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: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the years, the vascular protective role of apolipoprotein (apo) E has been attributed to the ability of apoE to induce cholesterol efflux from macrophage foam cells and its transport of extrahepatic cholesterol to the liver for excretion out of the body. Recently, apoE has been shown to protect against vascular disease by additional mechanisms that are independent of its cholesterol transport functions. This review summarizes data demonstrating apoE binding to specific cell surface receptors and proteoglycans in smooth muscle cells triggers distinct signalling pathways that result in inhibition of cell migration, proliferation, and excessive extracellular matrix deposition. apoE binding to the low density lipoprotein receptor-related protein is responsible for inhibition of cell migration, due to the induction of cyclic AMP accumulation and protein kinase A activation. apoE inhibition of cell proliferation is mediated by its binding to proteoglycans and the resulting activation of inducible nitric oxide synthase. apoE also inhibits excessive extracellular matrix protein synthesis. The receptor responsible for this latter apoE function remains to be identified.
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PMID:Distinct signaling mechanisms for apoE inhibition of cell migration and proliferation. 1563 9

The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.
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PMID:Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production. 1574 80

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders. We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration. We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12 cells and other media of apoptotic neuronal cells within 2-6 h of treatment of the cells, and SDM and catalytic domain of recombinant MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and cMMP-3 induced generation of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and interleukin-1 receptor antagonist but not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta1, were induced. SDM and cMMP-3 extensively released TNF-alpha from microglia and activated the nuclear factor-kappaB pathway, and these microglial responses were totally abolished by preincubation with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12 cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a major role in degenerative human brain disorders, such as Parkinson's disease.
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PMID:Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. 1581 1

During spermatogenesis, extensive restructuring of cell junctions takes place in the seminiferous epithelium to facilitate germ cell movement. However, the mechanism that regulates this event remains largely unknown. Recent studies have shown that nitric oxide (NO) likely regulates tight junction (TJ) dynamics in the testis via the cGMP/protein kinase G (cGMP-dependent protein kinase, PRKG) signaling pathway. Due to the proximity of TJ and adherens junctions (AJ) in the testis, in particular at the blood-testis barrier, it is of interest to investigate if NO can affect AJ dynamics. Studies using Sertoli-germ cell cocultures in vitro have shown that the levels of NOS (nitric oxide synthase), cGMP, and PRKG were induced when anchoring junctions were being established. Using an in vivo model in which adult rats were treated with adjudin [a molecule that induces adherens junction disruption, formerly called AF-2364, 1-(2,4-dichlorobenzyl)-IH-indazole-3-carbohydrazide], the event of AJ disruption was also associated with a transient iNOS (inducible nitric oxide synthase, NOS2) induction. Immunohistochemistry has illustrated that NOS2 was intensely accumulated in Sertoli and germ cells in the epithelium during adjudin-induced germ cell loss, with a concomitant accumulation of intracellular cGMP and an induction of PRKG but not cAMP or protein kinase A (cAMP-dependent protein kinase, PRKA). To identify the NOS-mediated downstream signaling partners, coimmunoprecipitation was used to demonstrate that NOS2 and eNOS (endothelial nitric oxide synthase, NOS3) were structurally associated with the N-cadherin (CDH2)/beta-catenin (CATNB)/actin complex but not the nectin-3 (poliovirus receptor-related 3, PVRL 3)/afadin (myeloid/lymphoid or mixed lineage-leukemia tranlocation to 4 homolog, MLLT4) nor the integrin beta1 (ITB1)-mediated protein complexes, illustrating the spatial vicinity of NOS with selected AJ-protein complexes. Interestingly, CDH2 and CATNB were shown to dissociate from NOS during the adjudin-mediated AJ disruption, implicating the CDH2/CATNB protein complex is the likely downstream target of the NO signaling. Furthermore, PRKG, the downstream signaling protein of NOS, was shown to interact with CATNB in the rat testis. Perhaps the most important of all, pretreatment of testes with KT5823, a specific PRKG inhibitor, can indeed delay the adjudin-induced germ cell loss, further validating NOS/NO regulates Sertoli-germ cell AJ dynamics via the cGMP/PRKG pathway. These results illustrate that the CDH2/CATNB-mediated adhesion function in the testis is regulated, at least in part, via the NOS/cGMP/PRKG/CATNB pathway.
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PMID:Regulation of Sertoli-germ cell adherens junction dynamics in the testis via the nitric oxide synthase (NOS)/cGMP/protein kinase G (PRKG)/beta-catenin (CATNB) signaling pathway: an in vitro and in vivo study. 1585 15

Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350-400 g) were anesthetised using Nembutal (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1 (bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation.
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PMID:Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation. 1588 74

Renal interstitial fibrosis is believed to play a key role in the development of diabetic nephropathy (DN), and advanced glycation end-products (AGE) may contribute importantly to this. Recent reports have shown that nitric oxide (NO) is closely linked to the renal interstitial fibrosis of DN. In this study, the mechanisms by which NO and its downstream signals mediate the AGE-induced proliferative response in normal rat kidney fibroblasts (NRK-49F) are examined. AGE decreased NO production, cyclic guanosine 5'monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation time- and dose-dependently. These effects were not observed when cells were treated with nonglycated BSA. NO and inducible nitric oxide synthase (iNOS) stimulated by NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and PKG activator 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) prevented both AGE-induced proliferation and Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) activation but not p42/p44 mitogen-activated protein kinase (MAPK) activation. The ability of NO-PKG to inhibit AGE-induced cell cycle progression was verified by the observation that SNAP, SNP, and 8-pCPT-cGMP inhibited both cyclin D1 and cdk4 activation. Furthermore, induction of NO-PKG significantly increased p21Waf1/Cip1 expression in AGE-treated NRK-49F cells. The data suggest that the NO-PKG pathway inhibits AGE-induced proliferation by suppressing activation of JAK2-STAT5 and cyclin D1/cdk4 and induction of p21Waf1/Cip1.
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PMID:Effect of nitric oxide-cGMP-dependent protein kinase activation on advanced glycation end-product-induced proliferation in renal fibroblasts. 1595 24

In this study, we provide evidence that the double-stranded RNA-dependent protein kinase (PKR) is not required for virus-induced expression of inducible nitric oxide synthase (iNOS) or the activation of specific signaling pathways in macrophages. The infection of RAW264.7 cells with encephalomyocarditis virus (EMCV) induces iNOS expression and nitric oxide production, which are unaffected by a dominant-negative mutant of PKR. EMCV infection also activates the mitogen-activated protein kinase, cyclic AMP response element binding protein, and nuclear factor kappaB (NF-kappaB) signaling cascades at 15 to 30 min postinfection in PKR+/+ and PKR-/- macrophages. Activation of these signaling cascades does not temporally correlate with PKR activity or the accumulation of EMCV RNA, suggesting that an interaction between a structural component of the virion and the cell surface may activate macrophages. Consistent with this hypothesis, empty EMCV capsids induced comparable levels of iNOS expression, nitrite production, and activation of these signaling cascades to those induced by intact virions. These findings support the hypothesis that virion-host cell interactions are primary mediators of the PKR-independent activation of signaling pathways that participate in the macrophage antiviral response of inflammatory gene expression.
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PMID:Encephalomyocarditis virus induces PKR-independent mitogen-activated protein kinase activation in macrophages. 1605 16

Catecholamines can suppress production of inflammatory mediators in different cell types, including airway epithelium, but downstream signaling mechanisms involved in regulation of these antiinflammatory effects are largely unknown. We theorized that acute beta2-adrenergic stimulation of airway epithelial cells with albuterol could suppress the production and release of inflammatory mediators, specifically granulocyte macrophage-colony stimulating factor (GM-CSF) via a pathway involving inducible nitric oxide synthase (iNOS). Normal human bronchial epithelial (NHBE) cells in primary culture were exposed to a cytokine mixture (10 ng/ml each IFN-gamma and IL-1beta) to induce iNOS expression. (R)- and (S)-enantiomers of albuterol, as well as racemic mixtures, were added with these cytokines, and effects on GM-CSF expression and production were assessed. Specific inhibitors and activators of protein kinases (PKs), beta2-adrenergic receptor antagonists, and small interfering RNAs against iNOS were used to delineate signaling pathways involved. iNOS message was significantly upregulated in a concentration-dependent manner by the active (R)-enantiomer of albuterol. (R)-albuterol also attenuated cytokine-induced increases in GM-CSF steady-state mRNA expression and protein release. The (S)-enantomer of albuterol had no effect on these parameters. PKC, specifically, the delta isoform, was required for iNOS message increase, but PKA and PKG were not involved in the pathway. Overall, this study identifies a novel pathway by which beta2-adrenergic agonists may exhibit antiinflammatory effects in airway epithelium and surrounding milieu.
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PMID:(R)-albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS. 1619 34

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. HMG-CoA reductase inhibitors (statins) possess several anti-inflammatory mechanisms and may be beneficial in the treatment of inflammatory diseases. Our previous study has shown that statins can inhibit iNOS gene expression in murine RAW264.7 macrophages. In this study, we showed that lovastatin, fluvastatin, atorvastatin, simvastatin, mevastatin and pravastatin are able to upregulate the mRNA expression of HO-1 gene. This effect of lovastatin was attenuated by farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), a protein kinase G (PKG) inhibitor (KT5823), a soluble guanylyl cyclase inhibitor (ODQ), a p38 MAPK inhibitor (SB203580), and MEK inhibitors (U0126 and PD98059), but not by inhibitors of protein kinase C (PKC), protein kinase A (PKA), c-jun N-terminal kinase (JNK) and Rho kinase. Consistent with this notion, our previous study has reported the ability of statins to activate ERK and p38 MAPK in RAW264.7 macrophages. Here we further found the participation of cyclic guanosine monophosphate (cGMP)/PKG pathway for ERK activation in cells stimulated with statin and the ability of statin to induce AP-1 activity, which is an essential transcription factor in the regulation of HO-1 gene expression. In addition, a Ras inhibitor (manumycin A) treatment also caused a marked induction of HO-1 mRNA followed by a corresponding increase in HO-1 protein; instead, inhibition of Rho activity by toxin B only led to a transient and weak induction of HO-1. The involvement of signal pathways in manumycin A-induced HO-1 gene expression was associated with p38 MAPK, JNK and ERK activation. Taken together, these results demonstrate for the first time that statins might activate PKG to elicit activations of ERK and p38 MAPK pathways and finally induce HO-1 gene expression, which provides a novel anti-inflammatory mechanism in the therapeutic validity.
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PMID:HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways. 1621 41

Nitric oxide (NO) production by astrocytes is a significant factor affecting brain physiology and pathology, but the mechanism by which it is regulated is not known. Previous studies using different specimens and stimuli might have described different aspects of a complex system. We investigated the effect of culture and stimulus conditions on NO production by cultured astrocytes and identified two combinations of these allowing NO production. Lipopolysaccharide (LPS)-induced NO production required a high seeding cell density and was independent of the serum concentration, whereas that induced by proinflammatory cytokines required simultaneous treatment with interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma and low-serum conditions but was less affected by the seeding density. These two pathways showed differential sensitivity to protein kinase inhibitors. Both LPS and cytokines induced expression of inducible nitric oxide synthase (iNOS). Although LPS-induced iNOS expression required a high seeding cell density, cytokine-induced iNOS expression, in contrast to NO production, was not affected by the serum concentration. These results suggest that astrocytes interact with the environment and alter their responsiveness to NO production-inducing stimuli by regulating iNOS expression and activity. This is the first evidence for the selective use of two different regulatory pathways in any cell type.
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PMID:Lipopolysaccharide and proinflammatory cytokines require different astrocyte states to induce nitric oxide production. 1624 8


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