The IRP/IRE system in vivo: Insights from mouse models

Frontiers in Pharmacology

Volumn 5 JUL, Issue , 2014, Pages

  Wilkinson, Nicole ^a   Pantopoulos, Kostas ^a  

^a MCGILL UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

5 AMINOLEVULINATE SYNTHASE 2; ACYLTRANSFERASE; CD71 ANTIGEN; HEME; HYPOXIA INDUCIBLE FACTOR 2ALPHA; IRON; IRON REGULATORY FACTOR; IRON REGULATORY PROTEIN 1; IRON REGULATORY PROTEIN 2; MESSENGER RNA; OXYGEN; UNCLASSIFIED DRUG;

ARTICLE; ENERGY METABOLISM; ERYTHROID PRECURSOR CELL; ERYTHROPOIESIS; GENE DISRUPTION; GENE EXPRESSION; GENE MUTATION; GENETIC ASSOCIATION; HEME SYNTHESIS; HUMAN; IN VIVO STUDY; IRON ABSORPTION; IRON METABOLISM; IRON OVERLOAD; IRON RESPONSIVE ELEMENT; IRON TRANSPORT; LETHALITY; LIVER FAILURE; MALABSORPTION; MICROCYTIC ANEMIA; NEOPLASM; NEUROLOGIC DISEASE; NONHUMAN; PATHOGENESIS; POLYCYTHEMIA; PROTEIN FUNCTION; PULMONARY HYPERTENSION; RNA STABILITY; TRANSCRIPTION REGULATION; TRANSLATION REGULATION;

EID: 84904764584     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2014.00176     Document Type: Article

References (128)

1. Aisen, P. (2004). Transferrin receptor 1. Int. J. Biochem. Cell Biol. 36, 2137-2143.
2. Aisen, P., Enns, C., and Wessling-Resnick, M. (2001). Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol. 33, 940-959.
3. Allerson, C.R., Cazzola, M., and Rouault, T.A. (1999). Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome. J. Biol. Chem. 274, 26439-26447.
4. Anderson, S.A., Nizzi, C.P., Chang, Y.I., Deck, K.M., Schmidt, P.J., Galy, B., Damnernsawad, A., Broman, A.T., Kendziorski, C., Hentze, M.W., Fleming, M.D., Zhang, J., and Eisenstein, R.S. (2013). The IRP1-HIF-2alpha Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption. Cell Metab 17, 282-290.
5. Ang, S.O., Chen, H., Hirota, K., Gordeuk, V.R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A.I., Miasnikova, G.Y., Mole, D., Maxwell, P.H., Stockton, D.W., Semenza, G.L., and Prchal, J.T. (2002). Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32, 614-621.
6. Arosio, P., Ingrassia, R., and Cavadini, P. (2009). Ferritins: A family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta 1790, 589-599.
7. Beaumont, C., Leneuve, P., Devaux, I., Scoazec, J.-Y., Berthier, M., Loiseau, M.-N., Grandchamp, B., and Bonneau, D. (1995). Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract. Nat. Genet. 11, 444-446.
8. Brasse-Lagnel, C., Karim, Z., Letteron, P., Bekri, S., Bado, A., and Beaumont, C. (2011). Intestinal DMT1 cotransporter is down-regulated by hepcidin via proteasome internalization and degradation. Gastroenterology 140, 1261-1271 e1261.
9. Burn, J., and Chinnery, P.F. (2006). Neuroferritinopathy. Semin Pediatr Neurol 13, 176-181.
10. Camaschella, C., Campanella, A., De Falco, L., Boschetto, L., Merlini, R., Silvestri, L., Levi, S., and Iolascon, A. (2007). The human counterpart of zebrafish shiraz shows sideroblasticlike microcytic anemia and iron overload. Blood 110, 1353-1358.
11. Canonne-Hergaux, F., Gruenheid, S., Ponka, P., and Gros, P. (1999). Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93, 4406-4417.
12. Casarrubea, D., Viatte, L., Hallas, T., Vasanthakumar, A., Eisenstein, R.S., Schumann, K., Hentze, M.W., and Galy, B. (2013). Abnormal body iron distribution and erythropoiesis in a novel mouse model with inducible gain of iron regulatory protein (IRP)-1 function. J Mol Med (Berl) 91, 871-881.
13. Casey, J.L., Hentze, M.W., Koeller, D.M., Caughman, S.W., Rouault, T.A., Klausner, R.D., and Harford, J.B. (1988). Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science 240, 924-928.
14. Casey, J.L., Koeller, D.M., Ramin, V.C., Klausner, R.D., and Harford, J.B. (1989). Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA. EMBO J. 8, 3693-3699.
15. Cavill, I. (2002). Erythropoiesis and iron. Best Pract Res Clin Haematol 15, 399-409.
16. Cazzola, M., Bergamaschi, G., Tonon, L., Arbustini, E., Grasso, M., Vercesi, E., Baroi, G., Bianchi, P.E., Cairo, G., and Arosio, P. (1997). Hereditary hyperferritinemia-cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA. Blood 90, 814-821.
17. Chappell, S.L., Daly, L., Lotya, J., Alsaegh, A., Guetta-Baranes, T., Roca, J., Rabinovich, R., Morgan, K., Millar, A.B., Donnelly, S.C., Keatings, V., Macnee, W., Stolk, J., Hiemstra, P.S., Miniati, M., Monti, S., O'connor, C.M., and Kalsheker, N. (2011). The role of IREB2 and transforming growth factor beta-1 genetic variants in COPD: a replication case-control study. BMC Med Genet 12, 24.
18. Chen, G., Fillebeen, C., Wang, J., and Pantopoulos, K. (2007). Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis 28, 785-791.
19. Cho, H.H., Cahill, C.M., Vanderburg, C.R., Scherzer, C.R., Wang, B., Huang, X., and Rogers, J.T. (2010). Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1. J Biol Chem 285, 31217-31232.
20. Cho, M.H., Castaldi, P.J., Wan, E.S., Siedlinski, M., Hersh, C.P., Demeo, D.L., Himes, B.E., Sylvia, J.S., Klanderman, B.J., Ziniti, J.P., Lange, C., Litonjua, A.A., Sparrow, D., Regan, E.A., Make, B.J., Hokanson, J.E., Murray, T., Hetmanski, J.B., Pillai, S.G., Kong, X., Anderson, W.H., Tal-Singer, R., Lomas, D.A., Coxson, H.O., Edwards, L.D., Macnee, W., Vestbo, J., Yates, J.C., Agusti, A., Calverley, P.M., Celli, B., Crim, C., Rennard, S., Wouters, E., Bakke, P., Gulsvik, A., Crapo, J.D., Beaty, T.H., Silverman, E.K., on behalf of the ICGN, ECLIPSE, and COPDGene Investigators (2012). A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet 21, 947-957.
21. Chollangi, S., Thompson, J.W., Ruiz, J.C., Gardner, K.H., and Bruick, R.K. (2012). Hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5) communicates cellular iron and oxygen availability by distinct mechanisms. J Biol Chem 287, 23710-23717.
22. Chung, B., Chaston, T., Marks, J., Srai, S.K., and Sharp, P.A. (2009). Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells. J Nutr 139, 1457-1462.
23. Clarke, S.L., Vasanthakumar, A., Anderson, S.A., Pondarre, C., Koh, C.M., Deck, K.M., Pitula, J.S., Epstein, C.J., Fleming, M.D., and Eisenstein, R.S. (2006). Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. EMBO J. 25, 544-553.
24. Coon, K.D., Siegel, A.M., Yee, S.J., Dunckley, T.L., Mueller, C., Nagra, R.M., Tourtellotte, W.W., Reiman, E.M., Papassotiropoulos, A., Petersen, F.F., Stephan, D.A., and Kirsch, W.M. (2006). Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease. J Alzheimers Dis 9, 225-233.
25. Cooperman, S.S., Meyron-Holtz, E.G., Olivierre-Wilson, H., Ghosh, M.C., Mcconnell, J.P., and Rouault, T.A. (2005). Microcytic anemia, erythropoietic protoporphyria and neurodegeneration in mice with targeted deletion of iron regulatory protein 2. Blood 106, 1084-1091.
26. Corradini, E., Meynard, D., Wu, Q., Chen, S., Ventura, P., Pietrangelo, A., and Babitt, J.L. (2011). Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology 54, 273-284.
27. Daba, A., Koromilas, A.E., and Pantopoulos, K. (2012). Alternative ferritin mRNA translation via internal initiation. RNA 18, 547-556.
28. Dandekar, T., and Hentze, M.W. (1995). Finding the hairpin in the haystack: searching for RNA motifs. Trends in Genetics 11, 45-50.
29. Darshan, D., Wilkins, S.J., Frazer, D.M., and Anderson, G.J. (2011). Reduced expression of ferroportin-1 mediates hyporesponsiveness of suckling rats to stimuli that reduce iron absorption. Gastroenterology 141, 300-309.
30. Demeo, D.L., Mariani, T., Bhattacharya, S., Srisuma, S., Lange, C., Litonjua, A., Bueno, R., Pillai, S.G., Lomas, D.A., Sparrow, D., Shapiro, S.D., Criner, G.J., Kim, H.P., Chen, Z., Choi, A.M., Reilly, J., and Silverman, E.K. (2009). Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet 85, 493-502.
31. Drapier, J.C., Hirling, H., Wietzerbin, J., Kaldy, P., and Kühn, L.C. (1993). Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J. 12, 3643-3649.
32. Dupuy, J., Volbeda, A., Carpentier, P., Darnault, C., Moulis, J.M., and Fontecilla-Camps, J.C. (2006). Crystal structure of human iron regulatory protein 1 as cytosolic aconitase. Structure 14, 129-139.
33. Faucheux, B.A., Martin, M.E., Beaumont, C., Hunot, S., Hauw, J.J., Agid, Y., and Hirsch, E.C. (2002). 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.
34. Fehringer, G., Liu, G., Pintilie, M., Sykes, J., Cheng, D., Liu, N., Chen, Z., Seymour, L., Der, S.D., Shepherd, F.A., Tsao, M.S., and Hung, R.J. (2012). Association of the 15q25 and5p15 lung cancer susceptibility regions with gene expression in lung tumor tissue. Cancer Epidemiol Biomarkers Prev 21, 1097-1104.
35. Ferring-Appel, D., Hentze, M.W., and Galy, B. (2009). Cell-autonomous and systemic contextdependent functions of iron regulatory protein 2 in mammalian iron metabolism. Blood 113, 679-687.
36. Finch, C. (1994). Regulators of iron balance in humans. Blood 84, 1697-1702.
37. Galy, B., Ferring, D., and Hentze, M.W. (2005a). Generation of conditional alleles of the murine iron regulatory protein (IRP)-1 and -2 genes. Genesis 43, 181-188.
38. Galy, B., Ferring, D., Minana, B., Bell, O., Janser, H.G., Muckenthaler, M., Schumann, K., and Hentze, M.W. (2005b). Altered body iron distribution and microcytosis in mice deficient for iron regulatory protein 2 (IRP2). Blood 106, 2580-2589.
39. Galy, B., Ferring-Appel, D., Becker, C., Gretz, N., Grone, H.J., Schumann, K., and Hentze, M.W. (2013). Iron regulatory proteins control a mucosal block to intestinal iron absorption. Cell Rep 3, 844-857.
40. Galy, B., Ferring-Appel, D., Kaden, S., Grone, H.J., and Hentze, M.W. (2008). Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab. 7, 79-85.
41. Galy, B., Ferring-Appel, D., Sauer, S.W., Kaden, S., Lyoumi, S., Puy, H., Kolker, S., Grone, H.J., and Hentze, M.W. (2010). Iron regulatory proteins secure mitochondrial iron sufficiency and function. Cell Metab 12, 194-201.
42. Galy, B., Hölter, S.M., Klopstock, T., Ferring, D., Becker, L., Kaden, S., Wurst, W., Gröne, H.-J., and Hentze, M.W. (2006). Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat. Genet. 38, 967-969.
43. Ganz, T. (2013). Systemic iron homeostasis. Physiol Rev 93, 1721-1741.
44. Ghosh, M.C., Ollivierre-Wilson, H., Cooperman, S., and Rouault, T.A. (2006). Reply to Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat. Genet. 38, 969-970.
45. Ghosh, M.C., Tong, W.H., Zhang, D., Ollivierre-Wilson, H., Singh, A., Krishna, M.C., Mitchell, J.B., and Rouault, T.A. (2008). Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105, 12028-12033.
46. Ghosh, M.C., Zhang, D.L., Jeong, S.Y., Kovtunovych, G., Ollivierre-Wilson, H., Noguchi, A., Tu, T., Senecal, T., Robinson, G., Crooks, D.R., Tong, W.H., Ramaswamy, K., Singh, A., Graham, B.B., Tuder, R.M., Yu, Z.X., Eckhaus, M., Lee, J., Springer, D.A., and Rouault, T.A. (2013). Deletion of Iron Regulatory Protein 1 Causes Polycythemia and Pulmonary Hypertension in Mice through Translational Derepression of HIF2alpha. Cell Metab 17, 271-281.
47. Gkouvatsos, K., Papanikolaou, G., and Pantopoulos, K. (2012). Regulation of iron transport and the role of transferrin. Biochim Biophys Acta 1820, 188-202.
48. Gunshin, H., Allerson, C.R., Polycarpou-Schwarz, M., Rofts, A., Rogers, J.T., Kishi, F., Hentze, M.W., Rouault, T.A., Andrews, N.C., and Hediger, M.A. (2001). Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett. 509, 309-316.
49. Gunshin, H., Mackenzie, B., Berger, U.V., Gunshin, Y., Romero, M.F., Boron, W.F., Nussberger, S., Gollan, J.L., and Hediger, M.A. (1997). Cloning and characterization of a mammalian protein-coupled metal-ion transporter. Nature 388, 482-488.
50. Haile, D.J., Rouault, T.A., Harford, J.B., Kennedy, M.C., Blondin, G.A., Beinert, H., and Klausner, R.D. (1992). Cellular regulation of the iron-responsive element binding protein: disassembly of the cubane iron-sulfur cluster results in high-affinity RNA binding. Proc. Natl. Acad. Sci. USA 89, 11735-11739.
51. Hansen, H.M., Xiao, Y., Rice, T., Bracci, P.M., Wrensch, M.R., Sison, J.D., Chang, J.S., Smirnov, I.V., Patoka, J., Seldin, M.F., Quesenberry, C.P., Kelsey, K.T., and Wiencke, J.K. (2010). Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans. Hum Mol Genet 19, 3652-3661.
52. Hausmann, A., Lee, J., and Pantopoulos, K. (2011). Redox control of iron regulatory protein 2 stability. FEBS Lett 585, 687-692.
53. Hentze, M.W., Caughman, S.W., Rouault, T.A., Barriocanal, J.G., Dancis, A., Harford, J.B., and Klausner, R.D. (1987). Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science 238, 1570-1573.
54. Huang, H., Constante, M., Layoun, A., and Santos, M.M. (2009). Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli. Blood 113, 3593-3599.
55. Hubert, N., and Hentze, M.W. (2002). Previously uncharacterized isoforms of divalent metal transporter (DMT)- 1: implications for regulation and cellular function. Proc. Natl. Acad. Sci. USA 99, 12345-12350.
56. Jeong, S.Y., Crooks, D.R., Wilson-Ollivierre, H., Ghosh, M.C., Sougrat, R., Lee, J., Cooperman, S., Mitchell, J.B., Beaumont, C., and Rouault, T.A. (2011). Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice. PLoS One 6, e25404.
57. Joshi, R., Morán, E., and Sanchez, M. (2012). Cellular iron metabolism. The IRP/IRE regulatory network, in Iron metabolism, ed. S. Arora. InTech), 25-58.
58. Kallianpur, A.R., Jia, P., Ellis, R.J., Zhao, Z., Bloss, C., Wen, W., Marra, C.M., Hulgan, T., Simpson, D.M., Morgello, S., Mcarthur, J.C., Clifford, D.B., Collier, A., C., Gelman, B.B., Mccutchan, J.A., Franklin, D., Samuels, D.C., Rosario, D., Holzinger, E., Murdock, D.G., Letendre, S., Grant, I., and CHARTER Study Group (2014). Genetic Variation in Iron Metabolism is Associated with Neuropathic Pain and Pain Severity in HIV-Infected Patients on Antiretroviral Therapy. PLoS One in press.
59. Kapitsinou, P.P., Liu, Q., Unger, T.L., Rha, J., Davidoff, O., Keith, B., Epstein, J.A., Moores, S.L., Erickson-Miller, C.L., and Haase, V.H. (2010). Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 116, 3039-3048.
60. Kato, J., Fujikawa, K., Kanda, M., Fukuda, N., Sasaki, K., Takayama, T., Kobune, M., Takada, K., Takimoto, R., Hamada, H., Ikeda, T., and Niitsu, Y. (2001). A mutation, in the ironresponsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am. J. Hum. Genet. 69, 191-197.
61. Keith, B., Johnson, R.S., and Simon, M.C. (2012). HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12, 9-22.
62. Koury, M.J., and Bondurant, M.C. (1990). Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248, 378-381.
63. Lavaute, T., Smith, S., Cooperman, S., Iwai, K., Land, W., Meyron-Holtz, E., Drake, S.K., Miller, G., Abu-Asab, M., Tsokos, M., Switzer, R., 3rd, Grinberg, A., Love, P., Tresser, N., and Rouault, T.A. (2001). Targeted deletion of the gene encoding iron regulatoryprotein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat. Genet. 27, 209-214.
64. Levi, S., and Arosio, P. (2004). Mitochondrial ferritin. Int. J. Biochem. Cell Biol. 36, 1887-1889.
65. Levi, S., Girelli, D., Perrone, F., Pasti, M., Beaumont, C., Corrocher, R., Albertini, A., and Arosio, P. (1998). Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome. Blood 91, 4180-4187.
66. Liu, Q., Davidoff, O., Niss, K., and Haase, V.H. (2012). Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest 122, 4635-4644.
67. Lobmayr, L., Brooks, D.G., and Wilson, R.B. (2005). Increased IRP1 activity in Friedreich ataxia. Gene 354, 157-161.
68. Luscieti, S., Tolle, G., Aranda, J., Campos, C.B., Risse, F., Moran, E., Muckenthaler, M.U., and Sanchez, M. (2013). Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome. Orphanet J Rare Dis 8, 30.
69. Maffettone, C., Chen, G., Drozdov, I., Ouzounis, C., and Pantopoulos, K. (2010). Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert. PLoS One 5, e10163.
70. Mastrogiannaki, M., Matak, P., Keith, B., Simon, M.C., Vaulont, S., and Peyssonnaux, C. (2009). HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest 119, 1159-1166.
71. Mastrogiannaki, M., Matak, P., Mathieu, J.R., Delga, S., Mayeux, P., Vaulont, S., and Peyssonnaux, C. (2012). Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica 97, 827-834
72. Mastrogiannaki, M., Matak, P., and Peyssonnaux, C. (2013). The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 122, 885-892.
73. Mckie, A.T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., Miret, S., Bomford, A., Peters, T.J., Farzaneh, F., Hediger, M.A., Hentze, M.W., and Simpson, R.J. (2000). A novel duodenal iron-regulated transporter IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 5, 299-309.
74. Meynard, D., Babitt, J.L., and Lin, H.Y. (2014). The liver: conductor of systemic iron balance. Blood 123, 168-176.
75. Meyron-Holtz, E.G., Ghosh, M.C., Iwai, K., Lavaute, T., Brazzolotto, X., Berger, U.V., Land, W., Ollivierre-Wilson, H., Grinberg, A., Love, P., and Rouault, T.A. (2004a). Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 23, 386-395.
76. Meyron-Holtz, E.G., Ghosh, M.C., and Rouault, T.A. (2004b). Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science 306, 2087-2090.
77. Moroishi, T., Nishiyama, M., Takeda, Y., Iwai, K., and Nakayama, K.I. (2011). The FBXL5-IRP2 Axis Is Integral to Control of Iron Metabolism In Vivo. Cell Metab 14, 339-351.
78. Müllner, E.W., and Kühn, L.C. (1988). A stem-loop in the 3' untranslated region mediates irondependent regulation of transferrin receptor mRNA stability in the cytoplasm. Cell 53, 815-825.
79. Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., Ganz, T., and Kaplan, J. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090-2093.
80. Pantopoulos, K., and Hentze, M.W. (1995). Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 14, 2917-2924.
81. Papanikolaou, G., and Pantopoulos, K. (2005). Iron metabolism and toxicity. Toxicol. Appl. Pharmacol. 202, 199-211.
82. Percy, M.J., Furlow, P.W., Lucas, G.S., Li, X., Lappin, T.R., Mcmullin, M.F., and Lee, F.S. (2008). A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 358, 162-168
83. Percy, M.J., Zhao, Q., Flores, A., Harrison, C., Lappin, T.R., Maxwell, P.H., Mcmullin, M.F., and Lee, F.S. (2006). A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 103, 654-659.
84. Piccinelli, P., and Samuelsson, T. (2007). Evolution of the iron-responsive element. RNA 13, 952-966.
85. Ponka, P. (1997). Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 89, 1-25.
86. Ramos, E., Kautz, L., Rodriguez, R., Hansen, M., Gabayan, V., Ginzburg, Y., Roth, M.P., Nemeth, E., and Ganz, T. (2011). Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 53, 1333-1341.
87. Rankin, E.B., Biju, M.P., Liu, Q., Unger, T.L., Rha, J., Johnson, R.S., Simon, M.C., Keith, B., and Haase, V.H. (2007). Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 117, 1068-1077.
88. Roetto, A., Bosio, S., Gramaglia, E., Barilaro, M.R., Zecchina, G., and Camaschella, C. (2002). Pathogenesis of hyperferritinemia cataract syndrome. Blood Cells Mol. Dis. 29, 532-535.
89. Rouault, T.A. (2006). The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol. 2, 406-414.
90. Ruiz, J.C., Walker, S.D., Anderson, S.A., Eisenstein, R.S., and Bruick, R.K. (2013). F-box and leucine-rich repeat protein 5 (FBXL5) is required for maintenance of cellular and systemic iron homeostasis. J Biol Chem 288, 552-560.
91. Salahudeen, A.A., Thompson, J.W., Ruiz, J.C., Ma, H.W., Kinch, L.N., Li, Q., Grishin, N.V., and Bruick, R.K. (2009). An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326, 722-726.
92. Sanchez, M., Galy, B., Dandekar, T., Bengert, P., Vainshtein, Y., Stolte, J., Muckenthaler, M.U., and Hentze, M.W. (2006). Iron regulation and the cell cycle: Identification of an ironresponsive 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.
93. Sanchez, M., Galy, B., Muckenthaler, M.U., and Hentze, M.W. (2007). Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat. Struct. Mol. Biol. 14, 420-426.
94. Sanchez, M., Galy, B., Schwanhaeusser, B., Blake, J., Bahr-Ivacevic, T., Benes, V., Selbach, M., Muckenthaler, M.U., and Hentze, M.W. (2011). Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins. Blood 118, e168-179.
95. Schofield, C.J., and Ratcliffe, P.J. (2004). Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell. Biol. 5, 343-354.
96. Schranzhofer, M., Schifrer, M., Cabrera, J.A., Kopp, S., Chiba, P., Beug, H., and Mullner, E.W. (2006). Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood 107, 4159-4167.
97. Sebastiani, G., and Pantopoulos, K. (2011). Disorders associated with systemic or local iron overload: from pathophysiology to clinical practice. Metallomics 3, 971-986.
98. Shah, Y.M., Matsubara, T., Ito, S., Yim, S.H., and Gonzalez, F.J. (2009). Intestinal Hypoxia-Inducible Transcription Factors Are Essential for Iron Absorption following Iron Deficiency. Cell Metab 9, 152-164.
99. Shah, Y.M., and Xie, L. (2014). Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology 146, 630-642.
100. Smith, S.R., Cooperman, S., Lavaute, T., Tresser, N., Ghosh, M., Meyron-Holtz, E., Land, W., Ollivierre, H., Jortner, B., Switzer, R., 3rd, Messing, A., and Rouault, T.A. (2004). Severity of neurodegeneration correlates with compromise of iron metabolism in mice with iron regulatory protein deficiencies. Ann. N Y Acad. Sci. 1012, 65-83.
101. Smith, S.R., Ghosh, M.C., Ollivierre-Wilson, H., Hang Tong, W., and Rouault, T.A. (2006). Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. Blood Cells Mol. Dis. 36, 283-287.
102. Synowiec, E., Pogorzelska, M., Blasiak, J., Szaflik, J., and Szaflik, J.P. (2012). Genetic polymorphism of the iron-regulatory protein-1 and -2 genes in age-related macular degeneration. Mol Biol Rep 39, 7077-7087.
103. Taylor, M., Qu, A., Anderson, E.R., Matsubara, T., Martin, A., Gonzalez, F.J., and Shah, Y.M. (2011). Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology 140, 2044-2055.
104. Thompson, J.W., Salahudeen, A.A., Chollangi, S., Ruiz, J.C., Brautigam, C.A., Makris, T.M., Lipscomb, J.D., Tomchick, D.R., and Bruick, R.K. (2012). Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). J Biol Chem 287, 7357-7365
105. Torti, S.V., and Torti, F.M. (2013). Iron and cancer: more ore to be mined. Nat Rev Cancer 13, 342-355.
106. Vanoaica, L., Darshan, D., Richman, L., Schumann, K., and Kuhn, L.C. (2010). Intestinal ferritin h is required for an accurate control of iron absorption. Cell Metab 12, 273-282.
107. Vashisht, A.A., Zumbrennen, K.B., Huang, X., Powers, D.N., Durazo, A., Sun, D., Bhaskaran, N., Persson, A., Uhlen, M., Sangfelt, O., Spruck, C., Leibold, E.A., and Wohlschlegel, J.A. (2009). Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326, 718-721.
108. Viatte, L., Grone, H.J., Hentze, M.W., and Galy, B. (2009). In vivo role(s) of the iron regulatory proteins (IRP) 1 and 2 in aseptic local inflammation. J Mol Med.
109. Waheed, A., Parkkila, S., Saarnio, J., Fleming, R.E., Zhou, X.Y., Tomatsu, S., Britton, R.S., Bacon, B.R., and Sly, W.S. (1999). Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc. Natl. Acad. Sci. USA 96, 1579-1584.
110. Walden, W.E., Selezneva, A.I., Dupuy, J., Volbeda, A., Fontecilla-Camps, J.C., Theil, E.C., and Volz, K. (2006). Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science 314, 1903-1908.
111. Wang, J., Chen, G., and Pantopoulos, K. (2005). Nitric oxide inhibits the degradation of IRP2. Mol. Cell. Biol. 25, 1347-1353.
112. Wang, J., Fillebeen, C., Chen, G., Biederbick, A., Lill, R., and Pantopoulos, K. (2007). Irondependent degradation of apo-IRP1 by the ubiquitin-proteasome pathway. Mol. Cell. Biol. 27, 2423-2430.
113. Wang, J., and Pantopoulos, K. (2002). Conditional de-repression of ferritin synthesis in cells expressing a constitutive IRP1 mutant. Mol. Cell. Biol. 22, 4638-4651.
114. Wang, J., and Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochem J 434, 365-381.
115. Wang, W., Deng, Z., Hatcher, H., Miller, L.D., Di, X., Tesfay, L., Sui, G., D'agostino, R.B., Jr., Torti, F.M., and Torti, S.V. (2014). IRP2 regulates breast tumor growth. Cancer Res 74, 497-507.
116. Weiss, G., and Goodnough, L.T. (2005). Anemia of chronic disease. N. Engl. J. Med. 352, 1011-1023.
117. Weiss, G., Goossen, B., Doppler, W., Fuchs, D., Pantopoulos, K., Werner-Felmayer, G., Wachter, H., and Hentze, M.W. (1993). Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway. EMBO J. 12, 3651-3657.
118. Wilkinson, N., and Pantopoulos, K. (2013). IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2alpha mRNA translation. Blood 122, 1658-1668
119. Wingert, R.A., Galloway, J.L., Barut, B., Foott, H., Fraenkel, P., Axe, J.L., Weber, G.J., Dooley, K., Davidson, A.J., Schmidt, B., Paw, B.H., Shaw, G.C., Kingsley, P., Palis, J., Schubert, H., Chen, O., Kaplan, J., and Zon, L.I. (2005). Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature 436, 1035-1039.
120. Wu, K.J., Polack, A., and Dalla-Favera, R. (1999). Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 283, 676-679.
121. Yang, X.R., Liang, X., Pfeiffer, R.M., Wheeler, W., Maeder, D., Burdette, L., Yeager, M., Chanock, S., Tucker, M.A., and Goldstein, A.M. (2010). Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanomaprone families with and without CDKN2A mutations. Fam Cancer 9, 625-633.
122. Ye, H., Jeong, S.Y., Ghosh, M.C., Kovtunovych, G., Silvestri, L., Ortillo, D., Uchida, N., Tisdale, J., Camaschella, C., and Rouault, T.A. (2010). Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749-1761.
123. Yin, D., Kulhalli, V., and Walker, A.P. (2014). Raised serum ferritin concentration in hereditary hyperferritinemia cataract syndrome is not a marker for iron overload. Hepatology 59, 1204-1206.
124. Zhang, D.L., Hughes, R.M., Ollivierre-Wilson, H., Ghosh, M.C., and Rouault, T.A. (2009). A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 9, 461-473.
125. Zhang, F., Wang, W., Tsuji, Y., Torti, S.V., and Torti, F.M. (2008). Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem 283, 33911-33918.
126. Zhou, H., Yang, J., Li, D., Xiao, J., Wang, B., Wang, L., Ma, C., Xu, S., Ou, X., and Feng, Y. (2012). Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPDrelated phenotypes in a Chinese Han population. J Hum Genet 57, 738-746
127. Zimmer, M., Ebert, B.L., Neil, C., Brenner, K., Papaioannou, I., Melas, A., Tolliday, N., Lamb, J., Pantopoulos, K., Golub, T., and Iliopoulos, O. (2008). Small-molecule inhibitors ofHIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing. Mol Cell 32, 838-848.
128. Zumbrennen-Bullough, K.B., Becker, L., Garrett, L., Hölter, S.M., Calzada-Wack, J., Mossburger, I., Quintanilla-Fend, L., Racz, I., Rathkolb, B., Klopstock, T., Wurst, W., Zimmer, A., Wolf, E., Fuchs, H., Gailus-Durner, V., De Angelis, M.H., Romney, S.J., and Leibold, E.A. (2014). Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments. PLoS One 9, e98072.