The Roles of NRF2 in Modulating Cellular Iron Homeostasis

Antioxidants and Redox Signaling

Volumn 29, Issue 17, 2018, Pages 1756-1773

  Kerins, Michael John ^a   Ooi, Aikseng ^a  

^a UNIVERSITY OF ARIZONA   (United States)

Author keywords

cancer; ferroptosis; heme; iron; NRF2; oxygen

Indexed keywords

FERRITIN; HEME; HEME OXYGENASE 1; HEMOGLOBIN; IRON; TRANSCRIPTION FACTOR NRF2;

ARTICLE; BIOSYNTHESIS; CANCER PREVENTION; CATABOLISM; CELL COMPARTMENTALIZATION; CELL DEATH; CELL PROLIFERATION; ELECTROPHILIC STRESS; ERYTHROPOIESIS; FERROPTOSIS; GENETIC REGULATION; HEME SYNTHESIS; HUMAN; IRON HOMEOSTASIS; IRON METABOLISM; IRON STORAGE; MALIGNANT NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; THERAPY RESISTANCE; ANIMAL; HOMEOSTASIS; METABOLISM; NEOPLASM; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

ANIMALS; HOMEOSTASIS; HUMANS; IRON; NEOPLASMS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 85053055670     PISSN: 15230864     EISSN: 15577716     Source Type: Journal    
DOI: 10.1089/ars.2017.7176     Document Type: Article

References (176)

1. Agyeman AS, Chaerkady R, Shaw PG, Davidson NE, Visvanathan K, Pandey A, and Kensler TW. Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphanetreated human breast epithelial cells reveals common expression profiles. Breast Cancer Res Treat 132: 175-187, 2012
2. Aisen P, Enns C, and Wessling-Resnick M. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol 33: 940-959, 2001
3. Alam J, Cai J, and Smith A. Isolation and characterization of the mouse heme oxygenase-1 gene. Distal 5c sequences are required for induction by heme or heavy metals. J Biol Chem 269: 1001-1009, 1994
4. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, and Cook JL. Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274: 26071-26078, 1999
5. Anderson SA, Nizzi CP, Chang Y-I, Deck KM, Schmidt PJ, Galy B, Damnernsawad A, Broman AT, Kendziorski C, Hentze MW, Fleming MD, Zhang J, and Eisenstein RS. The IRP1-HIF-2a axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab 17: 282-290, 2013
6. Andrews SC. The Ferritin-like superfamily: evolution of the biological iron storeman from a rubrerythrin-like ancestor. Biochim Biophys Acta 1800: 691-705, 2010
7. Aravind L and Koonin EV. The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate-and iron-dependent dioxygenases. Genome Biol 2: Research0007, 2001
8. Arosio P, Yokota M, and Drysdale JW. Structural and immunological relationships of isoferritins in normal and malignant cells. Cancer Res 36: 1735-1739, 1976
9. Benfeitas R, Selvaggio G, Antunes F, Coelho PM, and Salvador A. Hydrogen peroxide metabolism and sensing in human erythrocytes: a validated kinetic model and reappraisal of the role of peroxiredoxin II. Free Radic Biol Med 74: 35-49, 2014
10. Bratosin D, Mazurier J, Tissier J, Estaquier J, Huart J, Ameisen J, Aminoff D, and Montreuil J. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie 80: 173-195, 1998
11. Brzoska K, Stepkowski TM, and Kruszewski M. Basal PIR expression in HeLa cells is driven by NRF2 via evolutionary conserved antioxidant response element. Mol Cell Biochem 389: 99-111, 2014
12. Cabantchik ZI. Labile iron in cells and body fluids: physiology, pathology, and pharmacology. Front Pharmacol 5: 45, 2014
13. Cairo G, Tacchini L, Pogliaghi G, Anzon E, Tomasi A, and Bernelli-Zazzera A. 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
14. Campbell MR, Karaca M, Adamski KN, Chorley BN, Wang X, and Bell DA. Novel hematopoietic target genes in the NRF2-mediated transcriptional pathway. Oxid Med Cell Longev 2013: 120305, 2013
15. Chan K, Lu R, Chang JC, and Kan YW. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S A 93: 13943-13948, 1996
16. Chang CF, Cho S, and Wang J. Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways. Ann Clin Transl Neurol 1: 258-271, 2014
17. Choi AM and Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15: 9-19, 1996
18. Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, and Feinstein SI. Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism involving an antioxidant response element. Free Radic Biol Med 46: 146-153, 2009
19. Cloonan SM, Glass K, Laucho-Contreras ME, Bhashyam AR, Cervo M, Pabon MA, Konrad C, Polverino F, Siempos, II, Perez E, Mizumura K, Ghosh MC, Parameswaran H, Williams NC, Rooney KT, Chen ZH, Goldklang MP, Yuan GC, Moore SC, Demeo DL, Rouault TA, D'Armiento JM, Schon EA, Manfredi G, Quackenbush J, Mahmood A, Silverman EK, Owen CA, and Choi AM. Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22: 163-174, 2016
20. Cloud P. Paleoecological significance of the banded ironformation. Econ Geol 68: 1135-1143, 1973
21. Ungria M, Rao R, Wobken JD, Luciana M, Nelson CA, and Georgieff MK. Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain. Pediatr Res 48: 169-176, 2000
22. Delaby C, Pilard N, Hetet G, Driss F, Grandchamp B, Beaumont C, and Canonne-Hergaux F. A physiological model to study iron recycling in macrophages. Exp Cell Res 310: 43-53, 2005
23. Dinkova-Kostova AT. The role of sulfhydryl reactivity of small molecules for the activation of the KEAP1/NRF2 pathway and the heat shock response. Scientifica 2012: 606104, 2012
24. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, 3rd, and Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149: 1060-1072, 2012
25. Dixon SJ and Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10: 9-17, 2014
26. Doll S and Conrad M. Iron and ferroptosis: a still illdefined liaison. IUBMB Life 69: 423-434, 2017
27. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, and Andrews NC. The iron exporter ferroportin/ Slc40a1 is essential for iron homeostasis. Cell Metab 1: 191-200, 2005
28. Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, and Rabinowitz JD. Quantitative flux analysis reveals folatedependent NADPH production. Nature 510: 298-302, 2014
29. Fenton H. LXXIII.-oxidation of tartaric acid in presence of iron. J Chem Soc Trans 65: 899-910, 1894
30. Fibach E and Rachmilewitz E. The role of oxidative stress in hemolytic anemia. Curr Mol Med 8: 609-619, 2008
31. Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, and Hedley A. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477: 225-228, 2011
32. Gacesa R, Dunlap WC, Barlow DJ, Laskowski RA, and Long PF. Rising levels of atmospheric oxygen and evolution of Nrf2. Sci Rep 6: 27740, 2016
33. Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid Redox Signal 10: 1923-1940, 2008
34. Giudice A, Arra C, and Turco MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol 647: 37-74, 2010
35. Gorrini C, Harris IS, and Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12: 931-947, 2013
36. Hanahan D and Weinberg RA. Hallmarks of cancer: the next generation. Cell 144: 646-674, 2011
37. Harada N, Kanayama M, Maruyama A, Yoshida A, Tazumi K, Hosoya T, Mimura J, Toki T, Maher JM, Yamamoto M, and Itoh K. Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharideinduced ferroportin 1 mRNA suppression in macrophages. Arch Biochem Biophys 508: 101-109, 2011
38. Harder B, Jiang T, Wu T, Tao S, Vega MR, Tian W, Chapman E, and Zhang DD. Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention. Biochem Soc Trans 43: 680-686, 2015
39. Hayes JD and Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39: 199-218, 2014
40. Hayes JD and McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34: 176-188, 2009
41. Heinaniemi M and Levonen A-L. Role of the Keap1-Nrf2 pathway in cancer. Redox Cancer 122: 281, 2014
42. Helias V, Saison C, Ballif BA, Peyrard T, Takahashi J, Takahashi H, Tanaka M, Deybach J-C, Puy H, and Le Gall M. ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet 44: 170-173, 2012
43. Hintze KJ, Katoh Y, Igarashi K, and Theil EC. Bach1 repression of ferritin and thioredoxin reductase1 is hemesensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1. J Biol Chem 282: 34365-34371, 2007
44. Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, Engel JD, and Yamamoto M. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 40: 10228-10239, 2012
45. Hoffbrand AV, Ganeshaguru K, Hooton JW, and Tattersall MH. Effect of iron deficiency and desferrioxamine on DNA synthesis in human cells. Br J Haematol 33: 517-526, 1976
46. Hooda J, Shah A, and Zhang L. Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients 6: 1080-1102, 2014
47. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ, 3rd, Kang R, and Tang D. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12: 1425-1428, 2016
48. Hubner R, Schwartz JD, De Bishnu P, Ferris B, Omberg L, Mezey JG, Hackett NR, and Crystal RG. Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly responsive to cigarette smoking. Mol Med 15: 203-219, 2009
49. Inamdar NM, Ahn YI, and Alam J. The heme-responsive element of the mouse heme oxygenase-1 gene is an extended AP-1 binding site that resembles the recognition sequences for MAF and NF-E2 transcription factors. Biochem Biophys Res Commun 221: 570-576, 1996
50. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, and Yamamoto M. Transcription factor Nrf2 coordinately regulates a group of oxidative stressinducible genes in macrophages. J Biol Chem 275: 16023-16029, 2000
51. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, and Hatayama I. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236: 313-322, 1997
52. Iuchi Y, Okada F, Onuma K, Onoda T, Asao H, Kobayashi M, and Fujii J. Elevated oxidative stress in erythrocytes due to a SOD1 deficiency causes anaemia and triggers autoantibody production. Biochem J 402: 219-227, 2007
53. Jaakkola P, Mole DR, Tian Y-M, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, and Schofield CJ. Targeting of HIF-A to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468-472, 2001
54. Ji X, Wang H, Zhu J, Zhu L, Pan H, Li W, Zhou Y, Cong Z, Yan F, and Chen S. Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1a. Int J Cancer 135: 574-584, 2014
55. Johnson RM, Ho Y-S, Yu D-Y, Kuypers FA, Ravindranath Y, and Goyette GW. The effects of disruption of genes for peroxiredoxin-2, glutathione peroxidase-1, and catalase on erythrocyte oxidative metabolism. Free Radic Biol Med 48: 519-525, 2010
56. Kansanen E, Kuosmanen SM, Leinonen H, and Levonen A-L. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1: 45-49, 2013
57. Kawatani Y, Suzuki T, Shimizu R, Kelly VP, and Yamamoto M. Nrf2 and selenoproteins are essential for maintaining oxidative homeostasis in erythrocytes and protecting against hemolytic anemia. Blood 117: 986-996, 2011
58. Kensler TW, Wakabayashi N, and Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47: 89-116, 2007
59. Kerins MJ, Vashisht A, Liang X-T, Duckworth SJ, Praslicka BJ, Wohlschlegel JA, and Ooi A. Fumarate mediates a chronic proliferative signal in fumarate hydratase inactivated cancer cells by increasing transcription and translation of ferritin genes. Mol Cell Biol 37: 00079-17, 2017
60. Khan AA and Quigley JG. Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim Biophys Acta 1813: 668-682, 2011
61. Kim H-R, Kim S, Kim E-J, Park J-H, Yang S-H, Jeong ET, Park C, Youn M-J, So H-S, and Park R. Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. Lung Cancer 60: 47-56, 2008
62. Kim JH, Thimmulappa RK, Kumar V, Cui W, Kumar S, Kombairaju P, Zhang H, Margolick J, Matsui W, Macvittie T, Malhotra SV, and Biswal S. NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J Clin Invest 124: 730-741, 2014
63. Kim T-H, Hur E-g, Kang S-J, Kim J-A, Thapa D, Lee YM, Ku SK, Jung Y, and Kwak M-K. NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1a. Cancer Res 71: 2260-2275, 2011
64. Kim Y-J, Ahn J-Y, Liang P, Ip C, Zhang Y, and Park YM. Human prx1 gene is a target of Nrf2 and is upregulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res 67: 546-554, 2007
65. Knutson MD, Vafa MR, Haile DJ, and Wessling-Resnick M. Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood 102: 4191-4197, 2003
66. Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y, and Yamamoto M. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol 29: 493-502, 2009
67. Kohen R and Nyska A. Invited review: oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30: 620-650, 2002
68. Koorts AM and Viljoen M. Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion. Arch Physiol Biochem 113: 30-54, 2007
69. Kovac S, Angelova PR, Holmstrom KM, Zhang Y, Dinkova-Kostova AT, and Abramov AY. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys Acta 1850: 794-801, 2015
70. Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, Wang J, Sosa-Pineda B, Murti KG, and Schuetz JD. Identification of a mammalian mitochondrial porphyrin transporter. Nature 443: 586-589, 2006
71. Kuroda H, Takeno M, Murakami S, Miyazawa N, Kaneko T, and Ishigatsubo Y. Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells. Lung Cancer 67: 31-36, 2010
72. Kwak EL, Larochelle DA, Beaumont C, Torti SV, and Torti FM. Role for NF-jB in the regulation of ferritin H by tumor necrosis factor a. J Biol Chem 270: 15285-15293, 1995
73. Kwak M-K, Itoh K, Yamamoto M, and Kensler TW. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22: 2883-2892, 2002
74. Kwak MK, Itoh K, Yamamoto M, Sutter TR, and Kensler TW. Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol Med 7: 135-145, 2001
75. Kweon M-H, Adhami VM, Lee J-S, and Mukhtar H. Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem 281: 33761-33772, 2006
76. Kwon M-Y, Park E, Lee S-J, and Chung SW. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget 6: 24393, 2015
77. Lau A, Villeneuve NF, Sun Z, Wong PK, and Zhang DD. Dual roles of Nrf2 in cancer. Pharmacol Res 58: 262-270, 2008
78. Lau A, Whitman SA, Jaramillo MC, and Zhang DD. Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway. J Biochem Mol Toxicol 27: 99-105, 2013
79. Lee J-M, Chan K, Kan YW, and Johnson JA. Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia. Proc Natl Acad Sci U S A 101: 9751-9756, 2004
80. Liu F, Rehmani I, Esaki S, Fu R, Chen L, de Serrano V, and Liu A. Pirin is an iron-dependent redox regulator of NF-jB. Proc Natl Acad Sci U S A 110: 9722-9727, 2013
81. Liu X, Madhankumar A, Slagle-Webb B, Sheehan JM, Surguladze N, and Connor JR. Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents. Cancer Res 71: 2240-2249, 2011
82. Liu Y, Liang Y, Zheng T, Yang G, Zhang X, Sun Z, Shi C, and Zhao S. Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells. J Neurooncol 104: 449-458, 2011
83. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, and Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73: 3221, 2016
84. Lukianova OA and David SS. A role for iron-sulfur clusters in DNA repair. Curr Opin Chem Biol 9: 145-151, 2005
85. Lyons TW, Reinhard CT, and Planavsky NJ. The rise of oxygen in Earth's early ocean and atmosphere. Nature 506: 307-315, 2014
86. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53: 401-426, 2013
87. Macara IG, Hoy T, and Harrison PM. The formation of ferritin from apoferritin. Kinetics and mechanism of iron uptake. Biochem J 126: 151-162, 1972
88. Macari ER and Lowrey CH. Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway. Blood 117: 5987-5997, 2011
89. Maiorino M, Bosello V, Cozza G, Roveri A, Toppo S, and Ursini F. Glutathione peroxidase-4. In: Selenium. New York, NY: Springer, 2011, pp. 181-195
90. Mancias JD, Vaites LP, Nissim S, Biancur DE, Kim AJ, Wang X, Liu Y, Goessling W, Kimmelman AC, and Harper JW. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife 4: e10308, 2015
91. Mancias JD, Wang X, Gygi SP, Harper JW, and Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509: 105-109, 2014
92. Manz DH, Blanchette NL, Paul BT, Torti FM, and Torti SV. Iron and cancer: recent insights. Ann N Y Acad Sci 1368: 149-161, 2016
93. Marini MG, Chan K, Casula L, Kan YW, Cao A, and Moi P. hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2. J Biol Chem 272: 16490-16497, 1997
94. Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, and Muckenthaler MU. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position-7007 of the FPN1 promoter. Haematologica 95: 1261-1268, 2010
95. Matte A, Falco L, Federti E, Levi S, Iolascon A, Federico G, Mohandas N, Janin A, Bruno M, and Leboeuf C. Peroxiredoxin-2: a novel factor involved in iron homeostasis. Am Soc Hematol, 126: 406, 2015
96. Meining W and Skerra A. The crystal structure of human a1-microglobulin reveals a potential haem-binding site. Biochem J 445: 175-182, 2012
97. Merchant AA, Singh A, Matsui W, and Biswal S. The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels. Blood 118: 6572-6579, 2011
98. Merikallio H, PaakkoP, Kinnula VL, Harju T, and Soini Y. Nuclear factor erythroid-derived 2-like 2 (Nrf2) and DJ1 are prognostic factors in lung cancer. Hum Pathol 43: 577-584, 2012
99. Mignotte V, Wall L, Grosveld F, and Romeo P-H. Two tissue-specific factors bind the erythroid promoter of the human porphobilinogen deaminase gene. Nucleic Acids Res 17: 37-54, 1989
100. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, and Motohashi H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22: 66-79, 2012
101. Moi P, Chan K, Asunis I, Cao A, and Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91: 9926-9930, 1994
102. Moi P and Kan YW. Synergistic enhancement of globin gene expression by activator protein-1-like proteins. Proc Natl Acad Sci U S A 87: 9000-9004, 1990
103. Muckenthaler MU, Galy B, and Hentze MW. Systemic iron homeostasis and the iron-responsive element/ironregulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 28: 197-213, 2008
104. Muckenthaler MU, Rivella S, Hentze MW, and Galy B. A red carpet for iron metabolism. Cell 168: 344-361, 2017
105. Murakami S and Motohashi H. Roles of NRF2 in cell proliferation and differentiation. Free Radic Biol Med 88: 168-178, 2015
106. Murakami S, Shimizu R, Romeo PH, Yamamoto M, and Motohashi H. Keap1-Nrf2 system regulates cell fate de-termination of hematopoietic stem cells. Genes Cells 19: 239-253, 2014
107. Na H-K and Surh Y-J. Oncogenic potential of Nrf2 and its principal target protein heme oxygenase-1. Free Radic Biol Med 67: 353-365, 2014
108. Netz DJ, Stith CM, Stumpfig M, Kopf G, Vogel D, Genau HM, Stodola JL, Lill R, Burgers PM, and Pierik AJ. Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes. Nat Chem Biol 8: 125-132, 2011
109. Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH, and Van Etten RA. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature 424: 561-565, 2003
110. Ney PA, Sorrentino BP, Lowrey CH, and Nienhuis AW. Inducibility of the HS II enhancer depends on binding of an erythroid specific nuclear protein. Nucleic Acids Res 18: 6011-6017, 1990
111. Ney PA, Sorrentino BP, McDonagh KT, and Nienhuis AW. Tandem AP-1-binding sites within the human betaglobin dominant control region function as an inducible enhancer in erythroid cells. Genes Dev 4: 993-1006, 1990
112. Oexle H, Gnaiger E, and Weiss G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta 1413: 99-107, 1999
113. Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, Hayashi N, Yamamoto M, Shibahara S, and Fujita H. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J 20: 2835-2843, 2001
114. Olsson MG, Allhorn M, Bulow L, Hansson SR, Ley D, Olsson ML, Schmidtchen A, and Akerstrom B. Pathological conditions involving extracellular hemoglobin: molecular mechanisms, clinical significance, and novel therapeutic opportunities for alpha(1)-microglobulin. Antioxid Redox Signal 17: 813-846, 2012
115. Olsson MG, Olofsson T, Tapper H, and Akerstrom B. The lipocalin a 1-microglobulin protects erythroid K562 cells against oxidative damage induced by heme and reactive oxygen species. Free Radic Res 42: 725-736, 2008
116. Ooi A and Furge KA. Fumarate hydratase inactivation in renal tumors: HIF1a, NRF2, and ''cryptic targets'' of transcription factors. Chin J Cancer 31: 413, 2012
117. Ooi A, Wong J-C, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BWH, Tan M-H, Zhang Z, and Yang XJ. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20: 511-523, 2011
118. Osburn WO, Wakabayashi N, Misra V, Nilles T, Biswal S, Trush MA, and Kensler TW. Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Arch Biochem Biophys 454: 7-15, 2006
119. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, and Igarashi K. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol 16: 6083-6095, 1996
120. Pang H, Bartlam M, Zeng Q, Miyatake H, Hisano T, Miki K, Wong L-L, Gao GF, and Rao Z. Crystal structure of human pirin An iron-binding nuclear protein and transcription cofactor. J Biol Chem 279: 1491-1498, 2004
121. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, and Beaumont C. Ferritin heavy chain upregulation by NF-jB inhibits TNFa-induced apoptosis by suppressing reactive oxygen species. Cell 119: 529-542, 2004
122. Pi J, Diwan BA, Sun Y, Liu J, Qu W, He Y, Styblo M, and Waalkes MP. Arsenic-induced malignant transformation of human keratinocytes: involvement of Nrf2. Free Radic Biol Med 45: 651-658, 2008
123. Pietsch EC, Chan JY, Torti FM, and Torti SV. Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones. J Biol Chem 278: 2361-2369, 2003
124. Praslicka BJ, Kerins MJ, and Ooi A. The complex role of NRF2 in cancer: a genomic view. Curr Opin Toxicol 1: 37-45, 2016
125. Primiano T, Kensler TW, Kuppusamy P, Zweier JL, and Sutter TR. Induction of hepatic heme oxygenase-1 and ferritin in rats by cancer chemopreventive dithiolethiones. Carcinogenesis 17: 2291-2296, 1996
126. Prousek J. Fenton chemistry in biology and medicine. Pure Appl Chem 79: 2325-2338, 2007
127. Rajagopal A, Rao AU, Amigo J, Tian M, Upadhyay SK, Hall C, Uhm S, Mathew M, Fleming MD, and Paw BH. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 453: 1127-1131, 2008
128. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li J-L, Pugh CW, Maxwell PH, Harris AL, and Ratcliffe PJ. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25: 5675-5686, 2005
129. Reichard JF, Motz GT, and Puga A. Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1. Nucleic Acids Res 35: 7074-7086, 2007
130. Roh J-L, Kim EH, Jang H, and Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 11: 254-262, 2017
131. Rudolf J, Makrantoni V, Ingledew WJ, Stark MJ, and White MF. The DNA repair helicases XPD and FancJ have essential iron-sulfur domains. Mol Cell 23: 801-808, 2006
132. Salahudeen AA, Thompson JW, Ruiz JC, Ma H-W, Kinch LN, Li Q, Grishin NV, and Bruick RK. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326: 722-726, 2009
133. Salazar M, Rojo AI, Velasco D, de Sagarra RM, and Cuadrado A. Glycogen synthase kinase-3b inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281: 14841-14851, 2006
134. Salminen A, Kauppinen A, and Kaarniranta K. 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process. Cell Mol Life Sci 72: 3897-3914, 2015
135. Sanchez M, Galy B, Muckenthaler MU, and Hentze MW. Iron-regulatory proteins limit hypoxia-inducible factor-2a expression in iron deficiency. Nat Struct Mol Biol 14: 420-426, 2007
136. Schonberg DL, Miller TE, Wu Q, Flavahan WA, Das NK, Hale JS, Hubert CG, Mack SC, Jarrar AM, and Karl RT. Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell 28: 441-455, 2015
137. Schultz IJ, Chen C, Paw BH, and Hamza I. Iron and porphyrin trafficking in heme biogenesis. J Biol Chem 285: 26753-26759, 2010
138. Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, and Hirohashi S. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A 105: 13568-13573, 2008
139. Shimada K, Hayano M, Pagano NC, and Stockwell BR. Cell-line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem Biol 23: 225-235, 2016
140. Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Vasyl'F C, Beland FA, and Pogribny IP. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat 126: 63-71, 2011
141. Siebel JF, Kosinsky RL, Akerstrom B, and Knipp M. Insertion of heme b into the structure of the Cys34-carbamidomethylated human lipocalin a1-microglobulin: formation of a [(heme) 2 (a1-microglobulin)] 3 complex. Chembiochem 13: 879-887, 2012
142. Siegert I, Schodel J, Nairz M, Schatz V, Dettmer K, Dick C, Kalucka J, Franke K, Ehrenschwender M, and Schley G. Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1a upon LPS activation in the presence of ample oxygen. Cell Rep 13: 2048-2055, 2015
143. Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC, Moran CA, Corvalan AH, Biswal S, Swisher SG, and Bekele BN. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res 16: 3743-3753, 2010
144. Song X, Xie Y, Kang R, Hou W, Sun X, Epperly MW, Greenberger JS, and Tang D. FANCD2 protects against bone marrow injury from ferroptosis. Biochem Biophys Res Commun 480: 443-449, 2016
145. Stohs S and Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18: 321-336, 1995
146. Sun X, Niu X, Chen R, He W, Chen D, Kang R, and Tang D. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64: 488-500, 2016
147. Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, and Tang D. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63: 173-184, 2016
148. Talbot D and Grosveld F. The 5'HS2 of the globin locus control region enhances transcription through the interaction of a multimeric complex binding at two functionally distinct NF-E2 binding sites. EMBO J 10: 1391, 1991
149. Talbot D, Philipsen S, Fraser P, and Grosveld F. Detailed analysis of the site 3 region of the human beta-globin dominant control region. EMBO J 9: 2169, 1990
150. Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, and Hayes JD. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med 88: 108-146, 2015
151. Tertil M, Skrzypek K, Florczyk U, Weglarczyk K, Was H, Collet G, Guichard A, Gil T, Kuzdzal J, and Jozkowicz A. Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer: crosstalk with Nrf2 and HO-1. PLoS One 9: e97070, 2014
152. Theil EC. Ferritin: the protein nanocage and iron biomineral in health and in disease. Inorg Chem 52: 12223-12233, 2013
153. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, and Biswal S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62: 5196-5203, 2002
154. Torti SV and Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer 13: 342-355, 2013
155. Tsai JJ, Dudakov JA, Takahashi K, Shieh J-H, Velardi E, Holland AM, Singer NV, West ML, Smith OM, and Young LF. Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol 15: 309-316, 2013
156. Tsuji Y, Ayaki H, Whitman SP, Morrow CS, Torti SV, and Torti FM. Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. Mol Cell Biol 20: 5818-5827, 2000
157. Tudor C, Lerner-Marmarosh N, Engelborghs Y, Gibbs PE, andMainesMD. Biliverdin reductase is a transporter of haem into the nucleus and is essential for regulation of HO-1 gene expression by haematin. Biochem J 413: 405-416, 2008
158. Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, and Sangfelt O. Control of iron homeostasis by an ironregulated ubiquitin ligase. Science 326: 718-721, 2009
159. Veal EA, Day AM, and Morgan BA. Hydrogen peroxide sensing and signaling. Mol Cell 26: 1-14, 2007
160. Wang X-J, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, ChenW, Yi X, Zheng W, and Wondrak GT. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29: 1235-1243, 2008
161. Wasserman WW and Fahl WE. Functional antioxidant responsive elements. Proc Natl Acad Sci U S A 94: 5361-5366, 1997
162. White C, Yuan X, Schmidt PJ, Bresciani E, Samuel TK, Campagna D, Hall C, Bishop K, CalicchioML, and Lapierre A. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17: 261-270, 2013
163. Wilkinson N and Pantopoulos K. The IRP/IRE system in vivo: insights from mouse models. Fron Pharmacol 5, 2014
164. Winterbourn CC. The biological chemistry of hydrogen peroxide. Methods Enzymol 528: 3-25, 2013
165. Wu KC, Cui JY, and Klaassen CD. Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci 123: 590-600, 2011
166. Xie Y, Song X, Sun X, Huang J, Zhong M, Lotze MT, Zeh HJ, Kang R, and Tang D. Identification of baicalein as a ferroptosis inhibitor by natural product library screening. Biochem Biophys Res Commun 473: 775-780, 2016
167. Yanagawa T, Itoh K, Uwayama J, Shibata Y, Yamaguchi A, Sano T, Ishii T, Yoshida H, and Yamamoto M. Nrf2 deficiency causes tooth decolourization due to iron transport disorder in enamel organ. Genes Cells 9: 641-651, 2004
168. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, and Stockwell BR. Regulation of ferroptotic cancer cell death by GPX4. Cell 156: 317-331, 2014
169. This reference has been deleted
170. Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, Asahara T, Tokunaga F, Iwai K, and Igarashi K. Heme induces ubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol 27: 6962-6971, 2007
171. Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38: 769-789, 2006
172. Zhang DD and Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23: 8137-8151, 2003
173. Zhang M, An C, Gao Y, Leak RK, Chen J, and Zhang F. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100: 30-47, 2013
174. Zhu H, Santo A, and Li Y. The antioxidant enzyme peroxiredoxin and its protective role in neurological disorders. Exp Biol Med 237: 143-149, 2012
175. Zimmer M, Ebert BL, Neil C, Brenner K, Papaioannou I, Melas A, Tolliday N, Lamb J, Pantopoulos K, Golub T, and Iliopoulos O. Small-molecule inhibitors of HIF-2a translation link its 5cUTR iron-responsive element to oxygen sensing. Mol Cell 32: 838-848, 2008
176. Zumbrennen KB, Wallander ML, Romney SJ, and Leibold EA. Cysteine oxidation regulates the RNA-binding activity of iron regulatory protein 2. Mol Cell Biol 29: 2219-2229, 2009