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Cited by 617Genomics, phytochemicals, and oxidative stressGlutathione Transferases and PolymorphismsRedox biology and oxidative stress

Increased Protein Stability as a Mechanism That Enhances Nrf2-mediated Transcriptional Activation of the Antioxidant Response Element

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Nguyen, Truyen, Sherratt, Philip J., Huang, H.-C., Yang, Chung S., Pickett, Cecil B.·2003·Journal of Biological Chemistry
DOI 10.1074/jbc.m207293200
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Abstract

Nrf2 (NF-E2-related factor 2) is a central transcription factor involved in the transcriptional activation of many genes encoding phase II drug-metabolizing enzymes via the antioxidant response element. Nrf2 has previously been found to undergo nuclear translocation by a phosphorylation-dependent mechanism mediated by protein kinase C in HepG2 cells treated with tert-butylhydroquinone, beta-naphthoflavone, or 12-O-tetradecanoylphorbol-13-acetate. In the present report, we have found that the levels of Nrf2 were increased in cells treated with tert-butylhydroquinone or beta-naphthoflavone by a post-transcriptional mechanism. Treatment of HepG2 cells with cycloheximide resulted in the loss of Nrf2 within 30 min. By contrast, treatment with the proteasome inhibitors (lactacystin or MG-132) caused an accumulation of Nrf2 as well as an induction of reporter gene activity in cells transfected with the GSTA2 antioxidant response element-chloramphenicol acetyl transferase construct. Similarly, the protein phosphatase inhibitor okadaic acid also caused an accumulation of Nrf2, whereas the reverse effects were observed with PD 98059 and U 0126, two compounds that block the activation of the MAPK/ERK signaling cascade. These data suggest that Nrf2 is degraded by the ubiquitin-dependent pathway and that phosphorylation of Nrf2 leads to an increase in its stability and subsequent transactivation activity.

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  • Nrf2 is negatively regulated by Keap1, which binds Nrf2 in the cytosol to facilitate its polyubiquitination by the Cul3 E3 ubiquitin ligase for proteasomal degradation.

    “Nrf2 regulates the expression of a multitude of antioxidant and phase II enzyme genes and is negatively regulated by Kelch-like ECH-associated protein (Keap1) [49], a substrate adaptor protein that binds to Nrf2 in the cytosol to facilitate its polyubiquitination by the Cullin 3 (Cul3) E3 ubiquitin ligase for proteasomal degradation [50,51,52].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [50]

  • Under basal conditions, Nrf2 has a short half-life of only 10-30 min.

    “Under basal conditions, Nrf2 has a short half-life of only 10–30 min [50,77].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [50]

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Research works printed but not linked: 8

  1. Rushmore, T. H., King, R. G., Paulson, K. E., and Pickett, C. B. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 3826 -3830
  2. Friling, R. S., Bensimon, A., Tichauer, Y., and Daniel, V. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 6258 -6262
  3. Moi, P., Chan, K., Asunis, I., Cao, A., and Kan, Y. W. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 9926 -9930
  4. Venugopal, R., and Jaiswal, A. K. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 14960 -14965
  5. Chan, K., Han, X. D., and Kan, Y. W. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 4611-4616
  6. Ramos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., and Kensler, T. W. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 3410 -3415
  7. Huang, H.-C., Nguyen, T., and Pickett, C. B. (2000) Proc. Natl. Acad. Sci. 97, 12475-12480
  8. Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and Talalay, P. (2002) Proc. Natl. Acad. Sci. 99, 11908 -11913

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Authors
Nguyen, T., Sherratt, P. J., Huang, H.-C., Yang, C. S., & Pickett, C. B.
Affiliations
Rutgers, The State University of New Jersey (US)
Corresponding author
Pickett, Cecil B.
ORCID
Yang, Chung S.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2003-02
Volume
278
Issue
7
Pages
4536-4541
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m207293200
OpenAlex
W2080435498
Cited by
615
References
44
Citations by year
2026: 15 · 2025: 13 · 2024: 24 · 2023: 25 · 2022: 29 · 2021: 25 · 2020: 24 · 2019: 31 · 2018: 23 · 2017: 24 · 2016: 29 · 2015: 31 · 2014: 21 · 2013: 31 · 2012: 36
FWCI
12.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
Nrf2, antioxidant response element, protein stability, ubiquitin-mediated proteolysis, Nrf2 phosphorylation, phase II enzymes, tert-butylhydroquinone, beta-naphthoflavone, proteasome inhibitors, ERK signaling, protein phosphatase, transcriptional activation, HepG2 cells
MeSH terms
Antioxidants, Butadienes, Cell Line, DNA-Binding Proteins, Enzyme Inhibitors, Flavonoids, Humans, Hydroquinones, Nitriles, Peptide Hydrolases, Phosphorylation, RNA Processing, Post-Transcriptional, Transcriptional Activation, Trans-Activators, Leucine Zippers, Oxidative Stress, beta-Naphthoflavone, Protein Subunits, Proteasome Endopeptidase Complex, NF-E2-Related Factor 2

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