Eukaryotic cells require iron for survival but, as an excess of poorly liganded iron can lead to the catalytic production of toxic radicals that can damage cell structures, regulatory mechanisms have been developed to maintain appropriate cell and body iron levels. The interactions of iron responsive elements (IREs) with iron regulatory proteins (IRPs) coordinately regulate the expression of the genes involved in iron uptake, use, storage, and export at the post-transcriptional level, and represent the main regulatory network controlling cell iron homeostasis. IRP1 and IRP2 are similar (but not identical) proteins with partially overlapping and complementary functions, and control cell iron metabolism by binding to IREs (i.e., conserved RNA stem-loops located in the untranslated regions of a dozen mRNAs directly or indirectly related to iron metabolism). The discovery of the presence of IREs in a number of other mRNAs has extended our knowledge of the influence of the IRE/IRP regulatory network to new metabolic pathways, and it has been recently learned that an increasing number of agents and physiopathological conditions impinge on the IRE/IRP system. This review focuses on recent findings concerning the IRP-mediated regulation of iron homeostasis, its alterations in disease, and new research directions to be explored in the near future. Antioxid. Redox Signal. 13, 1593–1616.
Aguilar–MartinezP, SchvedJF, BrissotP. The evaluation of hyperferritinemia: An updated strategy based on advances in detecting genetic abnormalities. Am J Gastroenterol, 100:1185–1194. 2005.
2.
AlberghiniA, RecalcatiS, TacchiniL, SantambrogioP, CampanellaA, CairoG. Loss of the von Hippel Lindau tumor suppressor disrupts iron homeostasis in renal carcinoma cells. J Biol Chem, 280:30120–30128. 2005.
3.
AndersonGJ, FrazerDM, McLarenGD. Iron absorption and metabolism. Curr Opin Gastroenterol, 25:129–135. 2009.
4.
AndrewsNC. Forging a field: The golden age of iron biology. Blood, 112:219–230. 2008.
5.
ArosioP, AdelmanTG, DrysdaleJW. On ferritin heterogeneity. Further evidence for heteropolymers. J Biol Chem, 253:4451–4458. 1978.
6.
ArosioP, IngrassiaR, CavadiniP. Ferritins: A family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta, 1790:589–599. 2009.
7.
BeinertH, KennedyMC. Aconitase, a two-faced protein: Enzyme and iron regulatory factor. FASEB J, 7:1442–1449. 1993.
8.
BianchiL, TacchiniL, CairoG. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res, 27:4223–4227. 1999.
9.
BrazzolottoX, AndriolloM, GuiraudP, FavierA, MoulisJM. Interactions between doxorubicin and the human iron regulatory system. Biochim Biophys Acta, 1593:209–218. 2003.
CairoG, BernuzziF, RecalcatiS. A precious metal: Iron, an essential nutrient for all cells. Genes Nutr, 1:25–39. 2006.
12.
CairoG, CastrusiniE, MinottiG, Bernelli–ZazzeraA. Superoxide and hydrogen peroxide-dependent inhibition of iron regulatory protein activity: A protective stratagem against oxidative injury. FASEB J, 10:1326–1335. 1996.
13.
CairoG, PietrangeloA. Transferrin receptor gene expression during rat liver regeneration. Evidence for post-transcriptional regulation by iron regulatory factorB, a second iron-responsive element-binding protein. J Biol Chem, 269:6405–6409. 1994.
14.
CairoG, PietrangeloA. Iron regulatory proteins in pathobiology. Biochem J 352 Pt, 2:241–250. 2000.
15.
CairoG, RecalcatiS. Iron regulatory proteins: Molecular biology and pathophysiological implications. Expert Rev Mol Med, 9:1–13. 2007.
16.
CairoG, RecalcatiS, PietrangeloA, MinottiG. The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. Free Radic Biol Med, 32:1237–1243. 2002.
17.
CairoG, RonchiR, BuccellatoFR, VeberD, SantambrogioP, ScalabrinoG. Regulation of the ferritin H subunit by vitamin B12 (cobalamin) in rat spinal cord. J Neurosci Res, 69:117–124. 2002.
18.
CairoG, TacchiniL, PogliaghiG, AnzonE, TomasiA, Bernelli–ZazzeraA. Induction of ferritin synthesis by oxidative stress. Transcriptional and post-transcriptional regulation by expansion of the “free” iron pool. J Biol Chem, 270:700–703. 1995.
19.
CaltagironeA, WeissG, PantopoulosK. Modulation of cellular iron metabolism by hydrogen peroxide. Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts. J Biol Chem, 276:19738–19745. 2001.
20.
CamaschellaC. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood, 106:3710–3717. 2005.
21.
CanzoneriJC, OyelereAK. Interaction of anthracyclines with iron responsive element mRNAs. Nucleic Acids Res, 36:6825–6834. 2008.
22.
CaoW, McMahonM, WangB, O'ConnorR, ClarksonM. A case report of spontaneous mutation (C33 >U) in the iron-responsive element of l-ferritin causing hyperferritinemia-cataract syndrome. Blood Cells Mol Dis, 44:22–27. 2010.
23.
CazzolaM, BergamaschiG, TononL, ArbustiniE, GrassoM, VercesiE, BarosiG, BianchiPE, CairoG, ArosioP. Hereditary hyperferritinemia-cataract syndrome: Relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA. Blood, 90:814–821. 1997.
24.
ChenG, FillebeenC, WangJ, PantopoulosK. Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis, 28:785–791. 2007.
25.
ChristovaT, TempletonDM. Effect of hypoxia on the binding and subcellular distribution of iron regulatory proteins. Mol Cell Biochem, 301:21–32. 2007.
26.
ChurchC, LeeS, BaggEA, McTaggartJS, DeaconR, GerkenT, LeeA, MoirL, MecinovicJ, QuwailidMM, SchofieldCJ, AshcroftFM, CoxRD. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet, 5:e1000599. 2009.
27.
CianettiL, SegnaliniP, CalzolariA, MorsilliO, FelicettiF, RamoniC, GabbianelliM, TestaU, SposiNM. Expression of alternative transcripts of ferroportin-1 during human erythroid differentiation. Haematologica, 90:1595–1606. 2005.
28.
ClarkeSL, VasanthakumarA, AndersonSA, PondarreC, KohCM, DeckKM, PitulaJS, EpsteinCJ, FlemingMD, EisensteinRS. Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. EMBO J, 25:544–553. 2006.
29.
CmejlaR, PetrakJ, CmejlovaJ. A novel iron responsive element in the 3'UTR of human MRCKalpha. Biochem Biophys Res Commun, 341:158–166. 2006.
30.
CoffmanLG, ParsonageD, D'AgostinoRJr., TortiFM, TortiSV. Regulatory effects of ferritin on angiogenesis. Proc Natl Acad Sci USA, 106:570–575. 2009.
31.
CoonKD, SiegelAM, YeeSJ, DunckleyTL, MuellerC, NagraRM, TourtellotteWW, ReimanEM, PapassotiropoulosA, PetersenFF, StephanDA, KirschWM. Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease. J Alzheimers Dis, 9:225–233. 2006.
32.
CoopermanSS, Meyron-HoltzEG, Olivierre–WilsonH, GhoshMC, McConnellJP, RouaultTA. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood, 106:1084–1091. 2005.
33.
CornaG, GalyB, HentzeMW, CairoG. IRP1-independent alterations of cardiac iron metabolism in doxorubicin-treated mice. J Mol Med, 84:551–560. 2006.
34.
CornaG, SantambrogioP, MinottiG, CairoG. Doxorubicin paradoxically protects cardiomyocytes against iron-mediated toxicity: Role of reactive oxygen species and ferritin. J Biol Chem, 279:13738–13745. 2004.
35.
CoxTC, BawdenMJ, MartinA, MayBK. Human erythroid 5-aminolevulinate synthase: Promoter analysis and identification of an iron-responsive element in the mRNA. EMBO J, 10:1891–1902. 1991.
36.
CozziA, CorsiB, LeviS, SantambrogioP, AlbertiniA, ArosioP. Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: In vivo role of ferritin ferroxidase activity. J Biol Chem, 275:25122–25129. 2000.
37.
CremonesiL, FoglieniB, FermoI, CozziA, ParoniR, RuggeriG, BelloliS, LeviS, FargionS, FerrariM, ArosioP. Identification of two novel mutations in the 5'-untranslated region of H-ferritin using denaturing high performance liquid chromatography scanning. Haematologica, 88:1110–1116. 2003.
38.
CrooksDR, GhoshMC, HallerRG, TongWH, RouaultTA. Post-translational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood, 115:860–869. 2010.
39.
DandekarT, StripeckeR, GrayNK, GoossenB, ConstableA, JohanssonHE, HentzeMW. Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA. EMBO J, 10:1903–1909. 1991.
40.
De DomenicoI, McVey WardD, KaplanJ. Regulation of iron acquisition and storage: Consequences for iron-linked disorders. Nat Rev Mol Cell Biol, 9:72–81. 2008.
41.
De DomenicoI, WardDM, NemethE, VaughnMB, MusciG, GanzT, KaplanJ. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci USA, 102:8955–8960. 2005.
42.
DeckKM, VasanthakumarA, AndersonSA, GoforthJB, KennedyMC, AntholineWE, EisensteinRS. Evidence that phosphorylation of iron regulatory protein 1 at Serine 138 destabilizes the [4Fe-4S] cluster in cytosolic aconitase by enhancing 4Fe-3Fe cycling. J Biol Chem, 284:12701–12709. 2009.
43.
DelabyC, PilardN, PuyH, Canonne–HergauxF. Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: Early mRNA induction by haem, followed by iron-dependent protein expression. Biochem J, 411:123–131. 2008.
44.
DeMeoDL, MarianiT, BhattacharyaS, SrisumaS, LangeC, LitonjuaA, BuenoR, PillaiSG, LomasDA, SparrowD, ShapiroSD, CrinerGJ, KimHP, ChenZ, ChoiAM, ReillyJ, SilvermanEK. Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet, 85:493–502. 2009.
45.
DonovanA, LimaCA, PinkusJL, PinkusGS, ZonLI, RobineS, AndrewsNC. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab, 1:191–200. 2005.
46.
dos SantosCO, DoreLC, ValentineE, ShelatSG, HardisonRC, GhoshM, WangW, EisensteinRS, CostaFF, WeissMJ. An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA. J Biol Chem, 283:26956–26964. 2008.
47.
DrakesmithH, PrenticeA. Viral infection and iron metabolism. Nat Rev Microbiol, 6:541–552. 2008.
48.
DrapierJC. Interplay between NO and [Fe-S] clusters: Relevance to biological systems. Methods, 11:319–329. 1997.
49.
DupuyJ, VolbedaA, CarpentierP, DarnaultC, MoulisJM, Fontecilla–CampsJC. Crystal structure of human iron regulatory protein 1 as cytosolic aconitase. Structure, 14:129–139. 2006.
50.
DyckeC, BougaultC, GaillardJ, AndrieuJP, PantopoulosK, MoulisJM. Human iron regulatory protein 2 is easily cleaved in its specific domain: Consequences for the haem binding properties of the protein. Biochem J, 408:429–439. 2007.
51.
DyckeC, CharbonnierP, PantopoulosK, MoulisJM. A role for lysosomes in the turnover of human iron regulatory protein 2. Int J Biochem Cell Biol, 40:2826–2832. 2008.
52.
EpsztejnS, GlicksteinH, PicardV, SlotkiIN, BreuerW, BeaumontC, CabantchikZI. H-ferritin subunit overexpression in erythroid cells reduces the oxidative stress response and induces multidrug resistance properties. Blood, 94:3593–3603. 1999.
53.
FaucheuxBA, MartinME, BeaumontC, HunotS, HauwJJ, AgidY, HirschEC. Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease. J Neurochem, 83:320–330. 2002.
54.
Ferring-AppelD, HentzeMW, GalyB. Cell-autonomous and systemic context-dependent functions of iron regulatory protein 2 in mammalian iron metabolism. Blood, 113:679–687. 2009.
55.
FestaM, RicciardelliG, MeleG, PietropaoloC, RuffoA, ColonnaA. Overexpression of H ferritin and up-regulation of iron regulatory protein genes during differentiation of 3T3-L1 pre-adipocytes. J Biol Chem, 275:36708–36712. 2000.
56.
FillebeenC, MuckenthalerM, AndriopoulosB, BisaillonM, MounirZ, HentzeMW, KoromilasAE, PantopoulosK. Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J Hepatol, 47:12–22. 2007.
57.
FlorenzanoF, SalmanP. Carvedilol for anthracycline cardiomyopathy prevention. J Am Coll Cardiol, 49:2142. 2007author reply 2142–2143.
58.
FriedlichAL, TanziRE, RogersJT. The 5'-untranslated region of Parkinson's disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry, 12:222–223. 2007.
GalyB, Ferring-AppelD, KadenS, GroneHJ, HentzeMW. Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab, 7:79–85. 2008.
61.
GalyB, FerringD, MinanaB, BellO, JanserHG, MuckenthalerM, SchumannK, HentzeMW. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2)Blood, 106:2580–2589. 2005.
62.
GalyB, HolterSM, KlopstockT, FerringD, BeckerL, KadenS, WurstW, GroneHJ, HentzeMW. Iron homeostasis in the brain: Complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat Genet, 38:967–969. 2006discussion 969–970.
63.
GehringNH, HentzeMW, PantopoulosK. Inactivation of both RNA binding and aconitase activities of iron regulatory protein-1 by quinone-induced oxidative stress. J Biol Chem, 274:6219–6225. 1999.
64.
GhoshM, Ollivierre–WilsonH, CoopermanS, RouaultT. Reply to “Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse”Nat Gen, 38:969–970. 2006.
65.
GhoshMC, TongWH, ZhangD, Ollivierre–WilsonH, SinghA, KrishnaMC, MitchellJB, RouaultTA. Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci USA, 105:12028–12033. 2008.
66.
GianniL, HermanEH, LipshultzSE, MinottiG, SarvazyanN, SawyerDB. Anthracycline cardiotoxicity: From bench to bedside. J Clin Oncol, 26:3777–3784. 2008.
67.
GoforthJB, AndersonSA, NizziCP, EisensteinRS. Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy. RNA, 16:154–169. 2010.
68.
GrayNK, PantopoulosK, DandekarT, AckrellBA, HentzeMW. Translational regulation of mammalian and Drosophila citric acid cycle enzymes via iron-responsive elements. Proc Natl Acad Sci USA, 93:4925–4930. 1996.
69.
GuJM, LimSO, OhSJ, YoonSM, SeongJK, JungG. HBx modulates iron regulatory protein 1-mediated iron metabolism via reactive oxygen species. Virus Res, 133:167–177. 2008.
70.
GuoB, PhillipsJD, YuY, LeiboldEA. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem, 270:21645–21651. 1995.
71.
GuoB, YuY, LeiboldEA. Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J Biol Chem, 269:24252–24260. 1994.
72.
HajdusekO, SojkaD, KopacekP, BuresovaV, FrantaZ, SaumanI, WinzerlingJ, GrubhofferL. Knockdown of proteins involved in iron metabolism limits tick reproduction and development. Proc Natl Acad Sci USA, 106:1033–1038. 2009.
73.
HalliwellB. Biochemistry of oxidative stress. Biochem Soc Trans, 35:1147–1150. 2007.
HansonES, RawlinsML, LeiboldEA. Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem, 278:40337–40342. 2003.
76.
HarrisonPM, ArosioP. The ferritins: Molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta, 1275:161–203. 1996.
77.
HasinoffBB, HermanEH. Dexrazoxane: How it works in cardiac and tumor cells. Is it a prodrug or is it a drug?Cardiovasc Toxicol, 7:140–144. 2007.
78.
HentzeMW, KuhnLC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA, 93:8175–8182. 1996.
79.
HentzeMW, RouaultTA, HarfordJB, KlausnerRD. Oxidation-reduction and the molecular mechanism of a regulatory RNA-protein interaction. Science, 244:357–379. 1989.
80.
HirlingH, HendersonBR, KuhnLC. Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase. EMBO J, 13:453–461. 1994.
81.
HowerV, MendesP, TortiFM, LaubenbacherR, AkmanS, ShulaevV, TortiSV. A general map of iron metabolism and tissue-specific subnetworks. Mol Biosyst, 5:422–443. 2009.
82.
IraceC, ScorzielloA, MaffettoneC, PignataroG, MatroneC, AdornettoA, SantamariaR, AnnunziatoL, ColonnaA. Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells. J Neurochem, 95:1321–1331. 2005.
83.
IshiiKA, FumotoT, IwaiK, TakeshitaS, ItoM, ShimohataN, AburataniH, TaketaniS, LelliottCJ, Vidal–PuigA, IkedaK. Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med, 15:259–266. 2009.
84.
IshikawaH, KatoM, HoriH, IshimoriK, KirisakoT, TokunagaF, IwaiK. Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2. Mol Cell, 19:171–181. 2005.
85.
IwaiK, DrakeSK, WehrNB, WeissmanAM, LaVauteT, MinatoN, KlausnerRD, LevineRL, RouaultTA. Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: Implications for degradation of oxidized proteins. Proc Natl Acad Sci USA, 95:4924–4928. 1998.
86.
IwaiK, KlausnerRD, RouaultTA. Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2. EMBO J, 14:5350–5357. 1995.
87.
IyerLM, TahilianiM, RaoA, AravindL. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle, 8:1698–1710. 2009.
88.
KalayN, BasarE, OzdogruI, ErO, CetinkayaY, DoganA, InancT, OguzhanA, EryolNK, TopsakalR, ErginA. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol, 48:2258–2262. 2006.
89.
KatoJ, FujikawaK, KandaM, FukudaN, SasakiK, TakayamaT, KobuneM, TakadaK, TakimotoR, HamadaH, IkedaT, NiitsuY. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet, 69:191–197. 2001.
90.
KeY, WuJ, LeiboldEA, WaldenWE, TheilEC. Loops and bulge/loops in iron-responsive element isoforms influence iron regulatory protein binding. Fine-tuning of mRNA regulation?J Biol Chem, 273:23637–23640. 1998.
91.
KeelSB, DotyRT, YangZ, QuigleyJG, ChenJ, KnoblaughS, KingsleyPD, De DomenicoI, VaughnMB, KaplanJ, PalisJ, AbkowitzJL. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science, 319:825–828. 2008.
92.
KennedyMC, Mende–MuellerL, BlondinGA, BeinertH. Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein. Proc Natl Acad Sci USA, 89:11730–11734. 1992.
93.
KerenyiMA, GrebienF, GehartH, SchifrerM, ArtakerM, KovacicB, BeugH, MorigglR, MullnerEW. Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1. Blood, 112:3878–3888. 2008.
94.
KhanMA, WaldenWE, GossDJ, TheilEC. Direct Fe2 + sensing by iron responsive messenger RNA/repressor complexes weakens binding. J Biol Chem, 284:30122–30128. 2009.
95.
KiemerAK, ForngesAC, PantopoulosK, BilzerM, AndriopoulosB, GerwigT, KenngottS, GerbesAL, VollmarAM. ANP-induced decrease of iron regulatory protein activity is independent of HO-1 induction. Am J Physiol Gastrointest Liver Physiol, 287:G518–526. 2004.
96.
KimBH, JunYC, JinJK, KimJI, KimNH, LeiboldEA, ConnorJR, ChoiEK, CarpRI, KimYS. Alteration of iron regulatory proteins (IRP1 and IRP2) and ferritin in the brains of scrapie-infected mice. Neurosci Lett, 422:158–163. 2007.
97.
KimS, PonkaP. Effects of interferon-gamma and lipopolysaccharide on macrophage iron metabolism are mediated by nitric oxide-induced degradation of iron regulatory protein 2. J Biol Chem, 275:6220–6226. 2000.
98.
KimS, PonkaP. Nitric oxide-mediated modulation of iron regulatory proteins: implication for cellular iron homeostasis. Blood Cells Mol Dis, 29:400–410. 2002.
99.
KohlerSA, HendersonBR, KuhnLC. Succinate dehydrogenase b mRNA of Drosophila melanogaster has a functional iron-responsive element in its 5'-untranslated region. J Biol Chem, 270:30781–30786. 1995.
100.
KohlerSA, MenottiE, KuhnLC. Molecular cloning of mouse glycolate oxidase. High evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA. J Biol Chem, 274:2401–2407. 1999.
101.
KwokJC, RichardsonDR. Unexpected anthracycline-mediated alterations in iron-regulatory protein-RNA-binding activity: The iron and copper complexes of anthracyclines decrease RNA-binding activity. Mol Pharmacol, 62:888–900. 2002.
102.
LadasEJ, JacobsonJS, KennedyDD, TeelK, FleischauerA, KellyKM. Antioxidants and cancer therapy: A systematic review. J Clin Oncol, 22:517–528. 2004.
Latunde–DadaGO, TakeuchiK, SimpsonRJ, McKieAT. Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells. FEBS Lett, 580:6865–6870. 2006.
105.
LaVauteT, SmithS, CoopermanS, IwaiK, LandW, Meyron–HoltzE, DrakeSK, MillerG, Abu–AsabM, TsokosM, SwitzerR3rd, GrinbergA, LoveP, TresserN, RouaultTA. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet, 27:209–214. 2001.
106.
LeePJ, JiangBH, ChinBY, IyerNV, AlamJ, SemenzaGL, ChoiAM. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem, 272:5375–5381. 1997.
107.
LeedmanPJ, SteinAR, ChinWW, RogersJT. Thyroid hormone modulates the interaction between iron regulatory proteins and the ferritin mRNA iron-responsive element. J Biol Chem, 271:12017–12023. 1996.
108.
LeipuvieneR, TheilEC. The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen. Cell Mol Life Sci, 64:2945–2955. 2007.
LiZ, Chen–RoetlingJ, ReganRF. Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity. Free Radic Res, 43:613–621. 2009.
111.
LillR. Function and biogenesis of iron–sulphur proteins. Nature, 460:831–838. 2009.
112.
LiuW, ShimomuraS, ImanishiH, IwamotoY, IkedaN, SaitoM, OhnoM, HaraN, YamamotoT, NakamuraH, HadaT. Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene. Intern Med, 44:285–289. 2005.
113.
LiuXB, HillP, HaileDJ. Role of the ferroportin iron-responsive element in iron and nitric oxide dependent gene regulation. Blood Cells Mol Dis, 29:315–326. 2002.
114.
LiuYL, AngSO, WeigentDA, PrchalJT, BloomerJR. Regulation of ferrochelatase gene expression by hypoxia. Life Sci, 75:2035–2043. 2004.
115.
LokCN, PonkaP. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem, 274:24147–24152. 1999.
116.
LymboussakiA, PignattiE, MontosiG, GarutiC, HaileDJ, PietrangeloA. The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. J Hepatol, 39:710–715. 2003.
117.
LyuYL, KerriganJE, LinCP, AzarovaAM, TsaiYC, BanY, LiuLF. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res, 67:8839–8846. 2007.
118.
MackenzieB, GarrickMD. Iron Imports. II. Iron uptake at the apical membrane in the intestine. Am J Physiol Gastrointest Liver Physiol, 289:G981–986. 2005.
119.
MacKenzieEL, IwasakiK, TsujiY. Intracellular iron transport and storage: From molecular mechanisms to health implications. Antioxid Redox Signal, 10:997–1030. 2008.
120.
MaffettoneC, De MartinoL, IraceC, SantamariaR, PagniniU, IovaneG, ColonnaA. Expression of iron-related proteins during infection by bovine herpes virus type-1. J Cell Biochem, 104:213–223. 2008.
121.
MastrogiannakiM, MatakP, KeithB, SimonMC, VaulontS, PeyssonnauxC. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest, 119:1159–1166. 2009.
122.
Mattace RasoG, IraceC, EspositoE, MaffettoneC, IaconoA, Di PascaleA, SantamariaR, ColonnaA, MeliR. Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue. Biochem Pharmacol, 78:1001–1007. 2009.
123.
McKieAT. The role of Dcytb in iron metabolism: An update. Biochem Soc Trans, 36:1239–1241. 2008.
124.
McKieAT, MarcianiP, RolfsA, BrennanK, WehrK, BarrowD, MiretS, BomfordA, PetersTJ, FarzanehF, HedigerMA, HentzeMW, SimpsonRJ. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell, 5:299–309. 2000.
125.
McMahonS, GrondinF, McDonaldPP, RichardDE, DuboisCM. Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: Impact on the bioactivation of proproteins. J Biol Chem, 280:6561–6569. 2005.
MennaP, SalvatorelliE, MinottiG. Cardiotoxicity of antitumor drugs. Chem Res Toxicol, 21:978–989. 2008.
128.
Meyron–HoltzEG, GhoshMC, RouaultTA. Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science, 306:2087–2090. 2004.
129.
MinottiG, CairoG, MontiE. Role of iron in anthracycline cardiotoxicity: New tunes for an old song?FASEB J, 13:199–212. 1999.
130.
MinottiG, LicataS, SaponieroA, MennaP, CalafioreAM, Di GiammarcoG, LiberiG, AnimatiF, CipolloneA, ManziniS, MaggiCA. Anthracycline metabolism and toxicity in human myocardium: Comparisons between doxorubicin, epirubicin, and a novel disaccharide analogue with a reduced level of formation and [4Fe-4S] reactivity of its secondary alcohol metabolite. Chem Res Toxicol, 13:1336–1341. 2000.
131.
MinottiG, MennaP, SalvatorelliE, CairoG, GianniL. Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev, 56:185–229. 2004.
132.
MinottiG, ParlaniM, SalvatorelliE, MennaP, CipolloneA, AnimatiF, MaggiCA, ManziniS. Impairment of myocardial contractility by anticancer anthracyclines: Role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue. Br J Pharmacol, 134:1271–1278. 2001.
133.
MinottiG, RecalcatiS, MordenteA, LiberiG, CalafioreAM, MancusoC, PreziosiP, CairoG. The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase/iron regulatory protein-1 in cytosolic fractions from human myocardium. FASEB J, 12:541–552. 1998.
134.
MinottiG, RonchiR, SalvatorelliE, MennaP, CairoG. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: Evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res, 61:8422–8428. 2001.
135.
MokH, JelinekJ, PaiS, CattanachBM, PrchalJT, YoussoufianH, SchumacherA. Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. Development, 131:1859–1868. 2004.
136.
MoleDR. Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal, 12:445–458. 2010.
137.
MuckenthalerM, GunkelN, FrishmanD, CyrklaffA, TomancakP, HentzeMW. Iron-regulatory protein-1 (IRP-1) is highly conserved in two invertebrate species—Characterization of IRP-1 homologues in Drosophila melanogaster and Caenorhabditis elegans. Eur J Biochem, 254:230–237. 1998.
138.
MuckenthalerMU, GalyB, HentzeMW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr, 28:197–213. 2008.
139.
MuellerC, MagakiS, SchragM, GhoshMC, KirschWM. Iron regulatory protein 2 is involved in brain copper homeostasis. J Alzheimers Dis, 18:201–210. 2009.
140.
MukhopadhyayCK, MazumderB, FoxPL. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem, 275:21048–21054. 2000.
141.
NairzM, TheurlI, LudwiczekS, TheurlM, MairSM, FritscheG, WeissG. The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol, 9:2126–2140. 2007.
142.
NemethE, GanzT. Regulation of iron metabolism by hepcidin. Annu Rev Nutr, 26:323–342. 2006.
143.
NemethE, TuttleMS, PowelsonJ, VaughnMB, DonovanA, WardDM, GanzT, KaplanJ. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 306:2090–2093. 2004.
144.
NicolasG, ChauvetC, ViatteL, DananJL, BigardX, DevauxI, BeaumontC, KahnA, VaulontS. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest, 110:1037–1044. 2002.
145.
Nurtjahja–TjendraputraE, FuD, PhangJM, RichardsonDR. Iron chelation regulates cyclin D1 expression via the proteasome: A link to iron deficiency-mediated growth suppression. Blood, 109:4045–4054. 2007.
146.
O'DonnellKA, YuD, ZellerKI, KimJW, RackeF, Thomas–TikhonenkoA, DangCV. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol, 26:2373–2386. 2006.
147.
OktayY, DioumE, MatsuzakiS, DingK, YanLJ, HallerRG, SzwedaLI, GarciaJA. Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. J Biol Chem, 282:11750–11756. 2007.
148.
OliveiraL, DrapierJC. Down-regulation of iron regulatory protein 1 gene expression by nitric oxide. Proc Natl Acad Sci USA, 97:6550–6555. 2000.
149.
OliveiraSJ, PintoJP, PicaroteG, CostaVM, CarvalhoF, RangelM, de SousaM, de AlmeidaSF. ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity. PLoS One, 4:e6618. 2009.
150.
OrinoK, LehmanL, TsujiY, AyakiH, TortiSV, TortiFM. Ferritin and the response to oxidative stress. Biochem J, 357:241–247. 2001.
151.
PattonSM, PineroDJ, SurguladzeN, BeardJ, ConnorJR. Subcellular localization of iron regulatory proteins to Golgi and ER membranes. J Cell Sci, 118:4365–4373. 2005.
152.
PeyssonnauxC, NizetV, JohnsonRS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle, 7:28–32. 2008.
153.
PeyssonnauxC, ZinkernagelAS, SchuepbachRA, RankinE, VaulontS, HaaseVH, NizetV, JohnsonRS. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)J Clin Invest, 117:1926–1932. 2007.
154.
PiccinelliP, SamuelssonT. Evolution of the iron-responsive element. RNA, 13:952–966. 2007.
155.
PietrangeloA. Hereditary hemochromatosis—A new look at an old disease. N Engl J Med, 350:2383–2397. 2004.
156.
PopelovaO, SterbaM, SimunekT, MazurovaY, GuncovaI, HrochM, AdamcovaM, GerslV. Deferiprone does not protect against chronic anthracycline cardiotoxicity in vivo. J Pharmacol Exp Ther, 326:259–269. 2008.
157.
QiuA, JansenM, SakarisA, MinSH, ChattopadhyayS, TsaiE, SandovalC, ZhaoR, AkabasMH, GoldmanID. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell, 127:917–928. 2006.
158.
QuigleyJG, YangZ, WorthingtonMT, PhillipsJD, SaboKM, SabathDE, BergCL, SassaS, WoodBL, AbkowitzJL. Identification of a human heme exporter that is essential for erythropoiesis. Cell, 118:757–766. 2004.
159.
RecalcatiS, AlberghiniA, CampanellaA, GianelliU, De CamilliE, ConteD, CairoG. Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: Expression and regulation in hereditary hemochromatosis and iron deficiency. Haematologica, 91:303–310. 2006.
160.
RecalcatiS, ConteD, CairoG. Preferential activation of iron regulatory protein-2 in cell lines as a result of higher sensitivity to iron. Eur J Biochem, 259:304–309. 1999.
161.
RecalcatiS, InvernizziP, ArosioP, CairoG. New functions for an iron storage protein: The role of ferritin in immunity and autoimmunity. J Autoimmun, 30:84–89. 2008.
162.
RecalcatiS, LocatiM, MariniA, SantambrogioP, ZaninottoF, De PizzolM, ZammataroL, GirelliD, CairoG. Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol, 40:824–835. 2010.
163.
RecalcatiS, PomettaR, LeviS, ConteD, CairoG. Response of monocyte iron regulatory protein activity to inflammation: Abnormal behavior in genetic hemochromatosis. Blood, 91:2565–2572. 1998.
164.
RecalcatiS, TacchiniL, AlberghiniA, ConteD, CairoG. Oxidative stress-mediated down-regulation of rat hydroxyacid oxidase 1, a liver-specific peroxisomal enzyme. Hepatology, 38:1159–1166. 2003.
165.
RecalcatiS, TaramelliD, ConteD, CairoG. Nitric oxide-mediated induction of ferritin synthesis in J774 macrophages by inflammatory cytokines: Role of selective iron regulatory protein-2 downregulation. Blood, 91:1059–1066. 1998.
166.
RobachP, CairoG, GelfiC, BernuzziF, PilegaardH, ViganoA, SantambrogioP, CerretelliP, CalbetJA, MoutereauS, LundbyC. Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle. Blood, 109:4724–4731. 2007.
167.
RobachP, RecalcatiS, GirelliD, GelfiC, Aachmann-AndersenNJ, ThomsenJJ, NorgaardAM, AlberghiniA, CampostriniN, CastagnaA, ViganoA, SantambrogioP, KempfT, WollertKC, MoutereauS, LundbyC, CairoG. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin. Blood, 113:6707–6715. 2009.
168.
RogersJT, BushAI, ChoHH, SmithDH, ThomsonAM, FriedlichAL, LahiriDK, LeedmanPJ, HuangX, CahillCM. Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: Riboregulation against neural oxidative damage in Alzheimer's disease. Biochem Soc Trans, 36:1282–1287. 2008.
169.
RogersJT, RandallJD, CahillCM, EderPS, HuangX, GunshinH, LeiterL, McPheeJ, SarangSS, UtsukiT, GreigNH, LahiriDK, TanziRE, BushAI, GiordanoT, GullansSR. An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem, 277:45518–45528. 2002.
170.
RolfsA, KvietikovaI, GassmannM, WengerRH. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem, 272:20055–20062. 1997.
171.
RothenbergerS, MullnerEW, KuhnLC. The mRNA-binding protein which controls ferritin and transferrin receptor expression is conserved during evolution. Nucleic Acids Res, 18:1175–1179. 1990.
172.
RouaultTA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol, 2:406–414. 2006.
173.
SalahudeenAA, ThompsonJW, RuizJC, MaHW, KinchLN, LiQ, GrishinNV, BruickRK. An E3 ligase possessing an iron responsive hemerythrin domain is a regulator of iron homeostasis. Science, 326:722–726. 2009.
174.
SamaniegoF, ChinJ, IwaiK, RouaultTA, KlausnerRD. Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2. Structure, function, and post-translational regulation. J Biol Chem, 269:30904–30910. 1994.
175.
SammarcoMC, DitchS, BanerjeeA, GrabczykE. Ferritin L and H subunits are differentially regulated on a post-transcriptional level. J Biol Chem, 283:4578–4587. 2008.
176.
SanchezM, GalyB, DandekarT, BengertP, VainshteinY, StolteJ, MuckenthalerMU, HentzeMW. Iron regulation and the cell cycle: Identification of an iron-responsive element in the 3'-untranslated region of human cell division cycle 14A mRNA by a refined microarray-based screening strategy. J Biol Chem, 281:22865–22874. 2006.
177.
SanchezM, GalyB, MuckenthalerMU, HentzeMW. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol, 14:420–426. 2007.
178.
SchalinskeKL, BlemingsKP, SteffenDW, ChenOS, EisensteinRS. Iron regulatory protein 1 is not required for the modulation of ferritin and transferrin receptor expression by iron in a murine pro-B lymphocyte cell line. Proc Natl Acad Sci USA, 94:10681–10686. 1997.
179.
SchalinskeKL, ChenOS, EisensteinRS. Iron differentially stimulates translation of mitochondrial aconitase and ferritin mRNAs in mammalian cells. Implications for iron regulatory proteins as regulators of mitochondrial citrate utilization. J Biol Chem, 273:3740–3746. 1998.
180.
SchneiderBD, LeiboldEA. Effects of iron regulatory protein regulation on iron homeostasis during hypoxia. Blood, 102:3404–3411. 2003.
181.
SchranzhoferM, SchifrerM, CabreraJA, KoppS, ChibaP, BeugH, MullnerEW. Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood, 107:4159–4167. 2006.
182.
SchroederSE, ReddyMB, SchalinskeKL. Retinoic acid modulates hepatic iron homeostasis in rats by attenuating the RNA-binding activity of iron regulatory proteins. J Nutr, 137:2686–2690. 2007.
183.
SeiserC, TeixeiraS, KuhnLC. Interleukin-2-dependent transcriptional and post-transcriptional regulation of transferrin receptor mRNA. J Biol Chem, 268:13074–13080. 1993.
184.
SemenzaGL. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda), 24:97–106. 2009.
185.
SemenzaGL, WangGL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol, 12:5447–5454. 1992.
186.
ShahYM, MatsubaraT, ItoS, YimSH, GonzalezFJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab, 9:152–164. 2009.
Sheikh-AliM, ChehadeJM, MooradianAD. The antioxidant paradox in diabetes mellitus. Am J Ther, 2009Sep 21. [Epub ahead of print]
189.
ShethS, BrittenhamGM. Genetic disorders affecting proteins of iron metabolism: Clinical implications. Annu Rev Med, 51:443–464. 2000.
190.
ShiR, HuangCC, AronstamRS, ErcalN, MartinA, HuangYW. N-acetylcysteine amide decreases oxidative stress but not cell death induced by doxorubicin in H9c2 cardiomyocytes. BMC Pharmacol, 9:7. 2009.
191.
SiesH. Oxidative stress: Oxidants and antioxidants. Exp Physiol, 82:291–295. 1997.
192.
SilvestriL, PaganiA, CamaschellaC. Furin-mediated release of soluble hemojuvelin: A new link between hypoxia and iron homeostasis. Blood, 111:924–931. 2008.
193.
SmithAG, ClothierB, RobinsonS, ScullionMJ, CarthewP, EdwardsR, LuoJ, LimCK, ToledanoM. Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: A hepatic oxidative mechanism. Mol Pharmacol, 53:52–61. 1998.
194.
SmithSR, CoopermanS, LavauteT, TresserN, GhoshM, Meyron–HoltzE, LandW, OllivierreH, JortnerB, SwitzerR3rd, MessingA, RouaultTA. Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies. Ann NY Acad Sci, 1012:65–83. 2004.
195.
StarzynskiRR, GoncalvesAS, MuzeauF, TyrolczykZ, SmudaE, DrapierJC, BeaumontC, LipinskiP. STAT5 proteins are involved in down-regulation of iron regulatory protein 1 gene expression by nitric oxide. Biochem J, 400:367–375. 2006.
196.
SterbaM, PopelovaO, SimunekT, MazurovaY, PotacovaA, AdamcovaM, KaiserovaH, PonkaP, GerslV. Cardioprotective effects of a novel iron chelator, pyridoxal 2-chlorobenzoyl hydrazone, in the rabbit model of daunorubicin-induced cardiotoxicity. J Pharmacol Exp Ther, 319:1336–1347. 2006.
TacchiniL, Fusar PoliD, Bernelli–ZazzeraA, CairoG. Transferrin receptor gene expression and transferrin-bound iron uptake are increased during postischemic rat liver reperfusion. Hepatology, 36:103–111. 2002.
199.
TacchiniL, GammellaE, De PontiC, RecalcatiS, CairoG. Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. J Biol Chem, 283:20674–20686. 2008.
200.
TacchiniL, RecalcatiS, Bernelli–ZazzeraA, CairoG. Induction of ferritin synthesis in ischemic-reperfused rat liver: Analysis of the molecular mechanisms. Gastroenterology, 113:946–953. 1997.
201.
TeixeiraS, KuhnLC. Post-transcriptional regulation of the transferrin receptor and 4F2 antigen heavy chain mRNA during growth activation of spleen cells. Eur J Biochem, 202:819–826. 1991.
202.
TestaU, KuhnL, PetriniM, QuarantaMT, PelosiE, PeschleC. Differential regulation of iron regulatory element-binding protein(s) in cell extracts of activated lymphocytes versus monocytes-macrophages. J Biol Chem, 266:13925–13930. 1991.
203.
TheilEC. Targeting mRNA to regulate iron and oxygen metabolism. Biochem Pharmacol, 59:87–93. 2000.
204.
TheilEC, EisensteinRS. Combinatorial mRNA regulation: Iron regulatory proteins and iso-iron-responsive elements (Iso-IREs)J Biol Chem, 275:40659–40662. 2000.
205.
TortiFM, TortiSV. Regulation of ferritin genes and protein. Blood, 99:3505–3516. 2002.
206.
TothI, YuanL, RogersJT, BoyceH, BridgesKR. Hypoxia alters iron-regulatory protein-1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells. J Biol Chem, 274:4467–4473. 1999.
207.
TsujiY, AyakiH, WhitmanSP, MorrowCS, TortiSV, TortiFM. Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. Mol Cell Biol, 20:5818–5827. 2000.
208.
van HeldenYG, KeijerJ, KnaapenAM, HeilSG, BriedeJJ, van SchootenFJ, GodschalkRW. Beta-carotene metabolites enhance inflammation-induced oxidative DNA damage in lung epithelial cells. Free Radic Biol Med, 46:299–304. 2009.
209.
VashishtAA, ZumbrennenKB, HuangX, PowersDN, DurazoA, SunD, BhaskaranN, PerssonA, UhlenM, SangfeltO, SpruckC, LeiboldEA, WohlschlegelJA. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science, 326:718–721. 2009.
210.
VecchiC, MontosiG, ZhangK, LambertiI, DuncanSA, KaufmanRJ, PietrangeloA. ER stress controls iron metabolism through induction of hepcidin. Science, 325:877–880. 2009.
211.
ViatteL, GroneHJ, HentzeMW, GalyB. In vivo role(s) of the iron regulatory proteins (IRP) 1 and 2 in aseptic local inflammation. J Mol Med, 87:913–921. 2009.
212.
VolzK. The functional duality of iron regulatory protein 1. Curr Opin Struct Biol, 18:106–111. 2008.
213.
WaldenWE, SeleznevaAI, DupuyJ, VolbedaA, Fontecilla-CampsJC, TheilEC, VolzK. Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science, 314:1903–1908. 2006.
214.
WallanderML, LeiboldEA, EisensteinRS. Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Biochim Biophys Acta, 1763:668–689. 2006.
215.
WallanderML, ZumbrennenKB, RodanskyES, RomneySJ, LeiboldEA. Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle. J Biol Chem, 283:23589–23598. 2008.
216.
WangJ, ChenG, MuckenthalerM, GalyB, HentzeMW, PantopoulosK. Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol, 24:954–965. 2004.
217.
WangJ, FillebeenC, ChenG, BiederbickA, LillR, PantopoulosK. Iron-dependent degradation of Apo-IRP1 by the ubiquitin-proteasome pathway. Mol Cell Biol, 27:2423–2430. 2007.
218.
WangW, DiX, D'AgostinoRBJr., TortiSV, TortiFM. Excess capacity of the iron regulatory protein system. J Biol Chem, 282:24650–24659. 2007.
219.
WeissG. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta, 1790:682–693. 2009.
220.
Wessling–ResnickM. Iron imports. III. Transfer of iron from the mucosa into circulation. Am J Physiol Gastrointest Liver Physiol, 290:G1–6. 2006.
WrightingDM, AndrewsNC. Iron homeostasis and erythropoiesis. Curr Top Dev Biol, 82:141–167. 2008.
223.
WuKJ, PolackA, Dalla–FaveraR. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science, 283:676–679. 1999.
224.
YamanakaK, IshikawaH, MegumiY, TokunagaF, KanieM, RouaultTA, MorishimaI, MinatoN, IshimoriK, IwaiK. Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cell Biol, 5:336–340. 2003.
225.
YuY, KovacevicZ, RichardsonDR. Tuning cell cycle regulation with an iron key. Cell Cycle, 6:1982–1994. 2007.
226.
ZahringerJ, BaligaBS, MunroHN. Novel mechanism for translational control in regulation of ferritin synthesis by iron. Proc Natl Acad Sci USA, 73:857–861. 1976.
ZhangAS, EnnsCA. Iron homeostasis: Recently identified proteins provide insight into novel control mechanisms. J Biol Chem, 284:711–715. 2009.
229.
ZhangDL, HughesRM, Ollivierre–WilsonH, GhoshMC, RouaultTA. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab, 9:461–473. 2009.
230.
ZhangF, WangW, TsujiY, TortiSV, TortiFM. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem, 283:33911–33918. 2008.
231.
ZimmerM, EbertBL, NeilC, BrennerK, PapaioannouI, MelasA, TollidayN, LambJ, PantopoulosK, GolubT, IliopoulosO. Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing. Mol Cell, 32:838–848. 2008.
232.
ZumbrennenKB, HansonES, LeiboldEA. HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells. Biochim Biophys Acta, 1783:246–252. 2008.
233.
ZumbrennenKB, WallanderML, RomneySJ, LeiboldEA. Cysteine oxidation regulates the RNA-binding activity of iron regulatory protein 2. Mol Cell Biol, 29:2219–2229. 2009.
