Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Gene/Protein
Disease
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Drug
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Target Concepts:
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Disease
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Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
DJ-1
is a highly conserved soluble protein that is associated to several cellular pathways. In humans,
DJ-1
has been implicated in several pathologies such as cancer, Parkinson's disease and amyotrophic lateral sclerosis. Several roles have been attributed to
DJ-1
, including defense against oxidative stress, chaperone activity and
proteasome
regulation. The recent finding that
DJ-1
acts as a protein and DNA deglycase further confirms the protective function of
DJ-1
and suggests a common mechanism of action in the various pathways in which
DJ-1
is involved. Cysteine 106, located in the putative active site of
DJ-1
, is critical for the biological activity of
DJ-1
and is easily oxidized to cysteine-sulfinate. While such oxidation modulates
DJ-1
activity, the underlying molecular mechanism has not yet been elucidated. Cysteine oxidation does not perturb the protein structure, therefore changes in protein dynamics in solution could modulate its function. Here, we report a revised and completed (98%) backbone assignment of reduced
DJ-1
, together with the backbone assignment of oxidized
DJ-1
. Chemical shift perturbation is observed in several regions across the sequence, while no changes in secondary structure are observed. These data will provide the starting point for further characterization of the changes in the backbone dynamics of
DJ-1
upon oxidation in solution at physiological temperature.
...
PMID:Backbone resonance assignment of human DJ-1 in the reduced state and in the cysteine sulfinic acid state. 3137 86
Bovine herpesvirus type 1 (BoHV-1) is a significant cofactor for bovine respiratory disease complex (BRDC), the most important inflammatory disease in cattle. BoHV-1 infection in cell cultures induces overproduction of pathogenic reactive oxygen species (ROS) and the depletion of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a master transcriptional factor regulating a panel of antioxidant and cellular defense genes in response to oxidative stress. In this study, we reported that the virus productive infection in MDBK cells at the later stage significantly decreased the expression levels of heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1) proteins, the canonical downstream targets regulated by Nrf2, inhibited Nrf2 acetylation, reduced the accumulation of Nrf2 proteins in the nucleus, and relocalized nuclear Nrf2 proteins to form dot-like staining patterns in confocal microscope assay. The differential expression of Kelch-like ECH associated protein 1 (KEAP1) and
DJ-1
proteins as well as the decreased association between KEAP1 and
DJ-1
promoted Nrf2 degradation through the ubiquitin
proteasome
pathway. These data indicated that the BoHV-1 infection may significantly suppress the Nrf2 signaling pathway. Moreover, we found that there was an association between Nrf2 and LaminA/C, H3K9ac, and H3K18ac, and the binding ratios were altered following the virus infection. Taken together, for the first time, we provided evidence showing that BoHV-1 infection inhibited the Nrf2 signaling pathway by complicated mechanisms including promoting Nrf2 degradation, relocalization of nuclear Nrf2, and inhibition of Nrf2 acetylation.
...
PMID:Bovine Herpesvirus 1 Productive Infection Led to Inactivation of Nrf2 Signaling through Diverse Approaches. 3168 81
DJ-1
was identified as an oncogene and also as a causative gene for a familial form of Parkinson disease (PD).
DJ-1
plays various roles in anti-oxidative stress response. Superfluous oxidation of
DJ-1
at cysteine residue 106 (C106), an inactive form of
DJ-1
, was observed in PD patients.
DJ-1
-binding compound B, which specifically bound to the C106 region of
DJ-1
, has been isolated and it has been shown to prevent oxidative stress-induced cell death through maintaining active forms of
DJ-1
by inhibiting its superfluous oxidation. The molecular mechanism of the action of compound B, however, has not been fully elucidated. In this study, we found that compound B stimulated transcriptional activity of Nrf2 in H
2
O
2
-treated SH-SY5Y cells by inhibiting its degradation through the ubiquitin-
proteasome
system. Although Keap 1 is a major negative regulator of Nrf2, compound B strongly increased Nrf2 activity in Keap1-mutant A549 cells but not in PTEN-null PC3 and PTEN-knockout SH-SY5Y cells. Furthermore, treatment of cells with inhibitors of the PI3-kinase/Akt pathway inhibited the effect of compound B, and compound B increased the binding of PTEN to
DJ-1
and decreased lipid phosphatase activity of PTEN concomitantly with increased oxidation of PTEN, an inactive form of PTEN. These results suggest that compound B enhances transcriptional activity of Nrf2 under an oxidative stress condition in a Keap1-independent manner and that its activity is elicited by activation of the PI3Kinase/Akt pathway with
DJ-1
-dependent inactivation of PTEN, leading to protection of oxidative stress-induced cell death.
...
PMID:DJ-1-binding compound B enhances Nrf2 activity through the PI3-kinase-Akt pathway by DJ-1-dependent inactivation of PTEN. 3189 90
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