Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

Cellular and Molecular Life Sciences

Volumn 73, Issue 17, 2016, Pages 3221-3247

  Loboda, Agnieszka ^a   Damulewicz, Milena ^a   Pyza, Elzbieta ^a   Jozkowicz, Alicja ^a   Dulak, Jozef ^a  

^a JAGIELLONIAN UNIVERSITY   (Poland)

Author keywords

Heme oxygenase 1 (HO 1); Kelch like ECH associated protein 1 (Keap1); Nuclear factor erythroid 2 related factor 2 (Nrf2); Oxidative stress; Reactive oxygen species (ROS)

Indexed keywords

BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR; CAP N COLLAR TRANSCRIPTION FACTOR; HEME OXYGENASE 1; MICRORNA; PROTEASOME; SKINHEAD 1 TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; ISOPROTEIN; REPRESSOR PROTEIN;

ADAPTATION; AGE RELATED MACULAR DEGENERATION; AGING; CANCER INHIBITION; CELL STRESS; CELLULAR STRESS RESPONSE; CELLULAR STRESS SIGNAL; DEVELOPMENT; DISEASE ASSOCIATION; DISEASES; EMBRYO DEVELOPMENT; EUKARYOTE; GENE; GENE CONTROL; GENE FUNCTION; GENE TARGETING; GENETIC CONSERVATION; HO 1 GENE; HUMAN; LONGEVITY; NEOPLASM; NERVE DEGENERATION; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PREGNANCY; PROKARYOTE; PROTEIN FUNCTION; REDUCTIVE STRESS; REVIEW; SEQUENCE HOMOLOGY; TUMOR PROMOTION; ANIMAL; GENETICS; METABOLISM; MOLECULAR EVOLUTION;

ANIMALS; EVOLUTION, MOLECULAR; HEME OXYGENASE-1; HUMANS; LONGEVITY; MICRORNAS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; PROTEASOME ENDOPEPTIDASE COMPLEX; PROTEIN ISOFORMS; REPRESSOR PROTEINS;

EID: 84964402775     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-016-2223-0     Document Type: Review

References (219)

1. Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116
2. Mitsuishi Y, Motohashi H, Yamamoto M (2012) The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol 2:200
3. Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1:45–49
4. Sykiotis GP, Bohmann D (2010) Stress-activated cap ‘n ‘collar transcription factors in aging and human disease. Sci Signal 3:re3
5. Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M (2004) Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci USA 101:2046–2051
6. Kobayashi M, Yamamoto M (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 46:113–140
7. Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272
8. Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, Yamamoto M (2006) Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26:221–229
9. Canning P, Sorrell FJ, Bullock AN (2015) Structural basis of Keap1 interactions with Nrf2. Free Radic Biol Med 88:101–107
10. Hu C, Eggler AL, Mesecar AD, van Breemen RB (2011) Modification of keap1 cysteine residues by sulforaphane. Chem Res Toxicol 24:515–521
11. Motohashi H, Yamamoto M (2004) Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 10:549–557
12. McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2004) Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive neh2 degron and the redox-insensitive neh6 degron. J Biol Chem 279:31556–31567
13. Holtzclaw WD, Dinkova-Kostova AT, Talalay P (2004) Protection against electrophile and oxidative stress by induction of phase 2 genes: the quest for the elusive sensor that responds to inducers. Adv Enzyme Regul 44:335–367
14. Li W, Kong AN (2009) Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 48:91–104
15. Kobayashi M, Itoh K, Suzuki T, Osanai H, Nishikawa K, Katoh Y, Takagi Y, Yamamoto M (2002) Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells 7:807–820
16. Williams LM, Timme-Laragy AR, Goldstone JV, McArthur AG, Stegeman JJ, Smolowitz RM, Hahn ME (2013) Developmental expression of the Nfe2-related factor (Nrf) transcription factor family in the zebrafish, danio rerio. PLoS One 8:e79574
17. Li L, Kobayashi M, Kaneko H, Nakajima-Takagi Y, Nakayama Y, Yamamoto M (2008) Molecular evolution of Keap1. Two Keap1 molecules with distinctive intervening region structures are conserved among fish. J Biol Chem 283:3248–3255
18. An JH, Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17:1882–1893
19. Glover-Cutter KM, Lin S, Blackwell TK (2013) Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf. PLoS Genet 9:e1003701
20. Bishop NA, Guarente L (2007) Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447:545–549
21. Hasegawa K, Miwa J (2010) Genetic and cellular characterization of Caenorhabditis elegans mutants abnormal in the regulation of many phase II enzymes. PLoS One 5:e11194
22. Choe KP, Przybysz AJ, Strange K (2009) The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans. Mol Cell Biol 29:2704–2715
23. Mohler J, Vani K, Leung S, Epstein A (1991) Segmentally restricted, cephalic expression of a leucine zipper gene during Drosophila embryogenesis. Mech Dev 34:3–9
24. Andrews NC, Erdjument-Bromage H, Davidson MB, Tempst P, Orkin SH (1993) Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature 362:722–728
25. Pitoniak A, Bohmann D (2015) Mechanisms and functions of Nrf2 signaling in Drosophila. Free Radic Biol Med 88:302–313
26. McGinnis N, Ragnhildstveit E, Veraksa A, McGinnis W (1998) A cap ‘n’ collar protein isoform contains a selective Hox repressor function. Development 125:4553–4564
27. Perrimon N, Lanjuin A, Arnold C, Noll E (1996) Zygotic lethal mutations with maternal effect phenotypes in Drosophila melanogaster. II. Loci on the second and third chromosomes identified by p-element-induced mutations. Genetics 144:1681–1692
28. Deng H, Kerppola TK (2014) Visualization of the Drosophila dKeap1-Cncc interaction on chromatin illumines cooperative, xenobiotic-specific gene activation. Development 141:3277–3288
29. Sykiotis GP, Bohmann D (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14:76–85
30. Blank V (2008) Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators? J Mol Biol 376:913–925
31. Veraksa A, McGinnis N, Li X, Mohler J, McGinnis W (2000) Cap ‘n’ collar B cooperates with a small Maf subunit to specify pharyngeal development and suppress deformed homeotic function in the Drosophila head. Development. 127:4023–4037
32. Misra JR, Lam G, Tmitsmmel CS (2013) Constitutive activation of the Nrf2/Keap1 pathway in insecticide-resistant strains of Drosophila. Insect Biochem Mol Biol 43:1116–1124
33. Misra JR, Horner MA, Lam G, Thummel CS (2011) Transcriptional regulation of xenobiotic detoxification in Drosophila. Genes Dev 25:1796–1806
34. Daborn PJ, Yen JL, Bogwitz MR, Le Goff G, Feil E, Jeffers S, Tijet N, Perry T, Heckel D, Batterham P, Feyereisen R, Wilson TG, ffrench-Constant RH (2002) A single p450 allele associated with insecticide resistance in Drosophila. Science 297:2253–2256
35. Daborn PJ, Lumb C, Boey A, Wong W, Ffrench-Constant RH, Batterham P (2007) Evaluating the insecticide resistance potential of eight Drosophila melanogaster cytochrome p450 genes by transgenic over-expression. Insect Biochem Mol Biol 37:512–519
36. Jones RM, Desai C, Darby TM, Luo L, Wolfarth AA, Scharer CD, Ardita CS, Reedy AR, Keebaugh ES, Neish AS (2015) Lactobacilli modulate epithelial cytoprotection through the Nrf2 pathway. Cell Rep 12:1217–1225
37. Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operana TN, Esmaillie R, Blackwell TK (2015) Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence. elife 4:e07836
38. Pang S, Lynn DA, Lo JY, Paek J, Curran SP (2014) SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nat Commun 5:5048
39. Seydoux G, Fire A (1994) Soma-germline asymmetry in the distributions of embryonic RNAs in Caenorhabditis elegans. Development 120:2823–2834
40. Page BD, Diede SJ, Tenlen JR, Ferguson EL (2007) EEL-1, a Hect e3 ubiquitin ligase, controls asymmetry and persistence of the skn-1 transcription factor in the early C. elegans embryo. Development 134:2303–2314
41. Bowerman B, Eaton BA, Priess JR (1992) Skn-1, a maternally expressed gene required to specify the fate of ventral blastomeres in the early C. elegans embryo. Cell 68:1061–1075
42. Bowerman B, Draper BW, Mello CC, Priess JR (1993) The maternal gene skn-1 encodes a protein that is distributed unequally in early C. elegans embryos. Cell 74:443–452
43. Maduro MF, Meneghini MD, Bowerman B, Broitman-Maduro G, Rothman JH (2001) Restriction of mesendoderm to a single blastomere by the combined action of SKN-1 and a GSK-3beta homolog is mediated by MED-1 and -2 in C. elegans. Mol Cell 7:475–485
44. Coroian C, Broitman-Maduro G, Maduro MF (2006) Med-type GATA factors and the evolution of mesendoderm specification in nematodes. Dev Biol 289:444–455
45. Broitman-Maduro G, Lin KT, Hung WW, Maduro MF (2006) Specification of the C. elegans MS blastomere by the T-box factor TBX-35. Development 133:3097–3106
46. Broitman-Maduro G, Owraghi M, Hung WW, Kuntz S, Sternberg PW, Maduro MF (2009) The NK-2 class homeodomain factor CEH-51 and the T-box factor TBX-35 have overlapping function in C. elegans mesoderm development. Development 136:2735–2746
47. Huang S, Shetty P, Robertson SM, Lin R (2007) Binary cell fate specification during C. elegans embryogenesis driven by reiterated reciprocal asymmetry of TCF POP-1 and its coactivator beta-catenin SYS-1. Development 134:2685–2695
48. Phillips BT, Kidd AR 3rd, King R, Hardin J, Kimble J (2007) Reciprocal asymmetry of SYS-1/beta-catenin and POP-1/TCF controls asymmetric divisions in Caenorhabditis elegans. Proc Natl Acad Sci USA 104:3231–3236
49. Fukushige T, Hendzel MJ, Bazett-Jones DP, McGhee JD (1999) Direct visualization of the elt-2 gut-specific GATA factor binding to a target promoter inside the living Caenorhabditis elegans embryo. Proc Natl Acad Sci USA 96:11883–11888
50. Maduro MF, Kasmir JJ, Zhu J, Rothman JH (2005) The Wnt effector POP-1 and the PAL-1/Caudal homeoprotein collaborate with SKN-1 to activate C. elegans endoderm development. Dev Biol 285:510–523
51. McGhee JD, Fukushige T, Krause MW, Minnema SE, Goszczynski B, Gaudet J, Kohara Y, Bossinger O, Zhao Y, Khattra J, Hirst M, Jones SJ, Marra MA, Ruzanov P, Warner A, Zapf R, Moerman DG, Kalb JM (2009) ELT-2 is the predominant transcription factor controlling differentiation and function of the C. elegans intestine, from embryo to adult. Dev Biol 327:551–565
52. Guichet A, Peri F, Roth S (2001) Stable anterior anchoring of the oocyte nucleus is required to establish dorsoventral polarity of the Drosophila egg. Dev Biol 237:93–106
53. Rogers B, Peterson M, Kaufman T (2002) The development and evolution of insect mouthparts as revealed by the expression patterns of gnathocephalic genes. Evol Dev 4:96–110
54. Seecoomar M, Agarwal S, Vani K, Yang G, Mohler J (2000) Knot is required for the hypopharyngeal lobe and its derivatives in the Drosophila embryo. Mech Dev 91:209–215
55. Vervoort M, Crozatier M, Valle D, Vincent A (1999) The COE transcription factor Collier is a mediator of short-range Hedgehog-induced patterning of the Drosophila wing. Curr Biol 9:632–639
56. Mohler J (1993) Genetic regulation of cnc expression in the pharnygeal primordia of Drosophila blastoderm embryos. Rouxs Arch Dev Biol 202:214–223
57. Mohler J, Mahaffey J, Deutsch E, Vani K (1995) Control of Drosophila head segment identity by the bZIP homeotic gene cnc. Development 121:237–247
58. Ntini E, Wimmer EA (2011) Second order regulator Collier directly controls intercalary-specific segment polarity gene expression. Dev Biol 360:403–414
59. Deng H (2014) Multiple roles of Nrf2-Keap1 signaling: regulation of development and xenobiotic response using distinct mechanisms. Fly 8:7–12
60. Deng H, Kerppola TK (2013) Regulation of Drosophila metamorphosis by xenobiotic response regulators. PLoS Genet 9:e1003263
61. Hochmuth CE, Biteau B, Bohmann D, Jasper H (2011) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8:188–199
62. Chan JY, Kwong M, Lu R, Chang J, Wang B, Yen TS, Kan YW (1998) Targeted disruption of the ubiquitous CNC-bZIP transcription factor, Nrf-1, results in anemia and embryonic lethality in mice. EMBO J 17:1779–1787
63. Chan K, Lu R, Chang JC, Kan YW (1996) NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci USA 93:13943–13948
64. Derjuga A, Gourley TS, Holm TM, Heng HH, Shivdasani RA, Ahmed R, Andrews NC, Blank V (2004) Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus. Mol Cell Biol 24:3286–3294
65. Leung L, Kwong M, Hou S, Lee C, Chan JY (2003) Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem 278:48021–48029
66. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL (1999) Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem 274:26071–26078
67. Loboda A, Jazwa A, Grochot-Przeczek A, Rutkowski AJ, Cisowski J, Agarwal A, Jozkowicz A, Dulak J (2008) Heme oxygenase-1 and the vascular bed: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 10:1767–1812
68. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM (1992) Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 267:18148–18153
69. Cheng HT, Yen CJ, Chang CC, Huang KT, Chen KH, Zhang RY, Lee PY, Miaw SC, Huang JW, Chiang CK, Wu KD, Hung KY (2015) Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress. Biochim Biophys Acta 1850:2506–2517
70. Loboda A, Jozkowicz A, Dulak J (2015) HO-1/CO system in tumor growth, angiogenesis and metabolism—targeting ho-1 as an anti-tumor therapy. Vascul Pharmacol 74:11–22
71. Ryter SW, Choi AM (2016) Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Transl Res 167:7–34
72. Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94:10925–10930
73. Poss KD, Tonegawa S (1997) Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 94:10919–10924
74. Yet SF, Perrella MA, Layne MD, Hsieh CM, Maemura K, Kobzik L, Wiesel P, Christou H, Kourembanas S, Lee ME (1999) Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest 103:R23–R29
75. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103:129–135
76. Radhakrishnan N, Yadav SP, Sachdeva A, Pruthi PK, Sawhney S, Piplani T, Wada T, Yachie A (2011) Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. J Pediatr Hematol Oncol 33:74–78
77. Taha H, Skrzypek K, Guevara I, Nigisch A, Mustafa S, Grochot-Przeczek A, Ferdek P, Was H, Kotlinowski J, Kozakowska M, Balcerczyk A, Muchova L, Vitek L, Weigel G, Dulak J, Jozkowicz A (2010) Role of heme oxygenase-1 in human endothelial cells: lesson from the promoter allelic variants. Arterioscler Thromb Vasc Biol 30:1634–1641
78. Pechlaner R, Willeit P, Summerer M, Santer P, Egger G, Kronenberg F, Demetz E, Weiss G, Tsimikas S, Witztum JL, Willeit K, Iglseder B, Paulweber B, Kedenko L, Haun M, Meisinger C, Gieger C, Muller-Nurasyid M, Peters A, Willeit J, Kiechl S (2015) Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease. Arterioscler Thromb Vasc Biol 35:229–236
79. Qiao H, Sai X, Gai L, Huang G, Chen X, Tu X, Ding Z (2014) Association between heme oxygenase 1 gene promoter polymorphisms and susceptibility to coronary artery disease: a huge review and meta-analysis. Am J Epidemiol 179:1039–1048
80. Chang KW, Lee TC, Yeh WI, Chung MY, Liu CJ, Chi LY, Lin SC (2004) Polymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewers. Br J Cancer 91:1551–1555
81. Lo SS, Lin SC, Wu CW, Chen JH, Yeh WI, Chung MY, Lui WY (2007) Heme oxygenase-1 gene promoter polymorphism is associated with risk of gastric adenocarcinoma and lymphovascular tumor invasion. Ann Surg Oncol 14:2250–2256
82. Kikuchi A, Yamaya M, Suzuki S, Yasuda H, Kubo H, Nakayama K, Handa M, Sasaki T, Shibahara S, Sekizawa K, Sasaki H (2005) Association of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphism. Hum Genet 116:354–360
83. Vashist YK, Uzungolu G, Kutup A, Gebauer F, Koenig A, Deutsch L, Zehler O, Busch P, Kalinin V, Izbicki JR, Yekebas EF (2011) Heme oxygenase-1 germ line gtn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancer. J Surg Oncol 104:305–311
84. Okamoto I, Krogler J, Endler G, Kaufmann S, Mustafa S, Exner M, Mannhalter C, Wagner O, Pehamberger H (2006) A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with risk for melanoma. Int J Cancer 119:1312–1315
85. npolymorphism of the HO-1 gene promoter region and cancer risk: a meta-analysis. Asian Pac J Cancer Prev 15:4617–4622
86. Wu MM, Lee CH, Hsu LI, Cheng WF, Lee TC, Wang YH, Chiou HY, Chen CJ (2016) Effect of heme oxygenase-1 gene promoter polymorphism on cancer risk by histological subtype: a prospective study in arseniasis-endemic areas in Taiwan. Int J Cancer 138:1875–1886
87. Kimpara T, Takeda A, Watanabe K, Itoyama Y, Ikawa S, Watanabe M, Arai H, Sasaki H, Higuchi S, Okita N, Takase S, Saito H, Takahashi K, Shibahara S (1997) Microsatellite polymorphism in the human heme oxygenase-1 gene promoter and its application in association studies with Alzheimer and Parkinson disease. Hum Genet 100:145–147
88. Funke C, Tomiuk J, Riess O, Berg D, Soehn AS (2009) Genetic analysis of heme oxygenase-1 (ho-1) in German Parkinson’s disease patients. J Neural Transm 116:853–859
89. Infante J, Garcia-Gorostiaga I, Sanchez-Juan P, Sierra M, Martin-Gurpegui JL, Terrazas J, Mateo I, Rodriguez-Rodriguez E, Berciano J, Combarros O (2010) Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson’s disease. Eur J Neurol 17:760–762
90. Watanabe S, Akagi R, Mori M, Tsuchiya T, Sassa S (2004) Marked developmental changes in heme oxygenase-1 (HO-1) expression in the mouse placenta: correlation between HO-1 expression and placental development. Placenta 25:387–395
91. Ihara N, Akagi R, Ejiri K, Kudo T, Furuyama K, Fujita H (1998) Developmental changes of gene expression in heme metabolic enzymes in rat placenta. FEBS Lett 439:163–167
92. Zenclussen ML, Linzke N, Schumacher A, Fest S, Meyer N, Casalis PA, Zenclussen AC (2014) Heme oxygenase-1 is critically involved in placentation, spiral artery remodeling, and blood pressure regulation during murine pregnancy. Front Pharmacol 5:291
93. Zhao H, Wong RJ, Kalish FS, Nayak NR, Stevenson DK (2009) Effect of heme oxygenase-1 deficiency on placental development. Placenta 30:861–868
94. Zenclussen ML, Anegon I, Bertoja AZ, Chauveau C, Vogt K, Gerlof K, Sollwedel A, Volk HD, Ritter T, Zenclussen AC (2006) Over-expression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a murine model of abortion. J Reprod Immunol 69:35–52
95. Kreiser D, Nguyen X, Wong R, Seidman D, Stevenson D, Quan S, Abraham N, Dennery PA (2002) Heme oxygenase-1 modulates fetal growth in the rat. Lab Invest 82:687–692
96. Lin TC, Yen JM, Gong KB, Hsu TT, Chen LR (2003) IGF-1/IGFP-1 increases blastocyst formation and total blastocyst cell number in mouse embryo culture and facilitates the establishment of a stem-cell line. BMC Cell Biol 4:14
97. Lin CY, Peng CY, Huang TT, Wu ML, Lai YL, Peng DH, Chen PF, Chen HF, Yen BL, Wu KK, Yet SF (2012) Exacerbation of oxidative stress-induced cell death and differentiation in induced pluripotent stem cells lacking heme oxygenase-1. Stem Cells Dev 21:1675–1687
98. Zhang X, Sato M, Sasahara M, Migita CT, Yoshida T (2004) Unique features of recombinant heme oxygenase of Drosophila melanogaster compared with those of other heme oxygenases studied. Eur J Biochem 271:1713–1724
99. Cui L, Yoshioka Y, Suyari O, Kohno Y, Zhang X, Adachi Y, Ikehara S, Yoshida T, Yamaguchi M, Taketani S (2008) Relevant expression of Drosophila heme oxygenase is necessary for the normal development of insect tissues. Biochem Biophys Res Commun 377:1156–1161
100. Ceriani MF, Hogenesch JB, Yanovsky M, Panda S, Straume M, Kay SA (2002) Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J Neurosci 22:9305–9319
101. Troxler RF, Brown AS, Brown SB (1979) Bile pigment synthesis in plants. Mechanism of 18O incorporation into phycocyanobilin in the unicellular rhodophyte. Cyanidium caldarium. J Biol Chem 254:3411–3418
102. Beale SI, Cornejo J (1984) Enzymatic heme oxygenase activity in soluble extracts of the unicellular red alga, Cyanidium caldarium. Arch Biochem Biophys 235:371–384
103. Muramoto T, Kohchi T, Yokota A, Hwang I, Goodman HM (1999) The arabidopsis photomorphogenic mutant hy1 is deficient in phytochrome chromophore biosynthesis as a result of a mutation in a plastid heme oxygenase. Plant Cell 11:335–348
104. Emborg TJ, Walker JM, Noh B, Vierstra RD (2006) Multiple heme oxygenase family members contribute to the biosynthesis of the phytochrome chromophore in Arabidopsis. Plant Physiol 140:856–868
105. Matsumoto F, Obayashi T, Sasaki-Sekimoto Y, Ohta H, Takamiya K, Masuda T (2004) Gene expression profiling of the tetrapyrrole metabolic pathway in arabidopsis with a mini-array system. Plant Physiol 135:2379–2391
106. Balestrasse KB, Noriega GO, Batlle A, Tomaro ML (2005) Involvement of heme oxygenase as antioxidant defense in soybean nodules. Free Radic Res 39:145–151
107. Frankenberg-Dinkel N (2004) Bacterial heme oxygenases. Antioxid Redox Signal 6:825–834
108. Wilks A, Schmitt MP (1998) Expression and characterization of a heme oxygenase (Hmu O) from corynebacterium diphtheriae. Iron acquisition requires oxidative cleavage of the heme macrocycle. J Biol Chem 273:837–841
109. Zhu W, Wilks A, Stojiljkovic I (2000) Degradation of heme in Gram-negative bacteria: the product of the hemO gene of Neisseriae is a heme oxygenase. J Bacteriol 182:6783–6790
110. Lewis KN, Mele J, Hayes JD, Buffenstein R (2010) Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integr Comp Biol 50:829–843
111. Rahman MM, Sykiotis GP, Nishimura M, Bodmer R, Bohmann D (2013) Declining signal dependence of Nrf2-MafS-regulated gene expression correlates with aging phenotypes. Aging Cell 12:554–562
112. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63
113. Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, Tamashiro KL, Poosala S, Csiszar A, Ungvari Z, Kensler TW, Yamamoto M, Egan JM, Longo DL, Ingram DK, Navas P, de Cabo R (2008) Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci USA 105:2325–2330
114. Smith-Vikos T, de Lencastre A, Inukai S, Shlomchik M, Holtrup B, Slack FJ (2014) Micrornas mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Curr Biol 24:2238–2246
115. de Lencastre A, Pincus Z, Zhou K, Kato M, Lee SS, Slack FJ (2010) MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol 20:2159–2168
116. Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132:1025–1038
117. Ewald CY, Landis JN, Porter Abate J, Murphy CT, Blackwell TK (2015) Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519:97–101
118. Olahova M, Veal EA (2015) A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIs-dependent regulation of stress resistance and longevity. Aging Cell 14:558–568
119. Seo HW, Cheon SM, Lee MH, Kim HJ, Jeon H, Cha DS (2015) Catalpol modulates lifespan via DAF-16/FOXO and SKN-1/Nrf2 activation in Caenorhabditis elegans. Evid Based Complement Alternat Med 2015:524878
120. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15:713–724
121. Mizunuma M, Neumann-Haefelin E, Moroz N, Li Y, Blackwell TK (2014) mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13:869–878
122. Palikaras K, Lionaki E, Tavernarakis N (2015) Coupling mitogenesis and mitophagy for longevity. Autophagy 11:1428–1430
123. Palikaras K, Lionaki E, Tavernarakis N (2015) Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521:525–528
124. Itoh K, Ye P, Matsumiya T, Tanji K, Ozaki T (2015) Emerging functional cross-talk between the keap1-nrf2 system and mitochondria. J Clin Biochem Nutr 56:91–97
125. Amador-Noguez D, Yagi K, Venable S, Darlington G (2004) Gene expression profile of long-lived ames dwarf mice and little mice. Aging Cell 3:423–441
126. Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, Buffenstein R (2015) Regulation of nrf2 signaling and longevity in naturally long-lived rodents. Proc Natl Acad Sci USA 112:3722–3727
127. Tsakiri EN, Sykiotis GP, Papassideri IS, Gorgoulis VG, Bohmann D, Trougakos IP (2013) Differential regulation of proteasome functionality in reproductive vs. somatic tissues of Drosophila during aging or oxidative stress. FASEB J 27:2407–2420
128. Chondrogianni N, Stratford FL, Trougakos IP, Friguet B, Rivett AJ, Gonos ES (2003) Central role of the proteasome in senescence and survival of human fibroblasts: induction of a senescence-like phenotype upon its inhibition and resistance to stress upon its activation. J Biol Chem 278:28026–28037
129. Pickering AM, Davies KJ (2012) Degradation of damaged proteins: the main function of the 20S proteasome. Prog Mol Biol Transl Sci 109:227–248
130. Navon A, Ciechanover A (2009) The 26S proteasome: from basic mechanisms to drug targeting. J Biol Chem 284:33713–33718
131. Grimberg KB, Beskow A, Lundin D, Davis MM, Young P (2011) Basic leucine zipper protein Cnc-C is a substrate and transcriptional regulator of the Drosophila 26S proteasome. Mol Cell Biol 31:897–909
132. Lundgren J, Masson P, Mirzaei Z, Young P (2005) Identification and characterization of a Drosophila proteasome regulatory network. Mol Cell Biol 25:4662–4675
133. Pickering AM, Staab TA, Tower J, Sieburth D, Davies KJ (2013) A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster. J Exp Biol 216:543–553
134. Tsakiri EN, Sykiotis GP, Papassideri IS, Terpos E, Dimopoulos MA, Gorgoulis VG, Bohmann D, Trougakos IP (2013) Proteasome dysfunction in Drosophila signals to an Nrf2-dependent regulatory circuit aiming to restore proteostasis and prevent premature aging. Aging Cell 12:802–813
135. Wang J, Robida-Stubbs S, Tullet JM, Rual JF, Vidal M, Blackwell TK (2010) RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet 6:e1001048
136. Chondrogianni N, Georgila K, Kourtis N, Tavernarakis N, Gonos ES (2015) 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J 29:611–622
137. Kwak MK, Wakabayashi N, Greenlaw JL, Yamamoto M, Kensler TW (2003) Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol 23:8786–8794
138. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci USA 101:3381–3386
139. Duan W, Zhang R, Guo Y, Jiang Y, Huang Y, Jiang H, Li C (2009) Nrf2 activity is lost in the spinal cord and its astrocytes of aged mice. In Vitro Cell Dev Biol Anim 45:388–397
140. Suzuki M, Betsuyaku T, Ito Y, Nagai K, Nasuhara Y, Kaga K, Kondo S, Nishimura M (2008) Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 39:673–682
141. Kraft AD, Johnson DA, Johnson JA (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci 24:1101–1112
142. Johnson JA, Johnson DA, Kraft AD, Calkins MJ, Jakel RJ, Vargas MR, Chen PC (2008) The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci 1147:61–69
143. Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci USA 102:244–249
144. Jakel RJ, Townsend JA, Kraft AD, Johnson JA (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Res 1144:192–201
145. Burton NC, Kensler TW, Guilarte TR (2006) In vivo modulation of the parkinsonian phenotype by nrf2. Neurotoxicology 27:1094–1100
146. Innamorato NG, Jazwa A, Rojo AI, Garcia C, Fernandez-Ruiz J, Grochot-Przeczek A, Stachurska A, Jozkowicz A, Dulak J, Cuadrado A (2010) Different susceptibility to the Parkinson’s toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1. PLoS One 5:e11838
147. Jazwa A, Rojo AI, Innamorato NG, Hesse M, Fernandez-Ruiz J, Cuadrado A (2011) Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal 14:2347–2360
148. Hung SY, Liou HC, Kang KH, Wu RM, Wen CC, Fu WM (2008) Overexpression of heme oxygenase-1 protects dopaminergic neurons against 1-methyl-4-phenylpyridinium-induced neurotoxicity. Mol Pharmacol 74:1564–1575
149. Trinh K, Moore K, Wes PD, Muchowski PJ, Dey J, Andrews L, Pallanck LJ (2008) Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson’s disease. J Neurosci 28:465–472
150. Trinh K, Andrews L, Krause J, Hanak T, Lee D, Gelb M, Pallanck L (2010) Decaffeinated coffee and nicotine-free tobacco provide neuroprotection in Drosophila models of Parkinson’s disease through an NRF2-dependent mechanism. J Neurosci 30:5525–5532
151. Barone MC, Sykiotis GP, Bohmann D (2011) Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson’s disease. Dis Model Mech 4:701–707
152. Wang B, Liu Q, Shan H, Xia C, Liu Z (2015) Nrf2 inducer and Cncc overexpression attenuates neurodegeneration due to α-synuclein in Drosophila. Biochem Cell Biol 93:351–358
153. Wang Y, Santa-Cruz K, DeCarli C, Johnson JA (2000) NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer’s disease. Neurobiol Aging 21:525–531
154. Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, Takahashi H, Wakabayashi K (2013) Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases. J Neuropathol Exp Neurol 72:18–28
155. Schipper HM, Bennett DA, Liberman A, Bienias JL, Schneider JA, Kelly J, Arvanitakis Z (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiol Aging 27:252–261
156. Gupta A, Lacoste B, Pistell PJ, Ingram DK, Hamel E, Alaoui-Jamali MA, Szarek WA, Vlahakis JZ, Jie S, Song W, Schipper HM (2014) Neurotherapeutic effects of novel HO-1 inhibitors in vitro and in a transgenic mouse model of Alzheimer’s disease. J Neurochem 131:778–790
157. Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL (2007) Expression of nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85
158. Yamazaki H, Tanji K, Wakabayashi K, Matsuura S, Itoh K (2015) Role of the Keap1/Nrf2 pathway in neurodegenerative diseases. Pathol Int 65:210–219
159. Arnold P, Mojumder D, Detoledo J, Lucius R, Wilms H (2014) Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways. Clin Pharmacol 6:35–42
160. Cada DJ, Levien TL, Baker DE (2013) Dimethyl fumarate. Hosp Pharm 48:668–679
161. Bomprezzi R (2015) Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Ther Adv Neurol Disord 8:20–30
162. Nicholas JA, Boster AL, Imitola J, O’Connell C, Racke MK (2014) Design of oral agents for the management of multiple sclerosis: benefit and risk assessment for dimethyl fumarate. Drug Des Devel Ther 8:897–908
163. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Brück W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692
164. Lijnen R, Otters E, Balak D, Thio B (2016) Long-term safety and effectiveness of high-dose dimethylfumarate in the treatment of moderate to severe psoriasis: a prospective single-blinded follow-up study. J Dermatolog Treat 27:31–36
165. Gill AJ, Kolson DL (2013) Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy. Crit Rev Immunol 33:307–359
166. Karkkainen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen AL, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J (2014) Nrf2 regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells 32:1904–1916
167. Joshi G, Gan KA, Johnson DA, Johnson JA (2015) Increased Alzheimer’s disease-like pathology in the APP/PSΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36:664–679
168. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30:3275–3285
169. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura S, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12:213–223
170. Ichimura Y, Waguri S, Sou YS, Kageyama S, Hasegawa J, Ishimura R, Saito T, Yang Y, Kouno T, Fukutomi T, Hoshii T, Hirao A, Takagi K, Mizushima T, Motohashi H, Lee MS, Yoshimori T, Tanaka K, Yamamoto M, Komatsu M (2013) Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell 51:618–631
171. Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA, Overvatn A, McMahon M, Hayes JD, Johansen T (2010) p62/SQSTM1 is a target gene for transcription factor Nrf2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285:22576–22591
172. Kageyama S, Sou YS, Uemura T, Kametaka S, Saito T, Ishimura R, Kouno T, Bedford L, Mayer RJ, Lee MS, Yamamoto M, Waguri S, Tanaka K, Komatsu M (2014) Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway. J Biol Chem 289:24944–24955
173. Zhao Z, Chen Y, Wang J, Sternberg P, Freeman ML, Grossniklaus HE, Cai J (2011) Age-related retinopathy in Nrf2-deficient mice. PLoS One 6:e19456
174. Sliwinski T, Kolodziejska U, Szaflik JP, Blasiak J, Szaflik J (2013) Association between the 25129a>c polymorphism of the nuclear respiratory factor 2 gene and age-related macular degeneration. Klin Oczna 115:96–102
175. Synowiec E, Szaflik J, Chmielewska M, Wozniak K, Sklodowska A, Waszczyk M, Dorecka M, Blasiak J, Szaflik JP (2012) An association between polymorphism of the heme oxygenase-1 and -2 genes and age-related macular degeneration. Mol Biol Rep 39:2081–2087
176. Jonasson F, Fisher DE, Eiriksdottir G, Sigurdsson S, Klein R, Launer LJ, Harris T, Gudnason V, Cotch MF (2014) Five-year incidence, progression, and risk factors for age-related macular degeneration: the age, gene/environment susceptibility study. Ophthalmology 121:1766–1772
177. Wang L, Kondo N, Cano M, Ebrahimi K, Yoshida T, Barnett BP, Biswal S, Handa JT (2014) Nrf2 signaling modulates cigarette smoke-induced complement activation in retinal pigmented epithelial cells. Free Radic Biol Med 70:155–166
178. Bertram KM, Baglole CJ, Phipps RP, Libby RT (2009) Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration. Am J Physiol Cell Physiol 297:C1200–C1210
179. Song D, Dunaief JL (2013) Retinal iron homeostasis in health and disease. Front Aging Neurosci 5:24
180. Kannan R, Hinton DR (2014) Sodium iodate induced retinal degeneration: new insights from an old model. Neural Regen Res 9:2044–2045
181. Sachdeva MM, Cano M, Handa JT (2014) Nrf2 signaling is impaired in the aging RPE given an oxidative insult. Exp Eye Res 119:111–114
182. Birch-Machin MA (2006) The role of mitochondria in ageing and carcinogenesis. Clin Exp Dermatol 31:548–552
183. Loboda A, Rojczyk-Golebiewska E, Bednarczyk-Cwynar B, Lucjusz Z, Jozkowicz A, Dulak J (2012) Targeting Nrf2-mediated gene transcription by triterpenoids and their derivatives. Biomol Ther 20:499–505
184. Kwak MK, Kensler TW (2010) Targeting nrf2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol 244:66–76
185. Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, Shimazui T, Akaza H, Yamamoto M (2004) Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 64:6424–6431
186. Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, Sutter TR, Baumgartner KJ, Roebuck BD, Liby KT, Yore MM, Honda T, Gribble GW, Sporn MB, Kensler TW (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res 66:2488–2494
187. Saw CL, Huang MT, Liu Y, Khor TO, Conney AH, Kong AN (2011) Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol Carcinog 50:479–486
188. Bauer AK, Hill T 3rd, Alexander CM (2013) The involvement of Nrf2 in lung cancer. Oxid Med Cell Longev. 2013:746432
189. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, Herman JG, Baylin SB, Sidransky D, Gabrielson E, Brock MV, Biswal S (2006) Dysfunctional Keap1-Nrf2 interaction in non-small-cell lung cancer. PLoS Med 3:e420
190. Kim YR, Oh JE, Kim MS, Kang MR, Park SW, Han JY, Eom HS, Yoo NJ, Lee SH (2010) Oncogenic nrf2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol 220:446–451
191. Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, Pollard PJ (2011) Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in keap1 succination and Nrf2 signaling. Cancer Cell 20:524–537
192. Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase-1. Annu Rev Pharmacol Toxicol 50:323–354
193. Deshane J, Chen S, Caballero S, Grochot-Przeczek A, Was H, Li Calzi S, Lach R, Hock TD, Chen B, Hill-Kapturczak N, Siegal GP, Dulak J, Jozkowicz A, Grant MB, Agarwal A (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204:605–618
194. Dulak J, Jozkowicz A, Foresti R, Kasza A, Frick M, Huk I, Green CJ, Pachinger O, Weidinger F, Motterlini R (2002) Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells. Antioxid Redox Signal 4:229–240
195. Jozkowicz A, Huk I, Nigisch A, Weigel G, Dietrich W, Motterlini R, Dulak J (2003) Heme oxygenase and angiogenic activity of endothelial cells: stimulation by carbon monoxide and inhibition by tin protoporphyrin-ix. Antioxid Redox Signal 5:155–162
196. Was H, Dulak J, Jozkowicz A (2010) Heme oxygenase-1 in tumor biology and therapy. Curr Drug Targets 11:1551–1570
197. Marinissen MJ, Tanos T, Bolos M, de Sagarra MR, Coso OA, Cuadrado A (2006) Inhibition of heme oxygenase-1 interferes with the transforming activity of the Kaposi sarcoma herpesvirus-encoded G protein-coupled receptor. J Biol Chem 281:11332–11346
198. Martin MJ, Tanos T, Garcia AB, Martin D, Gutkind JS, Coso OA, Marinissen MJ (2007) The Galpha12/13 family of heterotrimeric g proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis. J Biol Chem 282:34510–34524
199. Mayerhofer M, Florian S, Krauth MT, Aichberger KJ, Bilban M, Marculescu R, Printz D, Fritsch G, Wagner O, Selzer E, Sperr WR, Valent P, Sillaber C (2004) Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia. Cancer Res 64:3148–3154
200. Banerjee P, Basu A, Arbiser JL, Pal S (2013) The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways. Cancer Lett 338:292–299
201. Nagy P, Varga A, Pircs K, Hegedus K, Juhasz G (2013) Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster. PLoS Genet 9:e1003664
202. Levy S, Forman HJ (2010) C-Myc is a Nrf2-interacting protein that negatively regulates phase II genes through their electrophile responsive elements. IUBMB Life 62:237–246
203. Loboda A, Stachurska A, Florczyk U, Rudnicka D, Jazwa A, Wegrzyn J, Kozakowska M, Stalinska K, Poellinger L, Levonen AL, Yla-Herttuala S, Jozkowicz A, Dulak J (2009) HIF-1 induction attenuates Nrf2-dependent IL-8 expression in human endothelial cells. Antioxid Redox Signal 11:1501–1517
204. Was H, Sokolowska M, Sierpniowska A, Dominik P, Skrzypek K, Lackowska B, Pratnicki A, Grochot-Przeczek A, Taha H, Kotlinowski J, Kozakowska M, Mazan A, Nowak W, Muchova L, Vitek L, Ratajska A, Dulak J, Jozkowicz A (2011) Effects of heme oxygenase-1 on induction and development of chemically induced squamous cell carcinoma in mice. Free Radic Biol Med 51:1717–1726
205. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F, Roop DR, Harada T, Engel JD, Yamamoto M (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35:238–245
206. Narasimhan M, Rajasekaran NS (2015) Reductive potential—a savior turns stressor in protein aggregation cardiomyopathy. Biochim Biophys Acta 1852:53–60
207. Rajasekaran NS, Connell P, Christians ES, Yan LJ, Taylor RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leopold JA, Barry WH, Loscalzo J, Odelberg SJ, Benjamin IJ (2007) Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell 130:427–439
208. Zhang X, Min X, Li C, Benjamin IJ, Qian B, Zhang X, Ding Z, Gao X, Yao Y, Ma Y, Cheng Y, Liu L (2010) Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension 55:1412–1417
209. Rajasekaran NS, Varadharaj S, Khanderao GD, Davidson CJ, Kannan S, Firpo MA, Zweier JL, Benjamin IJ (2011) Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid Redox Signal 14:957–971
210. Kannan S, Muthusamy VR, Whitehead KJ, Wang L, Gomes AV, Litwin SE, Kensler TW, Abel ED, Hoidal JR, Rajasekaran NS (2013) Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy. Cardiovasc Res 100:63–73
211. Chorley BN, Campbell MR, Wang X, Karaca M, Sambandan D, Bangura F, Xue P, Pi J, Kleeberger SR, Bell DA (2012) Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid x receptor alpha. Nucleic Acids Res 40:7416–7429
212. Eades G, Yang M, Yao Y, Zhang Y, Zhou Q (2011) mirR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem 286:40725–40733
213. Yang M, Yao Y, Eades G, Zhang Y, Zhou Q (2011) Mir-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat 129:983–991
214. Sangokoya C, Telen MJ, Chi JT (2010) microRNA mir-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood 116:4338–4348
215. Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, Nasipuri P, Krausz KW, Wakabayashi N, Dewi R, Boros LG, Gonzalez FJ, Gabrielson E, Wong KK, Girnun G, Biswal S (2013) Transcription factor nrf2 regulates mir-1 and mir-206 to drive tumorigenesis. J Clin Invest 123:2921–2934
216. Kozakowska M, Ciesla M, Stefanska A, Skrzypek K, Was H, Jazwa A, Grochot-Przeczek A, Kotlinowski J, Szymula A, Bartelik A, Mazan M, Yagensky O, Florczyk U, Lemke K, Zebzda A, Dyduch G, Nowak W, Szade K, Stepniewski J, Majka M, Derlacz R, Loboda A, Dulak J, Jozkowicz A (2012) Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs. Antioxid Redox Signal 16:113–127
217. Skrzypek K, Tertil M, Golda S, Ciesla M, Weglarczyk K, Collet G, Guichard A, Kozakowska M, Boczkowski J, Was H, Gil T, Kuzdzal J, Muchova L, Vitek L, Loboda A, Jozkowicz A, Kieda C, Dulak J (2013) Interplay between heme oxygenase-1 and mir-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis. Antioxid Redox Signal 19:644–660
218. Tertil M, Golda S, Skrzypek K, Florczyk U, Weglarczyk K, Kotlinowski J, Maleszewska M, Czauderna S, Pichon C, Kieda C, Jozkowicz A, Dulak J (2015) Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: antitumoral effects associated with down-regulation of matrix metalloproteinases. Free Radic Biol Med 89:147–157
219. Lin SH, Song W, Cressatti M, Zukor H, Wang E, Schipper HM (2015) Heme oxygenase-1 modulates microRNA expression in cultured astroglia: implications for chronic brain disorders. Glia 63:1270–1284