DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

Clements, Casey M.; McNally, Richard S.; Conti, Brian J.; Mak, Tak W.; Ting, Jenny P.-Y.

doi:10.1073/pnas.0607260103

Cited by 818Genomics, phytochemicals, and oxidative stressParkinson's Disease Mechanisms and TreatmentsRedox biology and oxidative stress

DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

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Clements, Casey M., McNally, Richard S., Conti, Brian J., Mak, Tak W., Ting, Jenny P.-Y.·2006·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0607260103PMC PMC1586179

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Abstract

DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.

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The interaction between p62 and Keap1 is mediated by a 349DPSTGE354 motif in p62's Keap1-interacting region that resembles the ETGE motif in the Keap1-binding domain of Nrf2.
“This interaction is mediated by a 349DPSTGE354 motif in p62’s Keap1-interacting region (KIR) that resembles the ETGE motif in the Keap1-binding domain of Nrf2 [79,80,81].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [81]
DJ-1 inhibits Keap1-mediated Nrf2 degradation by competitively binding to Nrf2.
“DJ-1 inhibits Keap1-mediated Nrf2 degradation by competitively binding to Nrf2 [81].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [81]

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Questing the extremes of the cellular NAD(H) level using an Escherichia coli NAD+ auxotrophic mutant
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Authors: Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P.-Y.
Affiliations: University of North Carolina at Chapel Hill (US)
University Health Network (CA)
ORCID: Clements, Casey M.
Mak, Tak W.
Ting, Jenny P.-Y.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2006-10-10
Volume: 103
Issue: 41
Pages: 15091-15096
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0607260103
PMC: PMC1586179
OpenAlex: W2012112859
Cited by: 818
References: 45
Citations by year: 2026: 19 · 2025: 28 · 2024: 42 · 2023: 41 · 2022: 40 · 2021: 51 · 2020: 50 · 2019: 35 · 2018: 40 · 2017: 54 · 2016: 47 · 2015: 50 · 2014: 43 · 2013: 45 · 2012: 47
FWCI: 12.09
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: Stony Brook University
National Institutes of Health (2t32ar007416-25)
National Cancer Institute (P50 CA 58223, P50CA058223)
National Institute of Allergy and Infectious Diseases (AI-067798, U19AI067798)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR007416, 5T32AR007416-24)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: DJ-1, Nrf2, Keap1, NQO1, protein stabilization, ubiquitination, antioxidant response, detoxification enzymes, Parkinson's disease, cancer, tumor markers, therapeutic target
MeSH terms: Protein Deglycase DJ-1, Kelch-Like ECH-Associated Protein 1, Animals, Antioxidants, Embryo, Mammalian, Fibroblasts, Humans, Mice, Inbred C57BL, Neoplasm Proteins, Parkinson Disease, Oncogene Proteins, Mice, Knockout, Ubiquitin, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, Mice, Peroxiredoxins

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DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2

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