Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress contributes to the development of neurodegenerative diseases. DJ-1, a protein genetically linked to Parkinson's disease (PD), has been implicated in oxidative stress defense and transcriptional regulation. However, it is unclear whether these two aspects of the DJ-1 function are connected. Here, we show that the inactivation of DJ-1 causes decreased expression of the human MnSOD. DJ-1 stimulates the activity of a master regulator of mitochondrial biogenesis and stress response, peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha), in the transcription of the MnSOD. Although DJ-1 does not interact with PGC-1alpha directly, it inhibits the SUMOylation of a transcriptional repressor, pyrimidine tract-binding protein-associated splicing factor (PSF). PSF binds PGC-1alpha and suppresses its transcriptional activity. In contrast, a SUMOylation-deficient PSF mutant exhibits reduced binding to PGC-1alpha and promotes its activity. SUMO-specific isopeptidase SENP-1 further enhances the synergy between DJ-1 and PGC-1alpha, whereas an SUMO E3 ligase protein inhibitor of activated STAT Y completely blocks the synergy. Conversely, oxidative modification renders DJ-1 unable to inhibit SUMOylation, resulting in attenuated transcriptional synergy between DJ-1 and PGC-1alpha. Therefore, our results validate DJ-1 as a transcriptional regulator in mitochondrial oxidative stress response and imply that the oxidation-mediated functional impairment of DJ-1 leads to gradual dysregulation of the SUMO pathway. Consequent abnormal mitochondrial gene expression may contribute to the development of sporadic PD.
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PMID:Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation. 1868 99

Oxidative stress has been associated with the etipathogenesis of Diabetic retinopathy (DR). Studies have shown that DJ-1 plays an important role in regulating the reactive oxygen species (ROS) production and resistance to oxidative stress-induced apoptosis. This study aimed to investigate whether DJ-1 upregulates oxidative stress and prevents damage to retinal capillary pericytes by increasing antioxidant capacity through the Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Nrf2 is a redox-sensitive transcription factor that encode antioxidant enzymes and phase II metabolic enzymes, activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many tissues. Our results showed after DJ-1 overexpression, apoptosis of rat retinal pericytes (RRPs) decreased, the ratio of B-cell lymphoma-2 (Bcl-2) to BCL2-Associated X Protein (BAX) increased, the production of ROS decreased, and the protein expression and activity of manganese superoxide dismutase (MnSOD, also called SOD2) and catalase (CAT) increased. DJ-1 overexpression activated Nrf2 expression, however, after Nrf2 silencing, apoptosis of RRPs increased, the ratio of Bcl-2 to BAX decreased, the production of ROS increased, the protein expression of MnSOD and CAT decreased, and the expression of heme oxygenase-1 (HO-1), NADP(H) quinone oxidoreductase (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) decreased. These data suggest that enhancement of the Nrf2 pathway is a potential protective strategy for the treatment of DR. Therefore, DJ-1 may prevent high glucose-induced oxidative stress and RRPs apoptosis through the Nrf2 signaling pathway, thereby preventing the early onset and progression of DR.
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PMID:DJ-1 protects retinal pericytes against high glucose-induced oxidative stress through the Nrf2 signaling pathway. 3205 71