Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human ovarian cancer cell lines derived from A2780 by stepwise exposure to increasing cisplatin concentrations show progressive resistance to cisplatin. Previous studies have shown increased cellular glutathione and elevated steady-state expression of gamma-glutamylcysteine synthetase (gamma-GCS) and of the transcription factor c-Jun, all in proportion to the level of resistance in the resistant cells. We hypothesized that c-Jun was an important locus of control of the detoxicating enzymes mediating resistance, and that resistance reversal would be achieved by specific inhibition of this mechanism. A2780 (sensitive) and C30 (resistant) cells were treated with a 20-mer c-jun phosphorothioate antisense oligodeoxynucleotide (ISIS 10582, 1 microM), and a decrease in steady-state c-jun mRNA was demonstrated in the resistant cells. The expression of gamma-GCS mRNA was down-regulated and the cellular level of glutathione was decreased in C30 cells. No change in gamma-GCS expression occurred in A2780 cells. Using the microtetrazolium (MTT) cytotoxicity assay, we determined that the c-jun antisense decreased the IC50 value for cisplatin in C30 cells from 18.2 to 3.7 microM, and had a substantially smaller effect in A2780 cells. To determine if c-jun overexpression alone could confer resistance to the sensitive cell line, we transiently transfected A2780 cells with a c-jun expression vector. The transfected cells exhibited a 10.7-fold elevation of glutathione (GSH) content, a 9.2-fold increase in c-Jun protein content, and a 2-fold increase in the IC50 for cisplatin. These data suggest that altered regulation of transcription factor expression contributes to the acquired resistance phenotype in these ovarian cancer cells, and provide a novel potential target for therapeutic intervention.
 ...
PMID:Reversal of cisplatin resistance in human ovarian cancer cell lines by a c-jun antisense oligodeoxynucleotide (ISIS 10582): evidence for the role of transcription factor overexpression in determining resistant phenotype. 1200 73

In the lactating mammary gland, weaning produces mitochondrial cytochrome c release and nuclear DNA fragmentation, as determined by gel electrophoresis. This is followed by a significant decrease in lactation. Weaning for 2 h produces an early induction of the tumour suppressor/transcription factor p53, whereas the oncoprotein c-Jun and c-Jun N-terminal kinase are elevated after 24 h of weaning when compared with controls. The expression of p21(cip1) and p27(kip1), cyclin-dependent kinase inhibitors, was significantly higher in weaned rats when compared with control lactating rats. All the changes mentioned above also happen in the lactating mammary gland when propargylglycine, an inhibitor of the liver trans-sulphuration pathway, is administered. This effect is partially reversed by N -acetylcysteine administration. The administration of buthionine sulphoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, to lactating rats produces a decrease in GSH levels and changes in protein concentrations and gene transcripts similar to those in rats with impaired trans-sulphuration pathway. These data suggest that the inter-tissue flux of GSH is an important mechanism of L-cysteine delivery to the lactating mammary gland and emphasize the importance of this physiological event in maintaining the gene expression required to sustain lactation.
 ...
PMID:Inhibition of liver trans-sulphuration pathway by propargylglycine mimics gene expression changes found in the mammary gland of weaned lactating rats: role of glutathione. 1272 69

Because mitogen-activated protein kinases (MAPK) are downstream effectors of antioxidant responses, changes in GSH levels in an organism might induce organ-specific responses. To test our hypothesis, mice were treated intraperitoneally with L-buthionine-S-R-sulfoximine (BSO) to inhibit GSH synthesis. A time-related GSH depletion in the liver and kidney correlated with p38(MAPK) phosphorylation and induction of thioredoxin 1 (Tx-1) transcription. This positive regulation was associated with nuclear translocation of NF-kappaB and ATF-2 and c-Jun phosphorylation in the liver, but only c-Jun phosphorylation in the kidney. Increased levels of GSH were observed in the brain together with extracellular regulated kinase 2 (ERK2) activation, Nrf2 nuclear accumulation, and increases in transcription of Nrf2, xCT, gamma-glutamylcysteine synthetase (gammaGCSr), and Tx-1. Pretreatment with MAPK inhibitors SB203580 and U0126, or addition of the exogenous thiol N-acetylcysteine, abrogated both p38(MAPK) and ERK2 activation as well as downstream effects on gene expression. No effect on gammaGCSr was observed. These results indicate that in mice, GSH depletion is associated with p38(MAPK) phosphorylation in the liver and kidney and with ERK2 activation in the brain, in what could be considered part of the brain's protective response to thiol depletion.
 ...
PMID:Glutathione depletion activates mitogen-activated protein kinase (MAPK) pathways that display organ-specific responses and brain protection in mice. 1789 47

Sustained activation of the c-Jun NH(2)-terminal kinase (JNK) signaling pathway mediates the development and progression of experimental diet-induced nonalcoholic fatty liver disease (NAFLD). Delineating the mechanism of JNK overactivation in the setting of a fatty liver is therefore essential to understanding the pathophysiology of NAFLD. Both human and experimental NAFLD are associated with oxidative stress and resultant lipid peroxidation, which have been proposed to mediate the progression of this disease from simple steatosis to steatohepatitis. The ability of oxidants and the lipid peroxidation product 4-hydroxynonenal (HNE) to activate JNK signaling suggested that these two factors may act synergistically to trigger JNK overactivation. The effect of HNE on hepatocyte injury and JNK activation was therefore examined in cells under chronic oxidant stress from overexpression of the prooxidant enzyme cytochrome P450 2E1 (CYP2E1), which occurs in NAFLD. CYP2E1-generated oxidant stress sensitized a rat hepatocyte cell line to death from normally nontoxic concentrations of HNE. CYP2E1-overexpressing cells underwent a more profound depletion of glutathione (GSH) in response to HNE secondary to decreased gamma-glutamylcysteine synthetase activity. GSH depletion led to overactivation of JNK/c-Jun signaling at the level of mitogen-activated protein kinase kinase 4 that induced cell death. Oxidant stress and the lipid peroxidation product HNE cause synergistic overactivation of the JNK/c-Jun signaling pathway in hepatocytes, demonstrating that HNE may not be just a passive biomarker of hepatic oxidant stress but rather an active mediator of hepatocellular injury through effects on JNK signaling.
 ...
PMID:Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation. 2050 38


<< Previous 1 2