Skip to main content
SpringerLink
Log in

Mazes of Nrf2 regulation

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

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

References

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang, X., and Mosser, D. M. (2008) Macrophage activation by endogenous danger signals, J. Pathol., 214, 161–178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Katsuoka, F., and Yamamoto, M. (2016) Small Maf proteins (MafF, MafG, MafK): history, structure and function, Gene, 586, 197–205.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Suzuki, T., and Yamamoto, M. (2015) Molecular basis of the Keap1-Nrf2 system, Free Radic. Biol. Med., 88, 93–100.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jain, A. K., and Jaiswal, A. K. (2006) Phosphorylation of tyrosine 568 controls nuclear export of Nrf2, J. Biol. Chem., 281, 12132–12142.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  57. Ayers, D., Baron, B., and Hunter, T. (2015) miRNA influences in NRF2 pathway interactions within cancer models, J. Nucleic Acids, 2015, 143636.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Forman, H. J. (2016) Redox signaling: an evolution from free radicals to aging, Free Radic. Biol. Med., 97, 398–407.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hampton, M. B., and O’Connor, K. M. (2016) Peroxiredoxins and the regulation of cell death, Mol. Cells, 39, 72–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jeong, C. H., and Joo, S. H. (2016) Downregulation of reactive oxygen species in apoptosis, J. Cancer Prev., 21, 13–20.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Murakami, S., and Motohashi, H. (2015) Roles of Nrf2 in cell proliferation and differentiation, Free Radic. Biol. Med., 88, 168–178.

    Article  CAS  PubMed  Google Scholar 

  77. Blaser, H., Dostert, C., Mak, T. W., and Brenner, D. (2016) TNF and ROS crosstalk in inflammation, Trends Cell Biol., 26, 249–261.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Chen, Y., Zhang, H., Zhou, H. J., Ji, W., and Min, W. (2016) Mitochondrial redox signaling and tumor progression, Cancers (Basel), 8, 40.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute of Experimental and Clinical Medicine, 630117, Novosibirsk, Russia

    N. K. Zenkov, P. M. Kozhin, A. V. Chechushkov & E. B. Menshchikova

  2. Belarusian State University, 220030, Minsk, Belarus

    G. G. Martinovich

  3. Novosibirsk State Pedagogical University, 630126, Novosibirsk, Russia

    N. V. Kandalintseva

Authors
  1. N. K. Zenkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. M. Kozhin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. V. Chechushkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. G. Martinovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N. V. Kandalintseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. B. Menshchikova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. B. Menshchikova.

Additional information

To whom correspondence should be addressed.

Original Russian Text © N. K. Zenkov, P. M. Kozhin, A. V. Chechushkov, G. G. Martinovich, N. V. Kandalintseva, E. B. Menshchikova, 2017, published in Biokhimiya, 2017, Vol. 82, No. 5, pp. 749-759.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zenkov, N.K., Kozhin, P.M., Chechushkov, A.V. et al. Mazes of Nrf2 regulation. Biochemistry Moscow 82, 556–564 (2017). https://doi.org/10.1134/S0006297917050030

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297917050030

Keywords

Search

Navigation