[Frontiers in Bioscience, Landmark, 21, 192-202, January 1, 2016]

Nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated protein quality control in cardiomyocytes

Taixing Cui 1 , Yimu Lai 1 , Joseph S. Janicki 1 , Xuejun Wang 2

1Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA, 2Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA


1. Abstract
2. Introduction
3. Nrf2 in the UPS
4. Nrf2 in autophagy
5. Nrf2-mediated PQC in cardiomyocytes
6. A summary and future directions
7. Acknowledgements
8. References


Protein quality control (PQC) acts to minimize the level and toxicity of malfolded proteins in the cell. It is performed by an elaborate network of molecular chaperones and targeted protein degradation pathways. PQC monitors and maintains protein homeostasis or proteostasis in the cells. Whilst chaperones may actively promote refolding of malfolded proteins, the malfolded proteins which cannot be correctly refolded are degraded by the ubiquitin proteasome system (UPS) and the autophagic-lysosome pathway (ALP). The UPS degrades individual misfolded protein molecules, whereas the ALP removes large and less soluble protein aggregates and organelles. Emerging evidence indicates that dysregulated and inadequate PQC play an important role in the pathogenesis of not only classic conformational disease but more common forms of cardiac pathology such as cardiac pathological hypertrophy and heart failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor of cellular defense, appears to regulate the USP and the ALP by directly controlling the expression of UPS-and ALP-related genes. This article highlights an emerging role of Nrf2 in the regulation of intracellular PQC as well as its potential involvement in cardiac pathology.


35. C. Wang and X. Wang: The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity. Biochim Biophys Acta, 1852, 188-194 (2015)
DOI: 10.1016/j.bbadis.2014.07.028

2. U. Schubert, L. C. Anton, J. Gibbs, C. C. Norbury, J. W. Yewdell and J. R. Bennink: Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature, 404, 770-774 (2000)
DOI: 10.1038/35008096

3. E. M. Sontag, W. I. Vonk and J. Frydman: Sorting out the trash: the spatial nature of eukaryotic protein quality control. Curr Opin Cell Biol, 26, 139-146 (2014)
DOI: 10.1016/j.ceb.2013.12.006

4. W. E. Balch, J. I. Sznajder, S. Budinger, D. Finley, A. D. Laposky, A. M. Cuervo, I. J. Benjamin, E. Barreiro, R. I. Morimoto, L. Postow, A. M. Weissman, D. Gail, S. Banks-Schlegel, T. Croxton and W. Gan: Malfolded protein structure and proteostasis in lung diseases. Am J Respir Crit Care Med, 189, 96-103 (2014)
DOI: 10.1164/rccm.201306-1164WS

5. X. Wang, J. S. Pattison and H. Su: Posttranslational modification and quality control. Circ Res, 112, 367-381 (2013)
DOI: 10.1161/CIRCRESAHA.112.268706

6. I. Amm, T. Sommer and D. H. Wolf: Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim Biophys Acta, 1843, 182-196 (2014)
DOI: 10.1016/j.bbamcr.2013.06.031

7. X. Wang and J. Robbins: Proteasomal and lysosomal protein degradation and heart disease. J Mol Cell Cardiol, 71, 16-24 (2014)
DOI: 10.1016/j.yjmcc.2013.11.006

8. N. P. Dantuma and K. Lindsten: Stressing the ubiquitin-proteasome system. Cardiovasc Res, 85, 263-271 (2010)
DOI: 10.1093/cvr/cvp255

9. J. Li, S. R. Powell and X. Wang: Enhancement of proteasome function by PA28α overexpression protects against oxidative stress. FASEB J, 25, 883-893 (2011)
DOI: 10.1096/fj.10-160895

10. J. Li, K. M. Horak, H. Su, A. Sanbe, J. Robbins and X. Wang: Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice. J Clin Invest, 121, 3689-3700 (2011)
DOI: 10.1172/JCI45709

11. C. de Duve: (Introduction to the physiopathology of the lysosomes). Brux Med, 46, 1087-1094 (1966)

12. B. Ravikumar, S. Sarkar, J. E. Davies, M. Futter, M. Garcia-Arencibia, Z. W. Green-Thompson, M. Jimenez-Sanchez, V. I. Korolchuk, M. Lichtenberg, S. Luo, D. C. Massey, F. M. Menzies, K. Moreau, U. Narayanan, M. Renna, F. H. Siddiqi, B. R. Underwood, A. R. Winslow and D. C. Rubinsztein: Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev, 90, 1383-1435 (2010)
DOI: 10.1152/physrev.00030.2009

13. A. Stolz, A. Ernst and I. Dikic: Cargo recognition and trafficking in selective autophagy. Nat Cell Biol, 16, 495-501 (2014)
DOI: 10.1038/ncb2979

14. S. Kaushik and A. M. Cuervo: Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol, 22, 407-417 (2012)
DOI: 10.1016/j.tcb.2012.05.006

15. M. S. Willis, W. H. Townley-Tilson, E. Y. Kang, J. W. Homeister and C. Patterson: Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res, 106, 463-478 (2010)
DOI: 10.1161/CIRCRESAHA.109.208801

16. A. Thorburn, D. H. Thamm and D. L. Gustafson: Autophagy and cancer therapy. Mol Pharmacol, 85, 830-838 (2014)
DOI: 10.1124/mol.114.091850

17. J. Yang, S. Carra, W. G. Zhu and H. H. Kampinga: The regulation of the autophagic network and its implications for human disease. Int J Biol Sci, 9, 1121-1133 (2013)
DOI: 10.7150/ijbs.6666

18. A. Nemchenko, M. Chiong, A. Turer, S. Lavandero and J. A. Hill: Autophagy as a therapeutic target in cardiovascular disease. J Mol Cell Cardiol, 51, 584-593 (2011)
DOI: 10.1016/j.yjmcc.2011.06.010

19. Q. Zheng, H. Su, Z. Tian and X. Wang: Proteasome malfunction activates macroautophagy in the heart. Am J Cardiovasc Dis, 1, 214-226 (2011)

20. Q. Zheng, H. Su, M. J. Ranek and X. Wang: Autophagy and p62 in cardiac proteinopathy. Circ Res, 109, 296-308 (2011)
DOI: 10.1161/CIRCRESAHA.111.244707

21. S. Kageyama, Y. S. Sou, T. Uemura, S. Kametaka, T. Saito, R. Ishimura, T. Kouno, L. Bedford, R. J. Mayer, M. S. Lee, M. Yamamoto, S. Waguri, K. Tanaka and M. Komatsu: Proteasome dysfunction activates autophagy and the keap1-nrf2 pathway. J Biol Chem, 289, 24944-24955 (2014)
DOI: 10.1074/jbc.M114.580357

22. Z. Tian, C. Wang, C. Hu, Y. Tian, J. Liu and X. Wang: Autophagic-lysosomal inhibition compromises ubiquitin-proteasome system performance in a p62 dependent manner in cardiomyocytes. PLoS One, 9, e100715 (2014)
DOI: 10.1371/journal.pone.0100715

23. V. I. Korolchuk, A. Mansilla, F. M. Menzies and D. C. Rubinsztein: Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell, 33, 517-527 (2009)
DOI: 10.1016/j.molcel.2009.01.021

24. M. Kobayashi and M. Yamamoto: Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal, 7, 385-394 (2005)
DOI: 10.1089/ars.2005.7.385

25. T. W. Kensler, N. Wakabayashi and S. Biswal: Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol, 47, 89-116 (2007)
DOI: 10.1146/annurev.pharmtox.46.120604.141046

26. J. Li, T. Ichikawa, J. S. Janicki and T. Cui: Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets, 13, 785-794 (2009)
DOI: 10.1517/14728220903025762

27. T. Suzuki, H. Motohashi and M. Yamamoto: Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci, 34, 340-346 (2013)
DOI: 10.1016/j.tips.2013.04.005

28. J. Maher and M. Yamamoto: The rise of antioxidant signaling--the evolution and hormetic actions of Nrf2. Toxicol Appl Pharmacol, 244, 4-15 (2010)
DOI: 10.1016/j.taap.2010.01.011

29. Y. Zhang, D. H. Crouch, M. Yamamoto and J. D. Hayes: Negative regulation of the Nrf1 transcription factor by its N-terminal domain is independent of Keap1: Nrf1, but not Nrf2, is targeted to the endoplasmic reticulum. Biochem J, 399, 373-385 (2006)
DOI: 10.1042/BJ20060725

30. W. Wang and J. Y. Chan: Nrf1 is targeted to the endoplasmic reticulum membrane by an N-terminal transmembrane domain. Inhibition of nuclear translocation and transacting function. J Biol Chem, 281, 19676-19687 (2006)
DOI: 10.1074/jbc.M602802200

31. Z. Xu, L. Chen, L. Leung, T. S. Yen, C. Lee and J. Y. Chan: Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci U S A, 102, 4120-4125 (2005)
DOI: 10.1073/pnas.0500660102

32. K. Sankaranarayanan and A. K. Jaiswal: Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P) H:quinone oxidoreductase1 gene. J Biol Chem, 279, 50810-50817 (2004)
DOI: 10.1074/jbc.M404984200

33. M. K. Kwak, N. Wakabayashi, J. L. Greenlaw, M. Yamamoto and T. W. Kensler: Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol, 23, 8786-8794 (2003)
DOI: 10.1128/MCB.23.23.8786-8794.2003

34. M. K. Kwak, N. Wakabayashi, K. Itoh, H. Motohashi, M. Yamamoto and T. W. Kensler: Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem, 278, 8135-8145 (2003)
DOI: 10.1074/jbc.M211898200

35. A. Arlt, I. Bauer, C. Schafmayer, J. Tepel, S. S. Muerkoster, M. Brosch, C. Roder, H. Kalthoff, J. Hampe, M. P. Moyer, U. R. Folsch and H. Schafer: Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2). Oncogene, 28, 3983-3996 (2009)
DOI: 10.1038/onc.2009.264

36. A. M. Pickering, R. A. Linder, H. Zhang, H. J. Forman and K. J. Davies: Nrf2-dependent induction of proteasome and Pa28alphabeta regulator are required for adaptation to oxidative stress. J Biol Chem, 287, 10021-10031 (2012)
DOI: 10.1074/jbc.M111.277145

37. Y. Liu, C. L. Hettinger, D. Zhang, K. Rezvani, X. Wang and H. Wang: Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington’s disease. J Neurochem, 129, 539-547 (2014)
DOI: 10.1111/jnc.12647

38. J. Jang, Y. Wang, H. S. Kim, M. A. Lalli and K. S. Kosik: Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells. Stem Cells, 32, 2616-2625 (2014)
DOI: 10.1002/stem.1764

39. Y. Tsuchiya, H. Taniguchi, Y. Ito, T. Morita, M. R. Karim, N. Ohtake, K. Fukagai, T. Ito, S. Okamuro, S. Iemura, T. Natsume, E. Nishida and A. Kobayashi: The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression. Mol Cell Biol, 33, 3461-3472 (2013)
DOI: 10.1128/MCB.01271-12

40. Y. Zhang, J. Nicholatos, J. R. Dreier, S. J. Ricoult, S. B. Widenmaier, G. S. Hotamisligil, D. J. Kwiatkowski and B. D. Manning: Coordinated regulation of protein synthesis and degradation by mTORC1. Nature, 513, 440-443 (2014)
DOI: 10.1038/nature13492

41. S. K. Radhakrishnan, C. S. Lee, P. Young, A. Beskow, J. Y. Chan and R. J. Deshaies: Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol Cell, 38, 17-28 (2010)
DOI: 10.1016/j.molcel.2010.02.029

42. Z. Sha and A. L. Goldberg: Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr Biol, 24, 1573-1583 (2014)
DOI: 10.1016/j.cub.2014.06.004

43. B. E. Riley, S. E. Kaiser, T. A. Shaler, A. C. Ng, T. Hara, M. S. Hipp, K. Lage, R. J. Xavier, K. Y. Ryu, K. Taguchi, M. Yamamoto, K. Tanaka, N. Mizushima, M. Komatsu and R. R. Kopito: Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol, 191, 537-552 (2010)
DOI: 10.1083/jcb.201005012

44. V. A. Rao, S. R. Klein, S. J. Bonar, J. Zielonka, N. Mizuno, J. S. Dickey, P. W. Keller, J. Joseph, B. Kalyanaraman and E. Shacter: The antioxidant transcription factor Nrf2 negatively regulates autophagy and growth arrest induced by the anticancer redox agent mitoquinone. J Biol Chem, 285, 34447-34459 (2010)
DOI: 10.1074/jbc.M110.133579

45. K. Fujita, D. Maeda, Q. Xiao and S. M. Srinivasula: Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation. Proc Natl Acad Sci U S A, 108, 1427-1432 (2011)
DOI: 10.1073/pnas.1014156108

46. L. Mattart, D. Calay, D. Simon, L. Roebroek, L. Caesens-Koenig, M. Van Steenbrugge, V. Tevel, C. Michiels, T. Arnould, K. Z. Boudjeltia and M. Raes: The peroxynitrite donor 3-morpholinosydnonimine activates Nrf2 and the UPR leading to a cytoprotective response in endothelial cells. Cell Signal, 24, 199-213 (2012)
DOI: 10.1016/j.cellsig.2011.09.002

47. L. Zhu, E. C. Barrett, Y. Xu, Z. Liu, A. Manoharan and Y. Chen: Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2. PLoS One, 8, e55695 (2013)
DOI: 10.1371/journal.pone.0055695

48. C. Jo, S. Gundemir, S. Pritchard, Y. N. Jin, I. Rahman and G. V. Johnson: Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun, 5, 3496 (2014)
DOI: 10.1038/ncomms4496

49. G. Kroemer, G. Marino and B. Levine: Autophagy and the integrated stress response. Mol Cell, 40, 280-293 (2010)
DOI: 10.1016/j.molcel.2010.09.023

50. G. Filomeni, D. De Zio and F. Cecconi: Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ, 22, 377-388 (2015)
DOI: 10.1038/cdd.2014.150

51. Y. Ichimura, S. Waguri, Y. S. Sou, S. Kageyama, J. Hasegawa, R. Ishimura, T. Saito, Y. Yang, T. Kouno, T. Fukutomi, T. Hoshii, A. Hirao, K. Takagi, T. Mizushima, H. Motohashi, M. S. Lee, T. Yoshimori, K. Tanaka, M. Yamamoto and M. Komatsu: Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. Mol Cell, 51, 618-631 (2013)
DOI: 10.1016/j.molcel.2013.08.003

52. K. Taguchi, N. Fujikawa, M. Komatsu, T. Ishii, M. Unno, T. Akaike, H. Motohashi and M. Yamamoto: Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc Natl Acad Sci U S A, 109, 13561-13566 (2012)
DOI: 10.1073/pnas.1121572109

53. W. Wang, S. Li, H. Wang, B. Li, L. Shao, Y. Lai, G. Horvath, Q. Wang, M. Yamamoto, J. S. Janicki, X. L. Wang, D. Tang and T. Cui: Nrf2 enhances myocardial clearance of toxic ubiquitinated proteins. J Mol Cell Cardiol, 72, 305-315 (2014)
DOI: 10.1016/j.yjmcc.2014.04.006

54. S. Li, W. Wang, T. Niu, H. Wang, B. Li, L. Shao, Y. Lai, H. Li, J. S. Janicki, X. L. Wang, D. Tang and T. Cui: Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction. Oxid Med Cell Longev, 2014, 748524 (2014)
DOI: 10.1155/2014/748524

55. J. Li, T. Ichikawa, L. Villacorta, J. S. Janicki, G. L. Brower, M. Yamamoto and T. Cui: Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol, 29, 1843-1850 (2009)
DOI: 10.1161/ATVBAHA.109.189480

56. J. Li, C. Zhang, Y. Xing, J. S. Janicki, M. Yamamoto, X. L. Wang, D. Q. Tang and T. Cui: Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. Cardiovasc Res, 90, 315-324 (2011)
DOI: 10.1093/cvr/cvr010

57. P. Tannous, H. Zhu, A. Nemchenko, J. M. Berry, J. L. Johnstone, J. M. Shelton, F. J. Miller, Jr., B. A. Rothermel and J. A. Hill: Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation, 117, 3070-3078 (2008)
DOI: 10.1161/CIRCULATIONAHA.107.763870

58. N. S. Rajasekaran, S. Varadharaj, G. D. Khanderao, C. J. Davidson, S. Kannan, M. A. Firpo, J. L. Zweier and I. J. Benjamin: 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 (2011)
DOI: 10.1089/ars.2010.3587

59. S. Kannan, V. R. Muthusamy, K. J. Whitehead, L. Wang, A. V. Gomes, S. E. Litwin, T. W. Kensler, E. D. Abel, J. R. Hoidal and N. S. Rajasekaran: Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy. Cardiovasc Res, 100, 63-73 (2013)
DOI: 10.1093/cvr/cvt150

60. P. Vicart, A. Caron, P. Guicheney, Z. Li, M. C. Prevost, A. Faure, D. Chateau, F. Chapon, F. Tome, J. M. Dupret, D. Paulin and M. Fardeau: A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet, 20, 92-95 (1998)
DOI: 10.1038/1765

61. M. K. Gupta, J. Gulick, R. Liu, X. Wang, J. D. Molkentin and J. Robbins: Sumo E2 enzyme UBC9 is required for efficient protein quality control in cardiomyocytes. Circ Res, 115, 721-729 (2014)
DOI: 10.1161/CIRCRESAHA.115.304760

62. Q. Chen, J. B. Liu, K. M. Horak, H. Zheng, A. R. Kumarapeli, J. Li, F. Li, A. M. Gerdes, E. F. Wawrousek and X. Wang: Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ Res, 97, 1018-1026 (2005)
DOI: 10.1161/01.RES.0000189262.92896.0b

63. X. Wang, R. Klevitsky, W. Huang, J. Glasford, F. Li and J. Robbins: AlphaB-crystallin modulates protein aggregation of abnormal desmin. Circ Res, 93, 998-1005 (2003)
DOI: 10.1161/01.RES.0000102401.77712.ED

64. X. Wang, H. Osinska, R. Klevitsky, A. M. Gerdes, M. Nieman, J. Lorenz, T. Hewett and J. Robbins: Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. Circ Res, 89, 84-91 (2001)
DOI: 10.1161/hh1301.092688

65. M. S. Bhuiyan, J. S. Pattison, H. Osinska, J. James, J. Gulick, P. M. McLendon, J. A. Hill, J. Sadoshima and J. Robbins: Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest, 123, 5284-5297 (2013)
DOI: 10.1172/JCI70877

66. N. S. Rajasekaran, P. Connell, E. S. Christians, L. J. Yan, R. P. Taylor, A. Orosz, X. Q. Zhang, T. J. Stevenson, R. M. Peshock, J. A. Leopold, W. H. Barry, J. Loscalzo, S. J. Odelberg and I. J. Benjamin: Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell, 130, 427-439 (2007)
DOI: 10.1016/j.cell.2007.06.044

67. P. Tannous, H. Zhu, J. L. Johnstone, J. M. Shelton, N. S. Rajasekaran, I. J. Benjamin, L. Nguyen, R. D. Gerard, B. Levine, B. A. Rothermel and J. A. Hill: Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc Natl Acad Sci U S A, 105, 9745-9750 (2008)
DOI: 10.1073/pnas.0706802105

68. Y. Tan, T. Ichikawa, J. Li, Q. Si, H. Yang, X. Chen, C. S. Goldblatt, C. J. Meyer, X. Li, L. Cai and T. Cui: Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes, 60, 625-633 (2011)
DOI: 10.2337/db10-1164

69. D. de Zeeuw, T. Akizawa, P. Audhya, G. L. Bakris, M. Chin, H. Christ-Schmidt, A. Goldsberry, M. Houser, M. Krauth, H. J. Lambers Heerspink, J. J. McMurray, C. J. Meyer, H. H. Parving, G. Remuzzi, R. D. Toto, N. D. Vaziri, C. Wanner, J. Wittes, D. Wrolstad, G. M. Chertow and B. T. Investigators: Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med, 369, 2492-2503 (2013)
DOI: 10.1056/NEJMoa1306033

70. K. T. Liby, M. M. Yore and M. B. Sporn: Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer, 7, 357-369 (2007)
DOI: 10.1038/nrc2129

71. H. Kumar, I. S. Kim, S. V. More, B. W. Kim and D. K. Choi: Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep, 31, 109-139 (2014)
DOI: 10.1039/C3NP70065H

Key Words: autophagy; nuclear factor erythroid-2 related factor 2; proteasome; protein quality control

Send correspondence: Xuejun Wang, Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD 57069, USA, Tel: 605-658-6345, Fax: 605 677-6381, E-mail: xuejun.wang@usd.edu