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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antioxidants / metabolism*
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Antioxidants / physiology
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Cell Line, Tumor
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Embryo, Mammalian
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Fibroblasts / chemistry
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Fibroblasts / physiology
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / physiology*
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Kelch-Like ECH-Associated Protein 1
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-E2-Related Factor 2 / antagonists & inhibitors
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NF-E2-Related Factor 2 / metabolism*
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Neoplasm Proteins / metabolism
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Neoplasm Proteins / physiology*
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Oncogene Proteins / genetics
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Oncogene Proteins / physiology*
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Parkinson Disease / etiology
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Parkinson Disease / metabolism*
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Peroxiredoxins
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Protein Deglycase DJ-1
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Ubiquitin / metabolism
Substances
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Antioxidants
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Intracellular Signaling Peptides and Proteins
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Neoplasm Proteins
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Nfe2l2 protein, mouse
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Oncogene Proteins
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Ubiquitin
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Peroxiredoxins
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PARK7 protein, human
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PARK7 protein, mouse
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Protein Deglycase DJ-1