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Biochemistry (Moscow)

, Volume 82, Issue 5, pp 556–564 | Cite as

Mazes of Nrf2 regulation

  • N. K. Zenkov
  • P. M. Kozhin
  • A. V. Chechushkov
  • G. G. Martinovich
  • N. V. Kandalintseva
  • E. B. MenshchikovaEmail author
Review

Abstract

Nrf2 transcription factor plays a key role in maintaining cellular redox balance under stress and is a perspective target for oxidative stress-associated diseases. Under normal conditions, Nrf2 transcriptional activity is low due to its rapid ubiquitination and degradation in the 26S proteasome, as well as through various modifications of amino acid residues of this transcription factor that regulate its transport to the nucleus and binding to DNA. Continuous activation of Nrf2 is possible due to autophagy and epigenetic regulation that may underlie the increased resistance of tumor cells to radiotherapy and chemotherapy. This review deals with the mechanisms of regulation of Nrf2 transcriptional activity and its main elements, and pharmacological approaches to activation of the Keap1/Nrf2/ARE system.

Keywords

Nrf2 transcription factor ubiquitination autophagy epigenetic regulation 

Abbreviations

Akt

protein kinase B

AMPK

adenosine monophosphate-activated protein kinase

aPKC

atypical protein kinase C

ARE

antioxidant response element)

BTB

Broad-complex (Tramtrack, Bric-a-brac)

bZip

basic leucine zipper DNA-binding domain

CNC

Cap’n’Collar

ERK1/2

extracellular signal-regulated protein kinase 1/2

FXR

farnesoid X receptor

GSK-3

glycogen synthase kinase 3

HER2/ErbB2/neu

tyrosine protein kinase of EGFR/ErbB receptor family

IKKβ

β-subunit of IκB-kinase

JAK/STAT

tyrosine kinase Janus kinase/signal transducer and activator of transcription

JNK

kinases of MAPK family (c-Jun N-terminal kinases)

Keap1

Kelch-like ECH-associated protein 1

KIR

Keap-interacting region

LC3

microtubule-associated protein 1A/1B-light chain 3

LIR

LC3 interacting region

MAPK

mitogen-activated protein kinases

mTOR

mammalian target of rapamycin (a serine/threonine protein kinase)

mTORC1/2

mammalian target of rapamycin complex 1/2

Neh

Nrf2-ECH homology (ECH is a homolog of Nrf2 in chickens)

NES

nuclear export signal

NFE

nuclear factor-erythroid derived

NLS

nuclear localization signal

Nrf2

NF-E2-related factor 2

PB1

Phox and Bem1

PERK

protein kinase-like endoplasmic reticulum kinase

PGAM5

serine/threonine phosphatase (phosphoglycerate mutase family, member 5)

PI3K

phosphatidylinositol 3-kinase

PKC

protein kinase C

p38 MAPK

p38 mitogen activated protein kinase

PPARγ

receptor binding peroxisome proliferators (peroxisome proliferator-activated receptor γ)

p62/SQSTM1

ubiquitin-binding protein p62, same as sequestosome 1

PTEN

dual-specificity protein phosphatase (phosphatase and tensin homolog deleted on chromosome 10)

Rbx1

RING-box protein 1

ROS

reactive oxygen species

RXRα

retinoid X receptor α

TRAF6

TNFα receptor-associated factor 6

β-TrCP

β-transducin repeat containing protein

UBA

ubiquitin association

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References

  1. 1.
    Chevillard, G., and Blank, V. (2011) NFE2L3 (NRF3): the Cinderella of the Cap’n’Collar transcription factors, Cell. Mol. Life Sci., 68, 3337–3348.CrossRefPubMedGoogle Scholar
  2. 2.
    Kim, H. M., Han, J. W., and Chan, J. Y. (2016) Nuclear factor erythroid-2 like 1 (NFE2L1): structure, function and regulation, Gene, 584, 17–25.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang, X., and Mosser, D. M. (2008) Macrophage activation by endogenous danger signals, J. Pathol., 214, 161–178.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Chapple, S. J., Keeley, T. P., Mastronicola, D., Arno, M., Vizcay-Barrena, G., Fleck, R., Siow, R. C., and Mann, G. E. (2016) Bach1 differentially regulates distinct Nrf2-dependent genes in human venous and coronary artery endothelial cells adapted to physiological oxygen levels, Free Radic. Biol. Med., 92, 152–162.CrossRefPubMedGoogle Scholar
  5. 5.
    Biswas, M., and Chan, J. Y. (2010) Role of Nrf1 in antioxidant response elementmediated gene expression and beyond, Toxicol. Appl. Pharmacol., 244, 16–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Canning, P., Sorrell, F. J., and Bullock, A. N. (2015) Structural basis of Keap1 interactions with Nrf2, Free Radic. Biol. Med., 88, 101–107.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jaramillo, M. C., and Zhang, D. D. (2013) The emerging role of the Nrf2-Keap1 signaling pathway in cancer, Genes Dev., 27, 2179–2191.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., and Hayes, J. D. (2015) 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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Katsuoka, F., and Yamamoto, M. (2016) Small Maf proteins (MafF, MafG, MafK): history, structure and function, Gene, 586, 197–205.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang, Y., and Xiang, Y. (2016) Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity, Biochem. J., 473, 961–1000.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang, H., Liu, K., Geng, M., Gao, P., Wu, X., Hai, Y., Li, Y., Luo, L., Hayes, J. D., Wang, X. J., and Tang, X. (2013) RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2, Cancer Res., 73, 3097–3108.CrossRefPubMedGoogle Scholar
  12. 12.
    Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., and Hayes, J.D. (2013) Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity, Oncogene, 32, 3765–3781.CrossRefPubMedGoogle Scholar
  13. 13.
    Coyaud, E., Mis, M., Laurent, E. M., Dunham, W. H., Couzens, A. L., Robitaille, M., Gingras, A. C., Angers, S., and Raught, B. (2015) BioID-based identification of Skp Cullin F-box SCFβ-TrCP1/2 E3 ligase substrates, Mol. Cell. Proteom., 14, 1781–1795.CrossRefGoogle Scholar
  14. 14.
    Dodson, M., Redmann, M., Rajasekaran, N. S., Darley-Usmar, V., and Zhang, J. (2015) KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity, Biochem. J., 469, 347–355.CrossRefPubMedGoogle Scholar
  15. 15.
    Cuadrado, A. (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP, Free Radic. Biol. Med., 88, 147–157.CrossRefPubMedGoogle Scholar
  16. 16.
    Ma, Q., Battelli, L., and Hubbs, A. F. (2006) Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidantactivated transcription factor Nrf2, Am. J. Pathol., 168, 1960–1974.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ahmed, S. M., Luo, L., Namani, A., Wang, X. J., and Tang, X. (2017) Nrf2 signaling pathway: pivotal roles in inflammation, Biochim. Biophys. Acta, 1863, 585–597.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim, J., and Keum, Y. S. (2016) NRF2, a key regulator of antioxidants with two faces towards cancer, Oxid. Med. Cell. Longev., 2016, 2746457.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Sita, G., Hrelia, P., Tarozzi, A., and Morroni, F. (2016) Isothiocyanates are promising compounds against oxidative stress, neuroinflammation and cell death that may benefit neurodegeneration in Parkinson’s disease, Int. J. Mol. Sci., 17, 1454.CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Zhang, R., Xu, M., Wang, Y., Xie, F., Zhang, G., and Qin, X. (2016) Nrf2–a promising therapeutic target for defensing against oxidative stress in stroke, Mol. Neurobiol., in press.Google Scholar
  21. 21.
    Zenkov, N. K., Menshchikova, E. B., and Tkachev, V. O. (2013) Keap1/Nrf2/ARE redoxsensitive signaling system as a pharmacological target, Biochemistry (Moscow), 78, 19–36.CrossRefGoogle Scholar
  22. 22.
    Smith, E. J., Shay, K. P., Thomas, N. O., Butler, J. A., Finlay, L. F., and Hagen, T. M. (2015) Agerelated loss of hepatic Nrf2 protein homeostasis: potential role for heightened expression of miR-146a, Free Radic. Biol. Med., 89, 1184–1191.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Suzuki, T., and Yamamoto, M. (2015) Molecular basis of the Keap1-Nrf2 system, Free Radic. Biol. Med., 88, 93–100.CrossRefPubMedGoogle Scholar
  24. 24.
    Harder, B., Jiang, T., Wu, T., Tao, S., Rojo de la Vega, M., Tian, W., Chapman, E., and Zhang, D. D. (2015) Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention, Biochem. Soc. Trans., 43, 680–686.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Iso, T., Suzuki, T., Baird, L., and Yamamoto, M. (2016) Absolute amounts and status of Nrf2-Keap1-Cul3 complex within cells, Mol. Cell. Biol., 36, 3100–3112.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhu, J., Wang, H., Chen, F., Fu, J., Xu, Y., Hou, Y., Kou, H. H., Zhai, C., Nelson, M. B., Zhang, Q., Andersen, M. E., and Pi, J. (2016) An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy, Free Radic. Biol. Med., 99, 544–556.CrossRefPubMedGoogle Scholar
  27. 27.
    Holland, R., Hawkins, A. E., Eggler, A. L., Mesecar, A. D., Fabris, D., and Fishbein, J. C. (2008) Prospective type 1 and type 2 disulfides of Keap1 protein, Chem. Res. Toxicol., 21, 2051–2060.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wu, T., Zhao, F., Gao, B., Tan, C., Yagishita, N., Nakajima, T., Wong, P. K., Chapman, E., Fang, D., and Zhang, D. D. (2014) Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis, Genes Dev., 28, 708–722.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lewis, K. N., Wason, E., Edrey, Y. H., Kristan, D. M., Nevo, E., and Buffenstein, R. (2015) Regulation of Nrf2 signaling and longevity in naturally longlived rodents, Proc. Natl. Acad. Sci. USA, 112, 3722–3727.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhang, D. D., Lo, S. C., Sun, Z., Habib, G. M., Lieberman, M. W., and Hannink, M. (2005) Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasomeindependent pathway, J. Biol. Chem., 280, 30091–30099.CrossRefPubMedGoogle Scholar
  31. 31.
    Jiang, T., Harder, B., Rojo de la Vega, M., Wong, P. K., Chapman, E., and Zhang, D. D. (2015) p62 links autophagy and Nrf2 signaling, Free Radic. Biol. Med., 88, 199–204.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Katsuragi, Y., Ichimura, Y., and Komatsu, M. (2015) p62/SQSTM1 functions as a signaling hub and an autophagy adaptor, FEBS J., 282, 4672–4678.CrossRefPubMedGoogle Scholar
  33. 33.
    Rogov, V., Dotsch, V., Johansen, T., and Kirkin, V. (2014) Interactions between autophagy receptors and ubiquitinlike proteins form the molecular basis for selective autophagy, Mol. Cell., 53, 167–178.CrossRefPubMedGoogle Scholar
  34. 34.
    Copple, I. M., Lister, A., Obeng, A. D., Kitteringham, N. R., Jenkins, R. E., Layfield, R., Foster, B. J., Goldring, C. E., and Park, B. K. (2010) Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway, J. Biol. Chem., 285, 16782–16788.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jain, A., Lamark, T., Sjottem, E., Larsen, K. B., Awuh, J. A., Overvatn, A., McMahon, M., Hayes, J. D., and Johansen, T. (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response elementdriven gene transcription, J. Biol. Chem., 285, 22576–22591.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ichimura, Y., Waguri, S., Sou, Y. S., 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, M. S., Yoshimori, T., Tanaka, K., Yamamoto, M., and Komatsu, M. (2013) Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy, Mol. Cell, 51, 618–631.CrossRefPubMedGoogle Scholar
  37. 37.
    Ishimura, R., Tanaka, K., and Komatsu, M. (2014) Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy, FEBS Lett., 588, 822–828.CrossRefPubMedGoogle Scholar
  38. 38.
    Rhee, S. G., and Bae, S. H. (2015) The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1, Free Radic. Biol. Med., 88, 205–211.CrossRefPubMedGoogle Scholar
  39. 39.
    Bryan, H. K., Olayanju, A., Goldring, C. E., and Park, B. K. (2013) The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation, Biochem. Pharmacol., 85, 705–717.CrossRefPubMedGoogle Scholar
  40. 40.
    Huang, Y., Li, W., Su, Z. Y., and Kong, A. N. (2015) The complexity of the Nrf2 pathway: beyond the antioxidant response, J. Nutr. Biochem., 26, 1401–1413.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Niture, S. K., and Jaiswal, A. K. (2009) Prothymosin-α mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2, J. Biol. Chem., 284, 13856–13868.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Jain, A. K., and Jaiswal, A. K. (2006) Phosphorylation of tyrosine 568 controls nuclear export of Nrf2, J. Biol. Chem., 281, 12132–12142.CrossRefPubMedGoogle Scholar
  43. 43.
    Jain, A. K., Mahajan, S., and Jaiswal, A. K. (2008) Phosphorylation and dephosphorylation of tyrosine 141 regulate stability and degradation of INrf2: a novel mechanism in Nrf2 activation, J. Biol. Chem., 283, 17712–17720.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hardie, D. G., Ross, F. A., and Hawley, S. A. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis, Nat. Rev. Mol. Cell Biol., 13, 251–262.CrossRefPubMedGoogle Scholar
  45. 45.
    Joo, M. S., Kim, W. D., Lee, K. Y., Kim, J. H., Koo, J. H., and Kim, S. G. (2016) AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550, Mol. Cell. Biol., 36, 1931–1942.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Zenkov, N. K., Chechushkov, A. V., Kozhin, P. M., Kandalintseva, N. V., Martinovich, G. G., and Menshchikova, E. B. (2016) Plant phenols and autophagy, Biochemistry (Moscow), 81, 297–314.CrossRefGoogle Scholar
  47. 47.
    Liu, X., Li, H., Liu, L., Lu, Y., Gao, Y., Geng, P., Li, X., Huang, B., Zhang, Y., and Lu, J. (2016) Methylation of arginine by PRMT1 regulates Nrf2 transcriptional activity during the antioxidative response, Biochim. Biophys. Acta, 1863, 2093–2103.CrossRefPubMedGoogle Scholar
  48. 48.
    Yang, P., Hu, S., Yang, F., Guan, X. Q., Wang, S. Q., Zhu, P., Xiong, F., Zhang, S., Xu, J., Yu, Q. L., and Wang, C. Y. (2014) Sumoylation modulates oxidative stress relevant to the viability and functionality of pancreatic β cells, Am. J. Transl. Res., 6, 353–360.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kawai, Y., Garduno, L., Theodore, M., Yang, J., and Arinze, I. J. (2011) Acetylationdeacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization, J. Biol. Chem., 286, 7629–7640.CrossRefPubMedGoogle Scholar
  50. 50.
    Chen, Z., Ye, X., Tang, N., Shen, S., Li, Z., Niu, X., Lu, S., and Xu, L. (2014) The histone acetylranseferase hMOF acetylates Nrf2 and regulates antidrug responses in human nonsmall cell lung cancer, Br. J. Pharmacol., 171, 3196–3211.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Cheng, X., Ku, C. H., and Siow, R. C. (2013) Regulation of the Nrf2 antioxidant pathway by microRNAs: new players in micromanaging redox homeostasis, Free Radic. Biol. Med., 64, 4–11.CrossRefPubMedGoogle Scholar
  52. 52.
    Guo, Y., Yu, S., Zhang, C., and Kong, A. N. (2015) Epigenetic regulation of Keap1-Nrf2 signaling, Free Radic. Biol. Med., 88, 337–349.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Wagner, A. E., Terschluesen, A. M., and Rimbach, G. (2013) Health promoting effects of brassicaderived phytochemicals: from chemopreventive and antiinflammatory activities to epigenetic regulation, Oxid. Med. Cell. Longev., 2013, 964539.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Khor, T. O., Fuentes, F., Shu, L., Paredes-Gonzalez, X., Yang, A. Y., Liu, Y., Smiraglia, D. J., Yegnasubramanian, S., Nelson, W. G., and Kong, A. N. (2014) Epigenetic DNA methylation of antioxidative stress regulator NRF2 in human prostate cancer, Cancer Prev. Res., 7, 1186–1197.CrossRefGoogle Scholar
  55. 55.
    Chartoumpekis, D. V., Wakabayashi, N., and Kensler, T. W. (2015) Keap1/Nrf2 pathway in the frontiers of cancer and noncancer cell metabolism, Biochem. Soc. Trans., 43, 639–644.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kang, K. A., Piao, M. J., Ryu, Y. S., Kang, H. K., Chang, W. Y., Keum, Y. S., and Hyun, J. W. (2016) Interaction of DNA demethylase and histone methyltransferase upregulates Nrf2 in 5-fluorouracilresistant colon cancer cells, Oncotarget, 7, 40594–40620.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Ayers, D., Baron, B., and Hunter, T. (2015) miRNA influences in NRF2 pathway interactions within cancer models, J. Nucleic Acids, 2015, 143636.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Forman, H. J. (2016) Redox signaling: an evolution from free radicals to aging, Free Radic. Biol. Med., 97, 398–407.CrossRefPubMedGoogle Scholar
  59. 59.
    Lu, M. C., Ji, J. A., Jiang, Z. Y., and You, Q. D. (2016) The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update, Med. Res. Rev., 36, 924–963.CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang, D. D., Lo, S. C., Cross, J. V., Templeton, D. J., and Hannink, M. (2004) Keap1 is a redoxregulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex, Mol. Cell. Biol., 24, 10941–10953.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Baird, L., and Dinkova-Kostova, A. T. (2013) Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells, Biochem. Biophys. Res. Commun., 433, 58–65.CrossRefPubMedGoogle Scholar
  62. 62.
    Liby, K. T., and Sporn, M. B. (2012) Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease, Pharmacol. Rev., 64, 972–1003.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Wilson, A. J., Kerns, J. K., Callahan, J. F., and Moody, C. J. (2013) Keap calm, and carry on covalently, J. Med. Chem., 56, 7463–7476.CrossRefPubMedGoogle Scholar
  64. 64.
    Abed, D. A., Goldstein, M., Albanyan, H., Jin, H., and Hu, L. (2015) Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents, Acta Pharm. Sin. B, 5, 285–299.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Jiang, Z. Y., Lu, M. C., Xu, L. L., Yang, T. T., Xi, M. Y., Xu, X. L., Guo, X. K., Zhang, X. J., You, Q. D., and Sun, H. P. (2014) Discovery of potent Keap1–Nrf2 protein–protein interaction inhibitor based on molecular binding determinants analysis, J. Med. Chem., 57, 2736–2745.CrossRefPubMedGoogle Scholar
  66. 66.
    Lu, M. C., Yuan, Z. W., Jiang, Y. L., Chen, Z. Y., You, Q. D., and Jiang, Z. Y. (2016) A systematic molecular dynamics approach to the study of peptide Keap1–Nrf2 protein–protein interaction inhibitors and its application to p62 peptides, Mol. Biosyst., 12, 1378–1387.CrossRefPubMedGoogle Scholar
  67. 67.
    Ghorab, M. M., Alsaid, M. S., Higgins, M., Dinkova-Kostova, A. T., Shahat, A. A., Elghazawy, N. H., and Arafa, R. K. (2016) Synthesis, molecular modeling and NAD(P)H:quinone oxidoreductase 1 inducer activity of novel 2-phenylquinazolin-4-amine derivatives, J. Enzyme Inhib. Med. Chem., 31, 1612–1618.CrossRefPubMedGoogle Scholar
  68. 68.
    Hancock, R., Bertrand, H. C., Tsujita, T., Naz, S., El-Bakry, A., Laoruchupong, J., Hayes, J. D., and Wells, G. (2012) Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction, Free Radic. Biol. Med., 52, 444–451.CrossRefPubMedGoogle Scholar
  69. 69.
    Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., and Ting, J. P. (2006) DJ-1, a cancerand Parkinson’s diseaseassociated protein, stabilizes the antioxidant transcriptional master regulator Nrf2, Proc. Natl. Acad. Sci. USA, 103, 15091–15096.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Yu, M., Li, H., Liu, Q., Liu, F., Tang, L., Li, C., Yuan, Y., Zhan, Y., Xu, W., Li, W., Chen, H., Ge, C., Wang, J., and Yang, X. (2011) Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway, Cell. Signal., 23, 883–892.CrossRefPubMedGoogle Scholar
  71. 71.
    Lee, D. F., Kuo, H. P., Liu, M., Chou, C. K., Xia, W., Du, Y., Shen, J., Chen, C. T., Huo, L., Hsu, M. C., Li, C. W., Ding, Q., Liao, T. L., Lai, C. C., Lin, A. C., Chang, Y. H., Tsai, S. F., Li, L. Y., and Hung, M. C. (2009) KEAP1 E3 ligasemediated downregulation of NF-κB signaling by targeting IKKβ, Mol. Cell, 36, 131–140.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Lo, S. C., and Hannink, M. (2006) PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redoxregulated Keap1-dependent ubiquitin ligase complex, J. Biol. Chem., 281, 37893–37903.CrossRefPubMedGoogle Scholar
  73. 73.
    Kang, H. J., Hong, Y. B., Kim, H. J., and Bae, I. (2010) CR6-interacting factor 1 (CRIF1) regulates NF-E2-related factor 2 (NRF2) protein stability by proteasomemediated degradation, J. Biol. Chem., 285, 21258–21268.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Hampton, M. B., and O’Connor, K. M. (2016) Peroxiredoxins and the regulation of cell death, Mol. Cells, 39, 72–76.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Jeong, C. H., and Joo, S. H. (2016) Downregulation of reactive oxygen species in apoptosis, J. Cancer Prev., 21, 13–20.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Murakami, S., and Motohashi, H. (2015) Roles of Nrf2 in cell proliferation and differentiation, Free Radic. Biol. Med., 88, 168–178.CrossRefPubMedGoogle Scholar
  77. 77.
    Blaser, H., Dostert, C., Mak, T. W., and Brenner, D. (2016) TNF and ROS crosstalk in inflammation, Trends Cell Biol., 26, 249–261.CrossRefPubMedGoogle Scholar
  78. 78.
    Redmann, M., Darley-Usmar, V., and Zhang, J. (2016) The role of autophagy, mitophagy and lysosomal functions in modulating bioenergetics and survival in the context of redox and proteotoxic damage: implications for neurodegenerative diseases, Aging Dis., 7, 150–162.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Chen, Y., Zhang, H., Zhou, H. J., Ji, W., and Min, W. (2016) Mitochondrial redox signaling and tumor progression, Cancers (Basel), 8, 40.CrossRefGoogle Scholar
  80. 80.
    Xiang, M., Namani, A., Wu, S., and Wang, X. (2014) Nrf2: bane or blessing in cancer? J. Cancer Res. Clin. Oncol., 140, 1251–1259.CrossRefPubMedGoogle Scholar
  81. 81.
    Gacesa, R., Dunlap, W. C., Barlow, D. J., Laskowski, R. A., and Long, P. F. (2016) Rising levels of atmospheric oxygen and evolution of Nrf2, Sci. Rep., 6, 27740.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  • N. K. Zenkov
    • 1
  • P. M. Kozhin
    • 1
  • A. V. Chechushkov
    • 1
  • G. G. Martinovich
    • 2
  • N. V. Kandalintseva
    • 3
  • E. B. Menshchikova
    • 1
    Email author
  1. 1.Research Institute of Experimental and Clinical MedicineNovosibirskRussia
  2. 2.Belarusian State UniversityMinskBelarus
  3. 3.Novosibirsk State Pedagogical UniversityNovosibirskRussia

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