Cited by 640Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

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Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response

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Chen, Weimin, Sun, Zheng, Wang, Xiao-Jun, Jiang, Tao, Huang, Zheping, Fang, Deyu, Zhang, Donna D.·2009·Molecular Cell

DOI 10.1016/j.molcel.2009.04.029PMC PMC2714804

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Abstract

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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Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
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Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2
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Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress
Zhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480
Self-citation
Keap1 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
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Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression
McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141
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Self-citation
Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice
Ramos-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
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Protection against electrophile and oxidant stress by induction of the phase 2 response: Fate of cysteines of the Keap1 sensor modified by inducers
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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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.
ORCID: Chen, Weimin
Sun, Zheng
Wang, Xiao-Jun
Huang, Zheping
Fang, Deyu
Zhang, Donna D.
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2009-06
Volume: 34
Issue: 6
Pages: 663-673
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2009.04.029
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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Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response

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