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

Parkinson's disease is characterized by the mesencephalic dopaminergic neuronal loss, possibly by apoptosis, and the prevalence is higher in males than in females. The estrogen receptor (ER) subtype in the mesencephalon is exclusively ER beta, a recently cloned novel subtype. Bound with estradiol, it enhances gene transcription through the estrogen response element (ERE) or inhibits it through the activator protein-1 (AP-1) site. We demonstrated that 17beta-estradiol provided protection against nigral neuronal apoptosis caused by exposure to either bleomycin sulfate (BLM) or buthionine sulfoximine (BSO). BLM and BSO-induced nigral apoptosis was blocked by inhibitors for caspase-3 or c-Jun/AP-1. The antiapoptotic effect by estradiol was blocked by ICI 182,780, an antagonist for ER, but not by a synthesized peptide that inhibits binding of the ER to the ERE. Estradiol had no effects on caspase-3 activation and c-Jun NH(2)-terminal kinase (JNK), which were activated by BLM. It also suppressed apoptosis by serum deprivation, which was independent of caspase-3 activation. Therefore, the antiapoptotic neuroprotection by estradiol is mediated by transcription through AP-1 site downstream from JNK and caspase-3 activation. Furthermore, 17alpha-estradiol, a stereoisomer without female hormone activity, also provided an antiapoptotic effect. Therefore, the antiapoptotic effect is independent of female hormone activity.
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PMID:Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons. 1083 42

Activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) are two important transcription factors responsible for the regulation of cytokines, which are involved in cell proliferation and inflammation. Coal workers' pneumoconiosis (CWP) is an occupational lung disease that may be related to chronic inflammation caused by coal dust exposure. In the present study, we demonstrate that coal from the Pennsylvania (PA) coalmine region, which has a high prevalence of CWP, can activate both AP-1 and NFAT in JB6 mouse epidermal cells. In contrast, coal from the Utah (UT) coalmine region, which has a low prevalence of CWP, has no such effects. The PA coal stimulates mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-Jun-NH(2)-terminal kinases, as determined by the phosphorylation assay. The increase in AP-1 by the PA coal was completely eliminated by the pretreatment of cells with PD98059, a specific MAPK kinase inhibitor, and SB202190, a p38 kinase inhibitor, further confirming that the PA coal-induced AP-1 activation is mediated through ERKs and p38 MAPK pathways. Deferoxamine (DFO), an iron chelator, synergistically enhanced the PA coal-induced AP-1 activity, but inhibited NFAT activity. For comparison, cells were treated with ferrous sulfate and/or DFO. We have found that iron transactivated both AP-1 and NFAT, and DFO further enhanced iron-induced AP-1 activation but inhibited NFAT. These results indicate that activation of AP-1 and NFAT by the PA coal is through bioavailable iron present in the coal. These data are in agreement with our previous findings that the prevalence of CWP correlates well with levels of bioavailable iron in coals from various mining regions.
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PMID:Role of bioavailable iron in coal dust-induced activation of activator protein-1 and nuclear factor of activated T cells: difference between Pennsylvania and Utah coal dusts. 1239 16

Hydrogen sulfide (H2S), produced by commensal sulfate-reducing bacteria, is an environmental insult that potentially contributes to chronic intestinal epithelial disorders. We tested the hypothesis that exposure of nontransformed intestinal epithelial cells (IEC-18) to the reducing agent sodium hydrogen sulfide (NaHS) activates molecular pathways that underlie epithelial hyperplasia, a phenotype common to both ulcerative colitis (UC) and colorectal cancer. Exposure of IEC-18 cells to NaHS rapidly increased the NADPH/NADP ratio, reduced the intracellular redox environment, and inhibited mitochondrial respiratory activity. The addition of 0.2-5 mM NaHS for 4 h increased the IEC-18 proliferative cell fraction (P<0.05), as evidenced by analysis of the cell cycle and proliferating cell nuclear antigen expression, while apoptosis occurred only at the highest concentration of NaHS. Thirty minutes of NaHS exposure increased (P<0.05) c-Jun mRNA concentrations, consistent with the observed activation of mitogen activated protein kinases (MAPK). Microarray analysis confirmed an increase (P<0.05) in MAPK-mediated proliferative activity, likely reflecting the reduced redox environment of NaHS-treated cells. These data identify functional pathways by which H2S may initiate epithelial dysregulation and thereby contribute to UC or colorectal cancer. Thus, it becomes crucial to understand how genetic background may affect epithelial responsiveness to this bacterial-derived environmental insult.
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PMID:Hydrogen sulfide induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells. 1273 7

Epidemiologic studies have shown positive associations between changes in ambient particulate matter (PM) levels in Utah Valley during 1986-1988, and the respiratory health of the local population. Ambient PM reductions coincided with closure of an open-hearth steel mill, the major industrial source of particulate emissions in the valley. In this report, water extracts of PM filters from steel mill operational (UE-86, UE-88) and closure (UE-87) periods were analyzed for their elemental composition. Their relative toxicity was determined by exposing primary rodent airway epithelial cultures to equal masses of extracted material. To elucidate extract subcomponents mediating the effects observed, cells were also exposed to surrogate metal mixtures. Potential interactions between the two predominant metals in the UE-86/88 samples, zinc (Zn) and copper (Cu), were further investigated. Data indicated that, relative to the UE-87 (plant closed) sample, UE-86/88 samples contained more sulfate, calcium, potassium,magnesium and, although present in much lower amounts, a variety of metals including Zn,Cu, iron, lead, strontium, nickel, manganese, and vanadium (V). Cell exposure to UE-86 and UE-88, but not UE-87, resulted in time- and concentration-dependent epithelial injury based on biochemical and light/electron microscopic changes. Cell injury induced by metal mixtures containing equivalent amounts of Zn + Cu + V was commensurate with that induced by the corresponding extract, although divergent antioxidant responses were observed. Exposure to Zn + Cu resulted in significantly greater epithelial toxicity and stress (c-Jun N-terminal protein kinase activation) responses than did exposure to Zn or Cu individually. The parallel epithelial injury induced by the extracts and their surrogate Zn + Cu + V mixtures suggests that these metals are mediating the acute airway epithelial effects observed; however, metal interactions appear to play a critical role in the overall cellular effects induced by the PM-derived extracts. These experimental findings are in good accord with epidemiologic reports of adverse airway and respiratory health health effects in Utah Valley residents.
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PMID:Metals mimic airway epithelial injury induced by in vitro exposure to Utah Valley ambient particulate matter extracts. 1285 32

Nuclear factor kappa B (NF-kB) and activating protein-1 (AP-1) transcription factors are ubiquitously expressed signaling molecules known to regulate the transcription of a large number of genes involved in immune responses, namely the inducible isoform of nitric oxide synthase (iNOS). In this study, we demonstrate that a fetal skin-derived dendritic cell line (FSDC) produces nitric oxide (NO) in response to the contact sensitizer nickel sulfate (NiSO(4)) and increases the expression of the iNOS protein, as determined by immunofluorescence and Western blot analysis. The sensitizer NiSO(4) increased cytoplasmic iNOS expression by 31.9 +/- 10.3% and nitrite production, as assayed by the Griess reaction, by 27.6 +/- 9.5%. Electrophoretic mobility shift assay (EMSA), showed that 30 min of FSDC exposure to NiSO(4) activates the transcription factor NF-kB by 58.2 +/- 7.0% and 2 h of FSDC exposure to NiSO(4) activates the transcription factor AP-1 by 26.0 +/- 1.4%. Together, these results indicate that NiSO(4) activates the NF-kB and AP-1 pathways and induces iNOS expression in skin dendritic cells.
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PMID:Contact sensitizer nickel sulfate activates the transcription factors NF-kB and AP-1 and increases the expression of nitric oxide synthase in a skin dendritic cell line. 1500 12

The c-Jun N-terminal kinases (JNKs) are considered as novel targets for therapy of inflammatory bowel diseases (IBD). However, the relevant JNK isoforms have to be elucidated. Here, we analyze the individual contribution of the JNK1 and JNK2 isoforms in a dextran sulfate sodium (DSS) model of experimental colitis. JNK1 and JNK2 knockout mice (JNK1 ko, JNK2 ko) and their wild-type controls (WT1, WT2) received three cycles of DSS treatment, each consisting of 1.7% DSS for 5 days, followed by 5 days with water. Animals were daily evaluated by a disease activity index (DAI) comprising measurement of body weight, estimation of stool consistency, and test for occult blood/gross rectal bleeding. After 30 days all animals were sacrificed, and the inflamed intestine was histologically evaluated by a crypt damage score. Unexpectedly, neither JNK1 ko nor JNK2 ko prevented mice from developing a chronic colitis when compared to wild-type controls WT1 and WT2, respectively. On the contrary, DAI and mortality were aggravated in JNK2 ko compared to WT2. DAI and mortality did not differ between JNK1 ko and WT1, but the histological crypt damage score was significantly enhanced in the cecum of JNK1 ko mice. Genetic deletion of JNK2 worsens the disease outcome in an experimental model of murine colitis. We hypothesize that the functional deletion of the otherwise proapoptotic JNK2 prolongs the activity of proinflammatory immune cells with deterioration of disease activity.
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PMID:Genetic deletion of JNK1 and JNK2 aggravates the DSS-induced colitis in mice. 1736 4

Interleukin (IL)-1 beta is a pro-inflammatory cytokine that has been shown to play a pivotal role in the onset of inflammatory bowel disease (IBD), however, the molecular mechanisms underlying the production of IL-1 beta in IBD are not fully understood. We investigated dextran sulfate sodium (DSS)-induced IL-1 beta production and caspase-1 activities in murine peritoneal macrophages (pM phi). Further, the activation status of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun NH(2)-terminal kinase (JNK1/2), as well as their upstream target kinases, were examined by Western blotting. In addition, mRNA expression was assessed by RT-PCR and CXC chemokine ligand 16 (CXCL16) protein was detected by immunocytochemistry. DSS-treated pM phi released IL-1 beta protein in a time-dependent manner without affecting mRNA levels during 3-24 h, and caspase-1 activity peaked at 5 min (29-fold). IL-1 beta release and caspase-1 activity induced by DSS were significantly inhibited by a MAPK kinase 1/2 inhibitor, a p38 MAPK inhibitor, and NAC, however, not by JNK1/2 or a protein kinase C inhibitor. In addition, DSS strikingly induced the phosphorylation of p38 MAPK and ERK1/2 within 2 and 10 min, respectively. DSS also induced intracellular generation of reactive oxygen species (ROS). Pre-treatment with anti-CXCL16 for 24 h, but not anti-scavenger receptor-A, anti-CD36, or anti-CD68 antibodies, significantly suppressed DSS-induced IL-1 beta production. Our results suggest that DSS triggers the release of IL-1 beta protein from murine pM phi at a post-translational level through binding with CXCL16, ROS generation, and resultant activation of both p38 MAPK and ERK1/2 pathways, and finally caspase-1 activation.
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PMID:Dextran sulfate sodium enhances interleukin-1 beta release via activation of p38 MAPK and ERK1/2 pathways in murine peritoneal macrophages. 1762 10

Protein tyrosine phosphatases (PTPs) are important regulators of cell functions but data on different PTP expression and dynamics in acute pancreatitis (AP) are very scarce. Additionally, both c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinases (ERK1/2), together with intracellular cAMP levels in inflammatory cells, play an essential role in AP. In this study we have detected an increase in PTP SHP-1 and SHP-2 in the pancreas at the level of both protein and mRNA as an early event during the development of Cerulein (Cer)-induced AP in rats. Nevertheless, while SHP-2 protein returned to baseline levels in the intermediate or later phases of AP, SHP-1 protein expression remained increased throughout the development of the disease. The increase in SHP-2 protein expression was associated with changes in its subcellular distribution, with higher percentages located in the fractions enriched in lysosomes+mitochondria or microsomes. Furthermore, while the increase in SHP-2 protein was also observed in sodium-taurocholate duct infusion or bile-pancreatic duct obstruction AP, that of SHP-1 was specific to the Cer-induced model. Neutrophil infiltration did not affect the increase in SHP-1 protein, but favoured the return of SHP-2 protein to control levels, as indicated when rats were rendered neutropenic by the administration of vinblastine sulfate. Inhibition of JNK and ERK1/2 with SP600125 pre-treatment further increased the expression of both SHP-1 and SHP-2 proteins in the early phase of Cer-induced AP, while the inhibition of type IV phosphodiesterase with rolipram only suppressed the increase in SHP-2 protein expression during the same phase. Our results show that AP is associated with increases in the expression of SHP-1 and SHP-2 and changes in the dynamics of SHP-2 subcellular distribution in the early phase of Cer-induced AP. Finally, both JNK and ERK1/2 and intracellular cAMP levels are able to modulate the expression of these PTPs.
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PMID:Changes in the expression and dynamics of SHP-1 and SHP-2 during cerulein-induced acute pancreatitis in rats. 1829 64

The purpose of this study was to investigate the preventive effect of glycoprotein (SNL glycoprotein, 150 kDa) isolated from Solanum nigrum Linne fruits on dextran sulfate sodium (DSS, 3%)-induced colitis in A/J mice. To determine the physiological change by SNL glycoprotein, we first evaluated nitric oxide production, lactate dehydrogenase release and thiobarbituric acid reactive substances formation in the mice serum. After that, we tested the activity of inflammation-related signals such as transcriptional factor [nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1)], inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the mice colon tissues. Our results showed that SNL glycoprotein has a dose-dependent inhibitory effect on nitric oxide production, lactate dehydrogenase release, and thiobarbituric acid reactive substances formation. In the inflammation-related signal, our finding showed that SNL glycoprotein (20 mg kg(-1)) has a suppressive effect on activities of NF-kappaB (p50) and AP-1 (c-Jun), and regulates the expression of iNOS and COX-2 in the downstream of signal pathway. Taken together, the results in this study indicated that SNL glycoprotein has potential for prevention of colitis caused by DSS in A/J mice.
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PMID:Phytoglycoprotein (150 kDa) isolated from Solanum nigrum Linne has a preventive effect on dextran sodium sulfate-induced colitis in A/J mouse. 1898 4

The goal of the study was to investigate bone morphogenetic protein 2 (BMP-2) and transforming growth factor beta (TGF-beta) control of the expression of beta1,3-glucuronosyl transferase 1 (GlcAT-1), an important regulator of chondroitin sulfate synthesis in cells of the nucleus pulposus. Treatment with both growth factors resulted in induction of GlcAT-1 expression and promoter activity. Deletion analysis indicated that promoter constructs lacking AP1 and TonE sites were unresponsive to growth factor treatment. Experiments using dominant-negative proteins showed that these transcription factors along with Sp1 were required for induction of GlcAT-1 promoter activity. Moreover, when either AP1 or TonE binding sites were mutated, induction was suppressed. Both BMP-2 and TGF-beta increased c-Jun and TonEBP expression and phosphorylation of transactivation domains. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway following growth factor treatment; a robust and transient activation of ERK1/2, p38, and JNK was noted. Treatment with MAPK inhibitors blocked BMP-2- and TGF-beta-induced AP1 reporter function, GlcAT-1 expression, and GAG accumulation. We found that DN-ERK1 but not DN-ERK2 resulted in suppression of growth factor-mediated induction of GlcAT-1 promoter activity; we also showed that p38 delta was important in GlcAT-1 activation. Results of these studies demonstrate that BMP-2 and TGF-beta regulate GlcAT-1 expression in nucleus pulposus cells through a signaling network comprising MAPK, AP1, Sp1, and TonEBP. It is concluded that by controlling both GAG and aggrecan synthesis, these growth factors positively influence disk cell function.
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PMID:BMP-2 and TGF-beta stimulate expression of beta1,3-glucuronosyl transferase 1 (GlcAT-1) in nucleus pulposus cells through AP1, TonEBP, and Sp1: role of MAPKs. 1996 37


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