. Koh, K. M. Deck, J. S. Pitula, C. J. Epstein, M. D. Fleming, and R. S. Eisenstein (2006)
EMBO J. 25, 544-553
   Abstract »    Full Text »    PDF »
DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression.
K. J. Hintze and E. C. Theil (2005)
PNAS 102, 15048-15052
   Abstract »    Full Text »    PDF »
Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2.
S. S. Cooperman, E. G. Meyron-Holtz, H. Olivierre-Wilson, M. C. Ghosh, J. P. McConnell, and T. A. Rouault (2005)
Blood 106, 1084-1091
   Abstract »    Full Text »    PDF »
Highlights from the Literature.
Physiology 20, 81-85
   Full Text »    PDF »
CELL BIOLOGY: " Pumping" Iron: The Proteins.
E. Beutler (2004)
Science 306, 2051-2053
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882