Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium

Stewart, Daniel; Killeen, Erin; Naquin, Ryan; Alam, Safdar; Alam, Jawed

doi:10.1074/jbc.m209195200

Cited by 463Genomics, phytochemicals, and oxidative stressHeme Oxygenase-1 and Carbon MonoxideUbiquitin and proteasome pathways

Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium

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Stewart, Daniel, Killeen, Erin, Naquin, Ryan, Alam, Safdar, Alam, Jawed·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m209195200

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Abstract

Nrf2 mediates inducer-dependent activation of the heme oxygenase-1 (HO-1) gene (Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M., and Cook, J. L. (1999) J. Biol. Chem. 274, 26071-26078), but the mechanism by which HO-1 inducers regulate Nrf2 function is not known. Treatment of mouse hepatoma (Hepa) cells with 50 microm CdCl(2) increased the amount of Nrf2 protein in a time-dependent manner; induction was observed within 30 min, prior to the accumulation of HO-1 mRNA. Cadmium did not significantly affect the steady-state level of Nrf2 mRNA or the initial rate of Nrf2 protein synthesis but increased the half-life of Nrf2 from approximately 13 to 100 min. Proteasome inhibitors, but not other protease inhibitors, enhanced the expression of Nrf2, and ubiquitinylated Nrf2 was detected after proteasome inhibition. Cycloheximide inhibited cadmium-stimulated Nrf2 expression and DNA binding activity and attenuated HO-1 mRNA accumulation. Conversely, proteasome inhibitors enhanced HO-1 mRNA and protein accumulation by a Nrf2-dependent mechanism. Together, these results indicate that Nrf2 is targeted for rapid degradation by the ubiquitin-proteasome pathway and that cadmium delays the rate of Nrf2 degradation leading to ho-1 gene activation.

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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 [77]

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Authors: Stewart, D., Killeen, E., Naquin, R., Alam, S., & Alam, J.
Affiliations: Ochsner Medical Center (US)
Tulane University (US)
Corresponding author: Alam, Jawed
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-01
Volume: 278
Issue: 4
Pages: 2396-2402
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m209195200
OpenAlex: W2050512725
Cited by: 463
References: 48
Citations by year: 2026: 8 · 2025: 11 · 2024: 12 · 2023: 15 · 2022: 17 · 2021: 23 · 2020: 17 · 2019: 14 · 2018: 15 · 2017: 15 · 2016: 14 · 2015: 12 · 2014: 30 · 2013: 18 · 2012: 27
FWCI: 12.18
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6497 d)
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 › Heme Oxygenase-1 and Carbon Monoxide
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: Nrf2, ubiquitin-proteasome system, cadmium, heme oxygenase-1, protein degradation, protein stabilization, proteasome inhibitors, cycloheximide, DNA-binding activity, metal-induced gene expression
MeSH terms: Animals, Cadmium, Cycloheximide, Cysteine Endopeptidases, DNA-Binding Proteins, Dose-Response Relationship, Drug, Multienzyme Complexes, Protein Binding, Protein Synthesis Inhibitors, RNA, RNA, Messenger, Time Factors, Tumor Cells, Cultured, Blotting, Western, Trans-Activators, Ubiquitin, Proteasome Endopeptidase Complex, NF-E2-Related Factor 2, Mice

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks