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)

The steroid hormone aldosterone is important for salt and water homeostasis as well as for pathological tissue modifications in the cardiovascular system and the kidney. The mechanisms of action include a classical genomic pathway, but physiological relevant nongenotropic effects have also been described. Unlike for estrogens or progesterone, the mechanisms for these nongenotropic effects are not well understood, although pharmacological studies suggest a role for the mineralocorticoid receptor (MR). Here we investigated whether the MR contributes to nongenotropic effects. After transfection with human MR, aldosterone induced a rapid and dose-dependent phosphorylation of ERK1/2 and c-Jun NH2-terminal kinase (JNK) 1/2 kinases in Chinese hamster ovary or human embryonic kidney cells, which was reduced by the MR-antagonist spironolactone and involved cSrc kinase as well as the epidermal growth factor receptor. In primary human aortic endothelial cells, similar results were obtained for ERK1/2 and JNK1/2. Inhibition of MAPK kinase (MEK) kinase but not of protein kinase C prevented the rapid action of aldosterone and also reduced aldosterone-induced transactivation, most probably due to impaired nuclear-cytoplasmic shuttling of MR. Cytosolic Ca2+ was increased by aldosterone in mock- and in human MR-transfected cells to the same extend due to Ca2+ influx, whereas dexamethasone had virtually no effect. Spironolactone did not prevent the Ca2+ response. We conclude that some nongenotropic effects of aldosterone are MR dependent and others are MR independent (e.g. Ca2+), indicating a higher degree of complexity of rapid aldosterone signaling. According to this model, we have to distinguish three aldosterone signaling pathways: 1) genomic via MR, 2) nongenotropic via MR, and 3) nongenotropic MR independent.
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PMID:Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. 1576 Oct 31

In DOCA-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA- and salt-induced proteinuria, glomerular sclerosis, tubular dilatation, and luminal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-beta1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-beta1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, proliferating tubular epithelial cells, and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1), and the phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite and cGMP levels, and suppression of superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis glomerular hypertrophy, and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation, and p27(Kip1) and TGF-beta1 expression.
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PMID:Kallikrein gene transfer reduces renal fibrosis, hypertrophy, and proliferation in DOCA-salt hypertensive rats. 1588 73

Melanocortins play a central role in autonomic modulation of metabolism by acting through a family of highly homologous G protein-coupled receptors. Studies with gene knockout mice have implicated neural melanocortin receptors, MC3R and MC4R, in the etiology of obesity, insulin resistance, and salt-sensitive hypertension. In an attempt to better understand the mechanisms of function of these receptors, we expressed MC3R and MC4R in neuronal cells and demonstrated their co-localization to several membrane regions. We now show that in cultured neuronal cells, MC3R localizes to lipid rafts and undergoes endocytic internalization upon activation by gamma-MSH through a protein kinase-sensitive pathway. The appearance of the internalized receptor in lysosomes suggests that it is subsequently degraded. The expression of protein kinase A regulatory subunits and of c-Jun and c-Fos was analyzed by either immunoblotting or real-time PCR. No discernable changes were observed in the expression levels of these protein kinase A and protein kinase C responsive genes. Immunohistochemical studies showed a robust expression of MC3R protein in brain nuclei with relevance to cardiovascular function and fluid homeostasis further supporting the notion that the physiological effects of melanocortins on the cardiovascular system arise from effects on the central nervous system.
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PMID:Activation and endocytic internalization of melanocortin 3 receptor in neuronal cells. 1740 38

Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed "anoikis." Resistance to anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of anoikis, we designed, automated, and conducted a high-throughput chemical screen for anoikis sensitizers. PPC-1 anoikis-resistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH(2)-kinase and p38, these kinases were not functionally important for the effect of anisomycin on anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy.
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PMID:A chemical screen identifies anisomycin as an anoikis sensitizer that functions by decreasing FLIP protein synthesis. 1780 46

The basic-region leucine zipper (BR-LZ or bZIP) transcription factors dimerize via their LZ domains to position the adjacent BRs for DNA binding. Members of the C/EBP, AP-1 and CREB/ATF bZIP subfamilies form homodimeric or heterodimeric complexes with other members of the same subset and bind-specific DNA motifs. Here we demonstrate that C/EBPalpha also zippers with AP-1 proteins and that this interaction allows contact with novel DNA elements and induction of monocyte lineage commitment in myeloid progenitors. A leucine zipper swap:gel shift assay demonstrates that C/EBPalpha zippers with c-Jun, JunB or c-Fos, but not with c-Maf or MafB. To evaluate activities of specific homodimers or heterodimers we utilized LZs with acid (LZE) or basic (LZK) residues in their salt bridge positions. C/EBPalphaLZE:C/EBPalphaLZK preferentially binds a C/EBP site, c-JunLZE:c-FosLZK an AP-1 site and C/EBPalphaLZE:c-JunLZK a hybrid element identified as TTGCGTCAT by oligonucleotide selection. In murine myeloid progenitors, C/EBPalpha:c-Jun or C/EBPalpha:c-Fos LZE:LZK heterodimers induce monocyte lineage commitment with markedly increased potency compared with C/EBPalpha or c-Jun homodimers or c-Jun:c-Fos heterodimers, demonstrating a positive functional consequence of C/EBP:AP-1 bZIP subfamily interaction. C/EBPalpha:cJun binds and activates the endogenous PU.1 promoter, providing one mechanism for induction of monopoiesis by this complex.
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PMID:C/EBP alpha:AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBP alpha homodimers or AP-1. 1802 36

Transcription factor c-Jun affects neuronal cell death and survival in mammalian brain. As general anesthetics, such as ketamine and propofol, are thought to provide some degree of neuroprotection, this study was intended to test whether the protection of injured neuronal PC12 cells by ketamine and propofol is related to the inhibition of phospho-c-Jun. Using neuronal PC12 cells from rat pheochromocytoma cells differentiated with nerve growth factor, we found that 24 hours of exposure to glutamate (1 to 100 mM) induced concentration-dependent cell death as determined by an ability to reduce the tetrazolium derivative, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) into a blue formazan salt. Neuronal PC12 cells were exposed to ketamine (0.1, 1.0 mM) or propofol (0.5, 5.0 microM) and glutamate (0, 20 mM) for 24 hours. Cell injury was assessed using MTT, in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling, and c-Jun activity assay. Glutamate, 20 mM, induced about 70% of cell death as determined by MTT and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. Glutamate-induced cell death was related to an increase in expression of phospho-c-Jun. Glutamate-induced cell death was reduced by ketamine (0.1, 1.0 mM) in a dose-dependent manner and also by propofol (0.5, 5.0 microM). In addition, the expression of phospho-c-Jun was substantially reduced by ketamine (0.1, 1.0 mM) and propofol (0.5, 5.0 microM), respectively, as determined by Western blot assay. These results suggest that inhibition of c-Jun activity is involved in the neuroprotective effects of ketamine and propofol on glutamate-induced injury in neuronal PC12 cells.
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PMID:Glutamate-induced c-Jun expression in neuronal PC12 cells: the effects of ketamine and propofol. 1836 74

Despite the marked advances in research on insulin resistance (IR) in humans and animal models of insulin resistance, the mechanisms underlying high salt-induced insulin resistance remain unclear. Insulin resistance is a multifactorial disease with both genetic and environmental factors (such as high salt) involved in its pathogenesis. High salt triggers insulin resistance in genetically susceptible patients and animal models of insulin resistance. One of the mechanisms by which high salt might precipitate insulin resistance is through its ability to enhance an oxidative stress-induced inflammatory response that disrupts the insulin signaling pathway. The aim of this hypothesis is to discuss two complementary approaches to find out how high salt might interact with genetic defects along the insulin signaling and inflammatory pathways to predispose to insulin resistance in a genetically susceptible model of insulin resistance. The first approach will consist of examining variations in genes involved in the insulin signaling pathway in the Dahl S rat (an animal model of insulin resistance and salt-sensitivity) and the Dahl R rat (an animal model of insulin sensitivity and salt-resistance), and the putative cellular mechanisms responsible for the development of insulin resistance. The second approach will consist of studying the over-expressed genes along the inflammatory pathway whose respective activation might be predictive of high salt-induced insulin resistance in Dahl S rats. Variations in genes encoding the insulin receptor substrates -1 and/or -2 (IRS-1, -2) and/or genes encoding the glucose transporter (GLUTs) proteins have been found in patients with insulin resistance. To better understand the combined contribution of excessive salt and genetic defects to the etiology of the disease, it is essential to investigate the following question:Question 1: Do variations in genes encoding the IRS -1 and -2 and/or genes encoding the GLUTs proteins predict high salt-induced insulin resistance in Dahl S rats?A significant amount of evidence suggested that salt-induced oxidative stress might predict an inflammatory response that upregulates mediators of inflammation such as the nuclear factor- kappa B (NF-kappa B), the tumor necrosis factor-alpha (TNF-alpha) and the c-Jun Terminal Kinase (JNK). These inflammatory mediators disrupt the insulin signaling pathway and predispose to insulin resistance. Therefore, the following question will be thoroughly investigated:Question 2: Do variations in genes encoding the NF-kappa B, the TNF-alpha and the JNK, independently or in synergy, predict an enhanced inflammatory response and subsequent insulin resistance in Dahl S rats in excessive salt environment?Finally, to better understand the combined role of these variations on glucose metabolism, the following question will be addressed:Question 3: What are the functional consequences of gene variations on the rate of glucose delivery, the rate of glucose transport and the rate of glucose phosphorylation in Dahl S rats?The general hypothesis is that "high-salt diet in combination with defects in candidate genes along the insulin signaling and inflammatory pathways predicts susceptibility to high salt-induced insulin resistance in Dahl S rats".
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PMID:Important genetic checkpoints for insulin resistance in salt-sensitive (S) Dahl rats. 1857 Jun 70

Sphingomyelinases (SMases) hydrolyze membrane sphingomyelin to ceramide and are expressed by diverse host and microbial cell types populating mucosal surfaces. Exogenous bacterial SMase acts on the basolateral membrane of polarized human intestinal epithelial cells to repress the cAMP-induced Cl(-) secretory response, but how this occurs is unknown. We show here that SMase acts by down-regulating a cAMP-gated basolateral membrane K(+) conductance. Neither phosphocholine, ceramide-1-phosphate, nor sphingosine-1-phosphate recapitulates this effect, indicating that ceramide production is the decisive factor. Basolaterally applied SMase induced the phosphorylation of c-Jun NH(2)-terminal kinase (JNK), and inhibition of JNK rescued the effect of SMase on cAMP-dependant secretion. SMase secreted by normal human fibroblasts specifically recapitulated the effect on cAMP-induced Cl(-) secretion, indicating that cell types inhabiting the subepithelial space can provide such an activity to the basolateral membrane of intestinal enterocytes in trans. Thus, conversion of sphingomyelin to ceramide in basolateral membranes of intestinal cells rapidly activates JNK to inhibit a cAMP-gated K(+) conductance and thereby attenuates Cl(-) secretion. These results define a novel lipid-mediated pathway for regulation of salt and water homeostasis at mucosal surfaces.
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PMID:Ceramide activates JNK to inhibit a cAMP-gated K+ conductance and Cl- secretion in intestinal epithelia. 1882 34

In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-kappaB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-beta), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in deoxycorticosterone acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, heme arginate against histopathological lesions in DOCA-hypertension. Treatment with heme arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 +/- 0.12 vs. 3.19 +/- 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 +/- 0.62 vs. 4.39 +/- 0.63; n = 16, P < 0.01), left ventricular mass (2.48 +/- 0.14 vs. 2.01 +/- 0.09 g/kg body wt; n = 16, P < 0.01) and left-ventricular wall thickness (2.82 +/- 0.16 vs. 1.98 +/- 0.14 mm; n = 16, P < 0.01), whereas the HO inhibitor, chromium mesoporphyrin, exacerbated hypertrophy and cardiac lesions. The suppression of cardiac hypertrophy was accompanied by a robust increase in HO-1, HO activity, cyclic guanosine monophosphate (cGMP), ferritin and the total antioxidant capacity, whereas 8-isoprostane, NF-kappaB, JNK, AP-1, TGF-beta, fibronectin and collagen-I were significantly abated. Correspondingly, histopathological parameters that depict progressive cardiac damage, including fibrosis, interstitial/perivascular collagen deposition, scarring, muscle-fiber thickness, muscular hypertrophy and coronary-arteriolar thickening were abated. Our study suggests that upregulating the HO system lowers blood pressure, potentiates the antioxidant status in tissues, suppresses oxidative stress/mediators such as NF-kappaB, AP-1 and cJNK, and suppresses the mobilization of ECM proteins like TGF-beta, collagen and fibronectin, with corresponding reduction of cardiac histopathological lesion and hypertrophy.
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PMID:Heme arginate suppresses cardiac lesions and hypertrophy in deoxycorticosterone acetate-salt hypertension. 1942 56

The dimer formed by the ATF-2 and c-Jun transcription factors is one of the main components of the human interferon-beta enhanceosome. Although these two transcription factors are able to form two homodimers and one heterodimer, it is mainly the heterodimer that participates in the formation of this enhanceosome, binding specifically to the positive regulatory domain IV (PRDIV) site of the enhancer DNA. To understand this surprising advantage of the heterodimer, we investigated the association of these transcription factors using fragments containing the basic DNA-recognition segment and the basic leucine zipper domain (bZIP). It was found that the probability of forming the hetero-bZIP significantly exceeds the probability of forming homo-bZIPs, and that the hetero-bZIP interacts more strongly with the PRDIV site of the interferon-beta enhancer, especially in the orientation that places the folded ATF-2 basic segment in the upstream half of this asymmetric site. The effect of salt on the formation of the ATF-2/c-Jun dimer and on its ability to bind the target PRDIV site showed that electrostatic interactions between the charged groups of these proteins and with DNA play an essential role in the formation of the asymmetric ATF-2/c-Jun/PRDIV complex.
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PMID:Stability and DNA-binding ability of the bZIP dimers formed by the ATF-2 and c-Jun transcription factors. 1994


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