Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Osmotic shock is well recognized as one of the factors activating stress-activated protein kinases (SAPKs), p38 MAP kinase and c-Jun N-terminal kinases (JNKs). In renal epithelial A6 cells, hypo-osmotic shock transiently activated SAPKs with maximal activation at 5 min. A6 cells showed a regulatory volume decrease (RVD) after swelling when the cells were exposed to a hypo-osmotic solution. In contrast, activation of SAPKs was maintained over 90 min after hypo-osmotic shock in the presence of 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, a Cl(-) channel blocker), which completely blocked the RVD and kept the cells continuously swelling. Exposure of the cells to a high K(+) iso-osmotic solution containing nystatin, which induces continuous cell swelling, also continuously activated SAPKs. Furthermore, membrane deformation induced by chlorpromazine activated SAPKs. These results suggest that changes in membrane tension by cell swelling or chlorpromazine, but not osmolality, are important steps for activation of SAPKs in A6 cells.
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PMID:Cell swelling activates stress-activated protein kinases, p38 MAP kinase and JNK, in renal epithelial A6 cells. 1060 May 38

The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration of macrophage functions. The aim of this study was to investigate whether ANP influences production of TNF-alpha. TNF-alpha production in murine bone marrow-derived macrophages was induced by LPS, and TNF-alpha secretion (+/-ANP) was determined by L929 bioassay. ANP dose dependently (10-8-10-6 M) inhibited TNF-alpha release by up to 95%. The effect was mediated via the guanylate cyclase-coupled A receptor, as was shown by employing dibutyryl-cGMP, the cGMP-inhibitory compound Ly-83583, and the A receptor antagonist HS-142-1. A specific ligand of the natriuretic peptide "clearance" receptor inhibited TNF-alpha production only at 10-7 and 10-8 M, but not at 10-6 M. The B receptor ligand C-type natriuretic peptide showed no TNF-alpha-inhibitory effect. To investigate the underlying mechanism of ANP-mediated TNF-alpha inhibition, Northern blot was performed. ANP-treated macrophages displayed decreased TNF-alpha-mRNA levels. Besides the known inhibition of NF-kappaB activation, in this study we demonstrated that ANP also attenuates the activation of the proinflammatory transcription factor AP-1 (gel shift assay). ANP did not alter subunit composition of AP-1 complexes, as was shown by supershift assays applying anti-c-jun and anti-c-fos Abs. To get information on the ANP effect for human inflammatory processes, we investigated cytokine production in human LPS-activated blood. ANP significantly attenuated production of TNF-alpha and IL-1beta without affecting production of IL-10 and IL-1ra. In summary, ANP was shown to attenuate TNF-alpha production of LPS-activated macrophages via cGMP. The inhibition is suggested to involve transcriptional processes that are the result of reduced activation of responsible transcription factors.
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PMID:cGMP-mediated inhibition of TNF-alpha production by the atrial natriuretic peptide in murine macrophages. 1086 Oct 50

Activation of brain natriuretic peptide (BNP) gene promoter activity represents one of the earliest and most reliable markers of ventricular cardiac myocyte hypertrophy. We recently demonstrated that mechanical strain increases immunoreactive BNP secretion, steady-state BNP mRNA levels and BNP gene transcriptional activity in neonatal rat myocyte cultures. We have also shown that strain-dependent BNP gene transcription is critically dependent on the functional integrity of a number of integrins (specfically beta1, beta3, and alpha(v)beta5 integrins) present on the surface of cardiac myocytes. When used alone, each of these antibodies resulted in a significant reduction in strain-dependent activation of a transfected hBNP-luciferase reporter and inhibition of a number of signaling pathways that have been linked to stimulation of this reporter (e.g., extracellular signal regulated kinase and c-Jun amino terminal kinase). The present study shows that combinations of these antibodies resulted in further reductions in hBNP gene promoter activity and inhibition of the relevant signaling cascades. These studies provide further support for the importance of integrin-matrix interactions in promoting strain-dependent changes in cardiac myocyte gene transcription.
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PMID:Signaling mechanisms underlying strain-dependent brain natriuretic peptide gene transcription. 1155 72

In the inner medullary collecting duct of the terminal nephron, the type A natriuretic peptide receptor (NPR-A) plays a major role in determining urinary sodium content. This nephron segment, by virtue of its medullary location, is subject to very high levels of extracellular tonicity. We have examined the ability of medium tonicity to regulate the activity and expression of this receptor in cultured rat inner medullary collecting duct cells. We found that NaCl (75 mm) and sucrose (150 mm), but not urea (150 mm), increased natriuretic peptide receptor activity, gene expression, and promoter activity. The osmotic stimulus also activated extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK). In the latter instance the beta isoform was selectively activated. Inhibition of p38 MAPK with SB203580 blocked the osmotic induction of receptor activity and expression, as well as receptor gene promoter activity, whereas inhibition of ERK with PD98059 had no effect. Cotransfection of p38 beta MAPK together with the receptor gene promoter resulted in amplification of the osmotic stimulation of the latter, whereas cotransfection of dominant negative MKK6, but not dominant-negative MEK, completely blocked the osmotic induction of receptor promoter activity. Collectively, the data indicate that extracellular osmolality stimulates receptor activity and receptor gene expression through a specific p38 beta-dependent mechanism, raising the possibility that changes in medullary tonicity could play an important role in the regulation of renal sodium handling in the terminal nephron.
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PMID:Osmoregulation of natriuretic peptide receptor signaling in inner medullary collecting duct. A requirement for p38 MAPK. 1174 37

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 micromol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours, P<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of (3)H-phenylalanine (1.4-fold by ET and 1.5-fold by PE, P<0.01), cell size (2.3-fold and 2.5-fold, P<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold, P<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold, P<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of (3)H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.
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PMID:Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine. 1179 83

The expression of cardiac hormones, atrial natriuretic peptide and B-type natriuretic peptide, is induced by cardiac wall stretch and responds to various hypertrophic agonists such as endothelin-1. In cardiac myocytes, endothelin-1 induces GATA-4 binding to the B-type natriuretic peptide gene, but the signaling pathways involved in endothelin-1-induced GATA-4 activation are unknown. Mitogen-activated protein kinase pathways are stimulated in response to various extracellular stimuli, and they modulate the function of several transcription activators. Here we show that inhibition of p38 kinase with SB203580 inhibited endothelin-1-induced GATA-4 binding to B-type natriuretic peptide gene and serine phosphorylation of GATA-4. Inhibition of extracellular signal-regulated protein kinase with MEK1 inhibitor PD98059 reduced basal and p38-induced GATA-4 binding activity, but it had no significant effect on endothelin-1-induced GATA-4 binding activity. Overexpression of p38 kinase pathway, but not extracellular signal-regulated kinase or c-Jun N-terminal protein kinase, activated GATA-4 binding to B-type natriuretic peptide gene and induced rat B-type natriuretic peptide promoter activity via proximal GATA binding sites. In conclusion, these findings demonstrate that activation of p38 kinase is necessary for hypertrophic agonist-induced GATA-4 binding to B-type natriuretic peptide gene and sufficient for GATA-dependent B-type natriuretic peptide gene expression.
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PMID:Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. 1182 58

The zinc finger transcription factor GATA-4 has been implicated as a critical regulator of inducible cardiac gene expression and as a potential mediator of the hypertrophic program. However, the precise intracellular mechanisms that regulate the DNA-binding activity of GATA-4 are not fully understood. The aim of the present study was to examine the role of mitogen-activated protein kinases (p38 kinase, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase) in the left ventricular wall stress-induced activation of GATA-4 DNA binding in adult heart. Isolated perfused rat hearts were subjected to increased left ventricular wall stress by inflating a balloon in the ventricle. Gel mobility shift assays were used to analyze the transacting factors that interact with the GATA motifs of the B-type natriuretic peptide promoter. The left ventricular wall stress rapidly activated GATA-4 DNA binding and significantly increased the levels of phosphorylated p38 kinase, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase. The wall stress-induced increase in the DNA-binding activity of GATA-4 was abolished both in the presence of the p38 inhibitor SB239063 and MEK1/2 inhibitor U0126. In contrast, the inhibition of c-Jun N-terminal protein kinase by CEP11004 had no effect on the baseline or stretch-induced GATA-4 DNA binding. Moreover, GATA-4 DNA binding was up-regulated by mechanical stretch in the isolated rat atria via p38 and extracellular signal-regulated protein kinase. In conclusion, the present study demonstrates that both p38 and extracellular signal-regulated protein kinase are required for the stretch-induced GATA-4 binding in intact heart.
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PMID:Mitogen-activated protein kinases p38 and ERK 1/2 mediate the wall stress-induced activation of GATA-4 binding in adult heart. 1505 23

Cardiac activator protein-1 (AP-1), composed of c-Jun, is significantly activated by hypertension or angiotensin II (AngII). This study was undertaken to elucidate whether c-Jun could be the potential target for treatment of cardiac hypertrophy. We constructed recombinant adenovirus carrying dominant-negative mutant of c-Jun (Ad.DN-c-Jun). Using catheter-based technique of adenoviral gene transfer, we achieved global myocardial transduction of DN-c-Jun in rats, to specifically inhibit cardiac AP-1. (1) AngII (200 ng/kg/min) infusion in rats caused cardiac hypertrophy, increased cardiac p70S6 kinase activity by 1.3-fold (P<0.05) and enhanced the gene expression of cardiac hypertrophic markers. Ad.DN-c-Jun, which was transferred to the heart 2 days before AngII infusion, prevented cardiac hypertrophy (P<0.01), decreased p70S6 kinase phosphorylation (P<0.05), and suppressed cardiac gene expression of brain natriuretic peptide, collagen I, III, and IV, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) (P<0.01). (2) In genetically hypertensive rats with cardiac hypertrophy, cardiac gene transfer of Ad.DN-c-Jun, without affecting hypertension, regressed cardiac hypertrophy (P<0.05), and suppressed p70S6 kinase phosphorylation by 20% (P<0.05) and suppressed the enhanced expression of collagen I, III, and IV, MCP-1 and PAI-1. These results provided the first evidence that in vivo blockade of cardiac c-Jun inhibits pathologic cardiac hypertrophy.
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PMID:Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension. 1625 94

Cell swelling is associated with the activation of an increase in the osmosensitive taurine release (OTR) rate, which serves to decrease cell volume as part of a process known as regulatory volume decrease. OTR, which is sensitive to many pharmacological agents including anion channel blockers and signalling pathway modulators, has also been suggested to play a role in cell cycle progression. At non-cytotoxic concentrations, the anion channel blocker NPPB (25 microM), the extra-cellular signal-regulated kinase inhibitor PD98059 (50 microM), and the c-Jun NH2-terminal kinase inhibitor SP 600125 (5 microM) each decreased the OTR rate by > or =50%, decreased cell proliferation, and increased G0/G1 cell cycle arrest.
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PMID:Inhibition of ERK and JNK decreases both osmosensitive taurine release and cell proliferation in glioma cells. 1756 64

Azaspiracids (AZAs) are a group of marine toxins recently described that currently includes 20 members. Not much is known about their mechanism of action, although the predominant analog in nature, AZA-1 targets several organs in vivo, including the central nervous system, and exhibits high neurotoxicity in vitro. AZA distribution is increasing globally with mussels being most widely implicated in AZA-related food poisoning events, with human poisoning by AZAs emerging as an increasing worldwide problem in recent years. We used pharmacological tools to inhibit the cytotoxic effect of the toxin in primary cultured neurons. Several targets for AZA-induced neurotoxicity were evaluated. AZA-1 elicited a concentration-dependent hyperpolarization in cerebellar granule cells of 2-3 days in vitro; however, it did not modify membrane potential in mature neurons. Furthermore, in immature cells, AZA-1 decreased the membrane depolarization evoked by exposure of the neurons to 50mM K(+). Preincubation of the neurons with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid (SITS), 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), amiloride, or ouabain before addition of AZA-1 decreased the AZA-1-induced neurotoxicity and the increase in phosphorylated c-Jun-N-terminal kinase (JNK) caused by the toxin, indicating that disruption in ion fluxes was involved in the neurotoxic effect of AZA-1. Furthermore, short exposures of cultured neurons to AZA-1 caused a significant decrease in neuronal volume that was reverted by preincubation of the neurons with DIDS or amiloride before addition of the toxin. The results presented here indicate that the JNK activation induced by AZA-1 is secondary to the decrease in cellular volume elicited by the toxin.
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PMID:Cell volume decrease as a link between azaspiracid-induced cytotoxicity and c-Jun-N-terminal kinase activation in cultured neurons. 2020 Feb 14


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