The DOI matches its Crossref record; 34 of the 36 references it cites were found in a registry or an index.
Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Open accessAbstract
In response to oxidative stress, Nrf2 and p21(Cip1/WAF1) are both upregulated to protect cells from oxidative damage. Nrf2 is constantly ubiquitinated by a Keap1 dimer that interacts with a weak-binding (29)DLG motif and a strong-binding (79)ETGE motif in Nrf2, resulting in degradation of Nrf2. Modification of the redox-sensitive cysteine residues on Keap1 disrupts the Keap1-(29)DLG binding, leading to diminished Nrf2 ubiquitination and activation of the antioxidant response. However, the underlying mechanism by which p21 protects cells from oxidative damage remains unclear. Here we present molecular and genetic evidence suggesting that the antioxidant function of p21 is mediated through activation of Nrf2 by stabilizing the Nrf2 protein. The (154)KRR motif in p21 directly interacts with the (29)DLG and (79)ETGE motifs in Nrf2 and thus competes with Keap1 for Nrf2 binding, compromising ubiquitination of Nrf2. Furthermore, the physiological significance of our findings was demonstrated in vivo using p21-deficient mice.
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“The 154KRR156 motif within p21 directly binds to the DLG and ETGE motifs in Nrf2, thereby competing with Keap1 for Nrf2 binding [26]; but instead of Nrf2 degradation, p21-Nrf2 binding leads to Nrf2 stabilization and increased response to oxidative stress [26].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [26]
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Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
Zhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480
Self-citationKeap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,284
Self-citationMcMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141
Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,105
Self-citationRamos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., & Kensler, T. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051618798 · Cited by 1,102
Molecular Mechanisms Activating the Nrf2-Keap1 Pathway of Antioxidant Gene Regulation
Kobayashi, M., & Yamamoto, M. P. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.385 · Cited by 1,087
Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M.-I., Kobayashi, A., Yamamoto, M., Kensler, T. W., & Talalay, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307301101 · Cited by 986 · cited 1×
“…for homodimerization, the linker domain contains several cysteine residues that sense intracellular redox imbalance, and the Kelch domain binds the N-terminal Neh2 domain of Nrf2 (Itoh et al., 1999; Wakabayashi et al., 2004; Yamamoto et al., 2008; Zhang and Hannink, 2003; Zipper and Mulcahy, 2002).”
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Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
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Transcriptional Regulation by Nrf2
Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7342 · Cited by 2,280
Metadata
- Authors
- Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D.
- Affiliations
- University of Arizona (US)
- University of Missouri (US)
- Corresponding author
- Zhang, Donna D.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 34
- Issue
- 6
- Pages
- 663-673
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2714804
- OpenAlex
- W2080155284
- Cited by
- 638
- References
- 36
- Citations by year
- 2026: 24 · 2025: 15 · 2024: 50 · 2023: 31 · 2022: 43 · 2021: 51 · 2020: 48 · 2019: 52 · 2018: 48 · 2017: 35 · 2016: 44 · 2015: 29 · 2014: 40 · 2013: 38 · 2012: 34
- FWCI
- 11.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1543 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society (ES006694, RSG-07-154)
- National Institute of Environmental Health Sciences (ES015010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- Nrf2, p21, Keap1, oxidative stress, antioxidant response, protein stabilization, ubiquitination, protein-protein interaction
- MeSH terms
- Animals, Antioxidants, Binding Sites, Male, Up-Regulation, Oxidative Stress, Amino Acid Motifs, Cyclin-Dependent Kinase Inhibitor p21, NF-E2-Related Factor 2, Mice, Ubiquitination
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