UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exhaled nitric oxide (NO) is increased in individuals with bronchial asthma. NO may have antiinflammatory and proinflammatory effects; however, its role in bronchial asthma is unclear. In the present study, to clarify this issue we examined the effect of NO in inducing activator protein-1 (AP-1) activation in human bronchial epithelial cells (BEC) and a role of apoptosis signal-regulating kinase1 (ASK1), an upstream kinase kinase of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in NO-mediated AP-1 activation. The results showed that (1) the reactive nitrogen generating species NOR-1(+/--(E)-methyl-2-[(E)-hydroxykmino]-5-nitro-6-methoxy-3-hexeneamide]) induced AP-1 activation determined by AP-1-dependent luciferase gene activity, and an NO scavenger, carboxyl-PTIO, attenuated NOR-1-induced AP-1 activation; (2) NOR-1 phosphorylated ASK1, JNK, and p38 MAPK; and (3) transient transfection of the dominant negative form of AKS1 attenuated NOR-1-induced AP-1 activation in BEC. To further characterize the role of ASK-1 cascade, the dominant negative form of ASK1-stable transfected porcine artery endothelial (PAE) cells were used. AP-1 activity and JNK and p38 MAPK phosphorylation were depressed in the dominant-negative form of ASK1-stable transfected PAE cells. These results indicate that NO is capable of inducing AP-1 activation, and that ASK1-p38 MAPK/JNK cascade regulates AP-1 activation in NO-stimulated BEC.
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PMID:Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates nitric oxide-induced activator protein-1 activation in human bronchial epithelial cells. 1262 59

IGF-I is a major anabolic hormone for skeletal muscle in vivo. Yet the mechanisms by which GH and cytokines regulate IGF-I expression remain obscure. Lipopolysaccharide (LPS) dramatically alters the circulating concentration of both TNF alpha and IGF-I, and TNF alpha in part mediates the cachectic activity of LPS. Little is known about the local synthesis of IGF-I and TNF alpha in skeletal muscle per se. The purpose of the present study was to determine whether LPS alters the expression of TNF alpha and IGF-I in mouse skeletal muscle and whether TNF alpha directly inhibits IGF-I mRNA expression in C2C12 myoblasts. Intraperitoneal injection of LPS in C3H/SnJ mice increased the expression of TNF alpha protein in plasma (16-fold) and TNF alpha mRNA in skeletal muscle (8-fold). LPS also decreased the plasma concentration of IGF-I (30%) and IGF-I mRNA in skeletal muscle (50%, between 6 and 18 h after LPS administration). Addition of LPS or TNF alpha directly to C2C12 myoblasts decreased IGF-I mRNA by 50-80%. The TNF alpha-induced decrease in IGF-I mRNA was both dose and time dependent and occurred in both myoblasts and differentiated myotubes. TNF alpha selectively decreased IGF-I but not IGF-II mRNA levels, and the effect of TNF alpha was blocked by a specific TNF-binding protein. TNF alpha did not alter IGF-I mRNA levels in the presence of the protein synthesis inhibitor cycloheximide. TNF alpha did not change the half-life of IGF-I mRNA. TNF alpha completely prevented GH-inducible IGF-I mRNA expression, but this GH resistance was not attributable to impairment in signal transducer and activator of transcription-3 or -5 phosphorylation. TNF alpha increased both nitric oxide synthase-II mRNA and protein, and the nitric oxide donor sodium nitroprusside decreased IGF-I mRNA levels in C2C12 cells. Yet inhibitor studies indicate that nitric oxide did not mediate the effect of TNF alpha on IGF-I mRNA expression. TNF alpha stimulated the phosphorylation of c-Jun and specific inhibition of the Jun N-terminal kinase pathway, but not other MAPK pathways, completely prevented the TNF alpha-induced drop in IGF-I mRNA. These data suggest that LPS stimulates TNF alpha expression in mouse skeletal muscle and autocrine-derived cytokines may contribute to the reduced expression of IGF-I in this tissue.
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PMID:Tumor necrosis factor-alpha decreases insulin-like growth factor-I messenger ribonucleic acid expression in C2C12 myoblasts via a Jun N-terminal kinase pathway. 1269 82

Exercise promotes positive bone remodeling through controlling cellular processes in bone. Nitric oxide (NO), generated from endothelial nitric-oxide synthase (eNOS), prevents resorption, whereas receptor activator of nuclear kappa B ligand (RANKL) promotes resorption through regulating osteoclast activity. Here we show that mechanical strain differentially regulates eNOS and RANKL expression from osteoprogenitor stromal cells in a magnitude-dependent fashion. Strain (0.25-2%) induction of eNOS expression was magnitude-dependent, reaching a plateau at 218 +/- 36% of control eNOS. This was accompanied by increases in eNOS protein and a doubling of NO production. Concurrently, 0.25% strain inhibited RANKL expression with increasing response up to 1% strain (44 +/- 3% of control RANKL). These differential responses to mechanical input were blocked when an ERK1/2 inhibitor was present during strain application. Inhibition of NO generation did not prevent strain-activated ERK1/2. To confirm the role of ERK1/2, cells were treated with an adenovirus encoding a constitutively activated MEK; Ad.caMEK significantly increased eNOS expression and NO production by more than 4-fold and decreased RANKL expression by half. In contrast, inhibition of strain-activated c-Jun kinase failed to prevent strain effects on either eNOS or RANKL. Our data suggest that physiologic levels of mechanical strain utilize ERK1/2 kinase to coordinately regulate eNOS and RANKL in a manner leading to positive bone remodeling.
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PMID:Mechanical strain differentially regulates endothelial nitric-oxide synthase and receptor activator of nuclear kappa B ligand expression via ERK1/2 MAPK. 1282 89

The production of matrix metalloproteinases (MMP) by UV-irradiated skin fibroblasts and the degradation of the extracellular matrix by these enzymes is known as one of the main causes of photoaging. Recently, the Fisher group showed that MMP expression is mainly regulated by members of the mitogen-activated protein kinase family such as extracellular signal-regulated kinase, c-Jun amino-terminal kinase, and p38, each of which forms a signaling pathway. In this work, we initially examined the effect of nitric oxide (NO) and nitric oxide synthase (NOS) inhibitors on the production of MMP-1 and MMP-2 by human dermal fibroblasts (HDF). NO is a multifunctional messenger molecule generated from L-arginine and can activate guanylate cyclase to increase cGMP. We found that treatment of HDF with an NO donor, sodium nitroprusside (50 microM), enhanced the expression of MMP-1 and -2 by 153% and 243%, respectively, and treatment by 8-Br-cGMP enhanced MMP-1 and -2 expression by 137% and 254%, respectively. When UV-irradiated HDF was treated with NOS inhibitors such as aminoguanidine (AG) and baicalein (BAC), there resulted a decrease in MMP production. When 20 microM of BAC was added in the culture media of UV-irradiated HDF, only 40% of MMP-1 and 42% of MMP-2 was produced, compared to the case without BAC. Taken together, we concluded that the production of MMP-1 and -2 by UV-irradiated HDF is regulated through the signaling pathway involving NO and that it can be downregulated using NOS inhibitors.
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PMID:Inhibition of matrix metalloproteinase-1 and -2 expression using nitric oxide synthase inhibitors in UV-irradiated human dermal fibroblasts. 1285 22

CpG oligodeoxynucleotides (ODN) activate immune cells to produce immune mediators by Toll-like receptor 9 (TLR9)-mediated signal transduction, which activates mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) through the MyD88/IRAK/TRAF6 kinases cascade. However, the precise mechanisms of CpG ODN activation of immune cells have not been fully elucidated. The small GTP-binding protein Ras mediates MAPK activation in response to a variety of stimuli. Up to now, it is not clear whether Ras plays a role in CpG ODN signaling. In the present study, we found that the dominant-negative version of Ras (RasN17) and specific Ras inhibitor, FTI-277, inhibited CpG ODN-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) production by murine macrophage cell line RAW264.7. While overexpression of wild-type Ras enhanced CpG ODN-induced extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and NF-kappaB activation, overexpression of RasN17 inhibited CpG ODN-induced ERK, JNK, and NF-kappaB activation. RasN17 overexpression also inhibited CpG ODN-induced IRAK1/TRAF6 complex formation. Further studies revealed that CpG ODN activated Ras in a time- and dose-dependent manner, and Ras associated with TLR9 in a CpG ODN-dependent manner. Most interestingly, activation of Ras preceded the association of Ras with TLR9, giving rise to a possibility that Ras activation might not be dependent on the interaction between Ras and TLR9. Our data demonstrate for the first time that Ras can be activated by CpG ODN in macrophages, and Ras is involved in CpG ODN signaling as an early event by associating with TLR9 and promoting IRAK1/TRAF6 complex formation, and MAPK and NF-kappaB activation.
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PMID:Ras participates in CpG oligodeoxynucleotide signaling through association with toll-like receptor 9 and promotion of interleukin-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor 6 complex formation in macrophages. 1286 18

In this study, we investigated the role of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, in lipopolysaccharide (LPS)-stimulated inducible nitric-oxide synthase (iNOS) expression and nitric oxide (NO) production in J774 murine macrophages. Anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), a pharmacological inhibitor of JNK, inhibited phosphorylation of c-Jun with an IC50 of 5 to 10 microM. At the same concentrations, SP600125 inhibited LPS-induced iNOS protein expression and NO production. SP600125 had no effect on the activation of nuclear factor kappaB, which is an important transcription factor for iNOS expression. SP600125 had no significant effect on iNOS mRNA levels if measured 4 h after LPS. In contrast, SP600125 reduced iNOS mRNA levels >90% when measured 8 h after LPS. These data suggest that SP600125 reduced iNOS mRNA stability, and this was confirmed in the mRNA degradation assay using actinomycin D, in which SP600125 reduced the iNOS mRNA half-life from 5 to 2 h. These results show that the JNK pathway is involved in the up-regulation of LPS-induced iNOS expression and NO production by a mechanism related to the stabilization of iNOS mRNA.
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PMID:c-Jun NH2-terminal kinase inhibitor anthra(1,9-cd)pyrazol-6(2H)-one reduces inducible nitric-oxide synthase expression by destabilizing mRNA in activated macrophages. 1286 35

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

JS-K, a non-ionic diazeniumdiolate derivative, is capable of arylating nucleophiles and spontaneously generating nitric oxide (NO) at physiological pH. This recently synthesized low molecular weight compound is shown here to be an inhibitor of cell growth with concomitant activation of mitogen-activated protein kinase (MAPK) members ERK, JNK, and p38 and their downstream effectors c-Jun and AP-1. Inhibitors of these MAPK pathways abrogated the growth inhibitory actions of JS-K. In addition to the well-described actions of JNK as a kinase for c-Jun, we show that c-Jun is also an ERK target. Furthermore, JS-K generated NO in culture and NO inhibitors antagonized both MAPK induction and the growth inhibitory effects of JS-K. These results suggest two possible mechanisms for the mediation of JS-K growth inhibitory actions, namely NO-induction of MAPK pathway constituents as well as possible arylation reactions. The data support the idea that prolonged MAPK activation by JS-K action is important in mediating its growth-inhibitory actions. JS-K thus represents a promising platform for novel growth inhibitory analog synthesis.
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PMID:JS-K, a novel non-ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c-Jun phosphorylation via multiple MAP kinase pathways. 1456 72

c-Jun NH2-terminal kinases (JNKs) potentiate transcriptional activity of c-Jun by phosphorylating serines 63 and 73. Moreover, JNK and c-Jun can modulate apoptosis. However, an involvement of nitric oxide (NO)-induced phosphorylation of c-Jun on Ser-63 and Ser-73 in apoptosis has not been explored. We report that in SH-Sy5y neuroblastoma cells, NO induced apoptosis following JNK activation and phosphorylation of c-Jun almost exclusively on Ser-63. Importantly, NO-induced apoptosis and caspase-3 activity were inhibited in cells stably transformed with dominant-negative c-Jun in which Ser-63 is mutated to alanine (S63A), but not in cells transformed with dominant-negative c-Jun (S73A). Ser-63 of c-Jun (but not Ser-73) was required for NO-induced, c-Jun-dependent transcriptional activity. NO-induced apoptosis, Ser-63 phosphorylation of c-Jun, and caspase-3 activity were all inhibited in SH-Sy5y cells transformed with dominant-negative jnk. A caspase-3 inhibitor prevented apoptosis but not c-Jun phosphorylation. In a different neuroblastoma cell line, NO-induced Ser-63 phosphorylation of c-Jun and apoptosis were blocked by a specific JNK inhibitor. We conclude that NO-inducible apoptosis is mediated by JNK-dependent Ser-63 phosphorylation of c-Jun upstream of caspase-3 activation in neuroblastoma cells.
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PMID:JNK-dependent phosphorylation of c-Jun on serine 63 mediates nitric oxide-induced apoptosis of neuroblastoma cells. 1461 28

The transcription factor NFAT (nuclear factor of activated T-cells) is implicated in cardiac hypertrophy and vasculogenesis. NFAT activation, reflecting dephosphorylation by the calcium-dependent phosphatase, calcineurin, and subsequent nuclear localization, is generally thought to require a sustained increase in intracellular calcium. However, in smooth muscle we have found that elevation of calcium by membrane depolarization fails to induce an increase in nuclear localization of the NFATc3 isoform. Here, we demonstrate that physiological intravascular pressure (100 mm Hg) induces an increase in NFATc3 nuclear localization in mouse cerebral arteries. Pressure-induced NFATc3 nuclear accumulation is abrogated by endothelial denudation and by nitric-oxide synthase, cGMP-dependent kinase (PKG), and voltage-dependent calcium channels inhibition. We further show that exogenous nitric oxide, in combination with an elevation in calcium, is an effective stimulus for NFATc3 nuclear accumulation. c-Jun terminal kinase 2 (JNK) activity, which has been shown to regulate NFATc3 nuclear export, is also reduced by pressure, an effect that is prevented by pretreatment with a PKG inhibitor. Consistent with this, pressure-induced NFATc3 nuclear accumulation is independent of PKG in arteries from JNK2(-/-) mice. Collectively, our results indicate that both activation of the NO/PKG pathway and elevation of smooth muscle calcium are required for NFATc3 nuclear accumulation and that PKG inhibits JNK2 to decrease NFAT nuclear export. Our findings suggest that at physiological intravascular pressures NFATc3 is localized to the nucleus in smooth muscle cells of intact arteries and indicate a novel and unexpected role for nitric oxide/PKG in NFAT activation.
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PMID:Intraluminal pressure is a stimulus for NFATc3 nuclear accumulation: role of calcium, endothelium-derived nitric oxide, and cGMP-dependent protein kinase. 1468 53

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