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Compensatory role of the Nrf2-ARE pathway against paraquat toxicity: Relevance of 26S proteasome activity
- Source :
- Journal of Pharmacological Sciences, Vol 129, Iss 3, Pp 150-159 (2015)
- Publication Year :
- 2015
-
Abstract
- Oxidative stress and the ubiquitin-proteasome system play a key role in the pathogenesis of Parkinson disease. Although the herbicide paraquat is an environmental factor that is involved in the etiology of Parkinson disease, the role of 26S proteasome in paraquat toxicity remains to be determined. Using PC12 cells overexpressing a fluorescent protein fused to the proteasome degradation signal, we report here that paraquat yielded an inhibitory effect on 26S proteasome activity without an obvious decline in 20S proteasome activity. Relative low concentrations of proteasome inhibitors caused the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is targeted to the ubiquitin-proteasome system, and activated the antioxidant response element (ARE)-dependent transcription. Paraquat also upregulated the protein level of Nrf2 without increased expression of Nrf2 mRNA, and activated the Nrf2-ARE pathway. Consequently, paraquat induced expression of Nrf2-dependent ARE-driven genes, such as γ-glutamylcysteine synthetase, catalase, and hemeoxygenase-1. Knockdown of Nrf2 or inhibition of γ-glutamylcysteine synthetase and catalase exacerbated paraquat-induced toxicity, whereas suppression of hemeoxygenase-1 did not. These data indicate that the compensatory activation of the Nrf2-ARE pathway via inhibition of 26S proteasome serves as part of a cellular defense mechanism to protect against paraquat toxicity.
- Subjects :
- Paraquat
Proteasome Endopeptidase Complex
NF-E2-Related Factor 2
Nrf2-ARE pathway
Glutamate-Cysteine Ligase
Proteasome activity
medicine.disease_cause
PC12 Cells
chemistry.chemical_compound
Downregulation and upregulation
Nrf2–ARE pathway
medicine
Animals
Glyceraldehyde 3-phosphate dehydrogenase
Pharmacology
Gene knockdown
biology
Herbicides
lcsh:RM1-950
Parkinson Disease
respiratory system
Catalase
Antioxidant Response Elements
Cell biology
Rats
lcsh:Therapeutics. Pharmacology
Biochemistry
Proteasome
chemistry
Oxidative stress
Toxicity
biology.protein
Molecular Medicine
Signal Transduction
Subjects
Details
- ISSN :
- 13478648
- Volume :
- 129
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of pharmacological sciences
- Accession number :
- edsair.doi.dedup.....ff69ce6a7cb3d9c1c8edbe96650b1897