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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plectin is a major intermediate filament (IF)-based cytolinker protein that stabilizes cells and tissues mechanically, regulates actin filament dynamics, and serves as a scaffolding platform for signaling molecules. In this study, we show that plectin deficiency is a cause of aberrant keratin cytoskeleton organization caused by a lack of orthogonal IF cross-linking. Keratin networks in plectin-deficient cells were more susceptible to osmotic shock-induced retraction from peripheral areas, and their okadaic acid-induced disruption (paralleled by stress-activated MAP kinase p38 activation) proceeded faster. Basal activities of the MAP kinase Erk1/2 and of the membrane-associated upstream protein kinases c-Src and PKCdelta were significantly elevated, and increased migration rates, as assessed by in vitro wound-closure assays and time-lapse microscopy, were observed. Forced expression of RACK1, which is the plectin-binding receptor protein for activated PKCdelta, in wild-type keratinocytes elevated their migration potential close to that of plectin-null cells. These data establish a link between cytolinker-controlled cytoarchitecture/scaffolding functions of keratin IFs and specific MAP kinase cascades mediating distinct cellular responses.
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PMID:Plectin-controlled keratin cytoarchitecture affects MAP kinases involved in cellular stress response and migration. 1690 71

In addition to their role in reverse cholesterol transport, high-density lipoproteins (HDL) exert several beneficial effects, including the prevention and correction of endothelial dysfunction. HDL promote endothelium proliferation and diminish endothelial apoptosis; they play a key role in vasorelaxation by increasing the release of nitric oxide and prostacyclin through the induction of the expression and the activity of endothelial nitric oxide synthase and the coupling of cyclooxygenase 2 and prostacyclin synthase. In addition, HDL affect coagulation, fibrinolysis, platelet adhesion, adhesion molecules, and protease expression, and they exert antioxidant activity. These effects are achieved at the gene expression level and are dependent on the activation of several intracellular signaling pathways, including PI3K/Akt, ERK1/2, PKC, and p38MAPK. The complexity of the signaling pathways modulated by HDL reflects the different effects of the components of this class of lipoproteins such as apolipoproteins or lipids on endothelial cell gene expression and the subsequent modulation of endothelial function observed. The in vivo relevance of these findings to endothelial recovery during physiological or pathological conditions remains to be addressed; nevertheless, the results of clinical studies with synthetic HDL, ApoA-I mimetics, and drugs that are becoming available that selectively affect HDL plasma levels and biological functions support the importance of the correction of endothelial function by HDL.
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PMID:Molecular mechanisms responsible for the antiinflammatory and protective effect of HDL on the endothelium. 1731 98

Polymorphonuclear granulocytes (neutrophils) release the reactive oxygen species (ROS) for destruction of pathogens, providing quicker of an organism from infections and own defective of transformed cells. Reactive oxygen species are also potential carcinogens because they facilitate mutagenesis, tumor promotion and progression. Balance between these opposite influences is supported by coordinated interrelations in intracellular signaling systems. Tumor growth influence on the NADPH oxidase in peripheral innate immune cells is unclear. A solid cancer model was developed after an intramuscular injection of Ehrlich carcinoma cells into hind leg of NMRI strain mice. Intensity of the respiratory burst was estimated by luminol-dependent chemiluminescence technique. Transformation of inflammatory reaction was revealed during tumor growth: greater amounts of neutrophils were recruited into peritoneal cavity; sizes of the cells, their nuclei and granules were enlarged; the ratio of different cell types in peritoneal exudation was changed. The study revealed that tumor progression was accompanied by significant changes in functional activity of neutrophils. Dynamic increase in spontaneous level of ROS production and concentration-dependent change of intensity of the respiratory burst induced with chemotactic peptide N-formyl-Met-Leu-Phe (fMLF) was revealed in peripheral neutrophils under tumor growth conditions. It was found that effects of inhibitors of tyrosine protein kinases, protein kinase C, mitogen-activated protein kinase p38MAPK (p38MAPK) and phosphatidylinositol 3-kinase (PI3K) were altered in neutrophils from tumor-bearing mice in comparison with the cells of control mice. This indicates a change in the role of the enzymes in regulation of the neutrophil respiratory burst. Data obtained show that p38MAPK and PI3K entangle up- and down-regulation of NADPH oxidase in peripheral neutrophils during tumor growth.
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PMID:[Dynamic analysis of modification of peripheral neutrophils functional activity and its regulation during tumor growth in vivo]. 1733 59

There is crosstalk in intracellular signaling between Angiotensin II (Ang II) and insulin. We hypothesized that the underlying mechanism might be related to changes in cytoskeleton. In the presence of 100 nM of Ang II, insulin-induced glucose uptake was decreased and insulin-induced actin filament organization was inhibited. PKC inhibitors, including GF109203x and p38MAPK inhibitor (SB203580) neither improved insulin-induced actin reorganization nor glucose uptake. In contrast, the Ang II-induced inhibition of glucose uptake and actin filament disorganization was reversed by 10 micromol ERK 1/2 MAPK inhibitor (PD98059). Pretreatment of Ang II increased ERK1/2 phosphorylation and inhibited insulin-induced Akt phosphorylation. The effect of Ang II on ERK1/2 phosphorylation was blocked by Ang II type 1 receptor antagonists, RNH6270 and PD98059 but not by SB203580 or Guanosine-5'-O-(2-ThioDiphosphate), a G-protein inhibitor. We next tested the effect of broad-spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) on Ang II-inhibition of insulin signaling pathway. GM6001 did not improve Ang II-induced actin filament disorganization and did not inhibit ERK1/2 phosphorylation. From these data in L6 myotube, we conclude that Ang II negatively regulates the insulin signal not through MMP signaling pathway but specifically through MMP-independent ERK1/2 activation pathway, providing an alternative molecular mechanism for angiotensin-induced insulin resistance.
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PMID:Angiotensin II inhibits insulin-induced actin stress fiber formation and glucose uptake via ERK1/2. 1738 10

Normal human epidermal keratinocytes (NHEK) respond to the autocrine activated extracellular signal-regulated kinase (ERK) signaling pathway, which contributes to the survival of keratinocytes. However, during the condition of calcium-induced differentiation, how the autocrine ERK signaling is regulated and affected is poorly understood. The purpose of this study was to understand and to obtain clues to the possible function of the autocrine ERK activation during the calcium-induced differentiation of NHEK. We demonstrated that the autocrine activated ERK was not interrupted by calcium triggering and that it was sustained for at least one day after changing the medium. We also found that the autocrine ERK activation was associated with the expression of cyclin D1 and the cell cycle regulation at the early stage of calcium triggering by treating the cells with the mitogen-activated protein kinase inhibitor PD98059. However, the PD98059 treatment did not have a significant influence on the expression of involucrin and loricrin. In addition, we demonstrated that autocrine ERK activation was associated with protein kinase C and p38MAPK signaling. We suggest that the activation of autocrine ERK is not interrupted by calcium triggering and it might participate in cell growth during the early stage of calcium-induced differentiation in NHEK.
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PMID:Autocrine extracellular signal-regulated kinase activation in normal human keratinocytes is not interrupted by calcium triggering and is involved in the control of cell cycle at the early stage of calcium-induced differentiation. 1744 39

Azaspiracid-1 (AZA-1) is a marine toxin discovered in 1995. Besides damage to several tissues in vivo, AZA-1 has been shown to cause cytotoxicity in a number of cell lines and alterations in actin cytoskeleton and cell morphology. We studied the reversibility of AZA-1-induced morphological changes in human neuroblastoma cells and their dependence on caspases and signaling pathways involved in cytoskeleton regulation. Morphological/cytoskeletal changes were clearly observed by confocal microscopy 24h after the addition of toxin, without recovery upon toxin removal. Interestingly, 2min of incubation with AZA-1 was enough for the cytoskeleton to be altered 24-48h later. The activation of caspases by AZA-1 was studied next using a fluorescent caspase inhibitor. A cell population with activated caspases was observed after 48h of exposure to the toxin, but not at 24h. Two fragments and a stereoisomer of AZA-1 were tested to analyze structure-activity relationship. Only ABCD-epi-AZA-1 was active with a similar effect to AZA-1. Additionally, regarding the involvement of apoptosis/cytoskeleton signaling in AZA-1-induced morphological effects, inhibition of caspases with Z-VAD-FMK did not affect AZA-1-induced cytoskeletal changes, suggesting, together with the activation kinetics, that caspases are not responsible for AZA-1-elicited morphological changes. Modulation of PKA, PKC, PI3K, Erk, p38MAPK, glutathione and microtubules with inhibitors/activators did not inhibit AZA-1-induced actin cytoskeleton rearrangement. The JNK inhibitor SP600125 seemed to slightly diminish AZA-1 effects, however due to the effects of the drug by itself the involvement of JNK in AZA-1 toxicity needs further investigation. The results suggest that AZA-1 binds irreversibly to its cellular target, needing moieties located in the ABCDE and FGHI rings of the molecule. Cytotoxicity of AZA-1 has been previously described without reference to the type of cell death, we report that AZA-1 induces the activation of caspases, commonly used as an early marker of apoptosis, and that these proteases are not responsible for AZA-1-induced cytoskeleton disarragement in human neuroblastoma cells.
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PMID:Irreversible cytoskeletal disarrangement is independent of caspase activation during in vitro azaspiracid toxicity in human neuroblastoma cells. 1748 74

Epidermal cell adhesion depends on the intercellular interactions of transmembrane cadherin glycoproteins, which form the basis of adherens junctions and desmosomes. Pemphigus is a blistering disease of the skin and mucous membranes characterized by autoantibodies against the cell surface desmosomal cadherins, desmoglein (Dsg) 3 and Dsg1. An unanswered question in pemphigus pathophysiology is the mechanism of acantholysis, or loss of keratinocyte cell adhesion. One longstanding theory for pemphigus pathogenesis is the concept of steric hindrance, in which pathogenic pemphigus autoantibodies cause loss of intercellular adhesion by directly interfering with desmosomal cadherin trans-interactions. However, several recent studies have demonstrated that modulation of p38MAPK, Rho family GTPase, c-myc, protein kinase C, and phospholipase C signaling pathways prevents keratinocyte dissociation induced by pemphigus autoantibodies. As it is unlikely that desmosomal signaling would occur only in response to pemphigus autoantibodies, these studies suggest that numerous different signaling molecules may play a role in desmosomal homeostasis. Many of these same signaling pathways regulate classical cadherins in adherens junctions. Given the recent discovery of bidirectional crosstalk between adherens junctions and desmosomes, it would be valuable to understand how signaling pathways implicated in pemphigus pathogenesis may be involved in more general mechanisms of desmosome and adherens junction regulation. In this review, we will summarize the evidence supporting a role for steric hindrance and signaling mechanisms in the pathogenesis of pemphigus acantholysis and discuss potential analogues in the classical cadherin literature.
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PMID:Beyond steric hindrance: the role of adhesion signaling pathways in the pathogenesis of pemphigus. 1757 91

Previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-kappaB) activation and homocysteine (Hcy)-induced cytokines expression in endothelial cells and vascular smooth muscle cells. However, the underlying mechanism remains illusive. In this study, we investigated the effects of Hcy on NF-kappaB-mediated sICAM-1, TNF-alpha production and the possible involvement of ERK(1/2)/p38MAPK pathway. The effects of rosiglitazone intervention were also examined. Our results show that Hcy increased the levels of sICAM-1 and TNF-alpha in cultured human umbilical vein endothelial cells (HUVECs) in a time- and concentration-dependent manner. This effect was significantly depressed by rosiglitazone and different inhibitors (PDTC, NF-kappaB inhibitor; PD98059, MEK inhibitor; SB203580, p38MAPK specific inhibitor; and staurosporine, PKC inhibitor). Next, we investigated the effect of Hcy on ERK(1/2)/p38MAPK pathway and NF-kappaB activity in HUVECs. The results show that Hcy activated both ERK(1/2)/p38MAPK pathway and NF-kappaB-DNA-binding activity. These effects were markedly inhibited by rosiglitazone as well as other inhibitors (SB203580, PD98059, and PDTC). Further, the pretreatment of staurosporine abrogated ERK(1/2)/p38MAPK phosphorylation, suggesting that Hcy-induced ERK(1/2)/p38MAPK activation is associated with PKC activity. Our results provide evidence that Hcy-induced NF-kappaB activation was mediated by activation of ERK(1/2)/p38MAPK pathway involving PKC activity. Rosiglitazone reduces the NF-kappaB-mediated sICAM-1 and TNF-alpha production induced by Hcy via inhibition of ERK(1/2)/p38MAPK pathway.
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PMID:Rosiglitazone attenuates NF-kappaB-dependent ICAM-1 and TNF-alpha production caused by homocysteine via inhibiting ERK1/2/p38MAPK activation. 1758 75

We investigated the mechanism of phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells focusing on the p38 mitogen-activated protein kinase (MAPK)/heat shock protein 27 (Hsp27) pathway. PMA-induced cell migration and activation of p38MAPK in A172 glioblastoma cells. PMA-induced formation of lamellipodia and focal complexes was blocked by inhibiting p38MAPK with SB203580 or small interfering RNA (siRNA). Furthermore, activation of p38MAPK resulted in phosphorylation of an F-actin polymerization regulator, Hsp27. Immunohistochemical analysis showed that upon PMA stimulation, both unphosphorylated and phosphorylated Hsp27 were translocated to the lamellipodia. SB203580 or p38MAPK siRNA blocked these phenomena, indicating that Hsp27 phosphorylation and translocation from cytosol to membrane were mediated by p38MAPK. To address the question of whether endogenous Hsp27 participates in PMA-induced migration, we inhibited the expression of Hsp27 using Hsp27 siRNA. Although knockdown of Hsp27 by siRNA had little effect on p38MAPK activation, lamellipodia and focal complex formation was markedly inhibited. Migration was also abolished in Hsp27 siRNA-transfected cells. In conclusion, p38MAPK activation followed by Hsp27 phosphorylation was required for PMA-induced migration. Furthermore, Hsp27 itself played critical roles in PMA-induced migration. Our data provide substantial evidence for a model elucidating the molecular mechanisms of regulation of actin dynamics and migration by PMA-activated protein kinase C in glioblastoma cells.
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PMID:Phorbol 12-myristate 13-acetate (PMA)-induced migration of glioblastoma cells is mediated via p38MAPK/Hsp27 pathway. 1764 Jun 20

N-acetylaspartic acid (NAA) is converted into aspartate and acetate by aspartoacylase. Abnormal levels of the enzyme leads to accumulation of NAA and these changes have been observed in Canavan disease and type 2 diabetes. How upregulation of NAA affect the gastrointestine protein levels and the function is not known. Incubation of rat stomach tissue with NAA 1.5 mM, 1.5 microM and 1.5 nM induced inflammatory agents TNFalpha, p38MAPK, iNOS, PKC, COX2 and ICAM3; transcription factors phospho-NF-kBp65, cjun and cfos; contractile proteins MLCK and phospho MLC; and calcium channel alpha1C and calcium channel, voltage-dependent, beta 3 subunit compared to their respective control. Incubation of circular smooth muscle cells with the above doses of NAA induced contractility compared to the control. These studies suggest that NAA alters proteins levels and smooth muscle contractility and these changes likely to contribute to gastrointestinal disorder seen in these diseases.
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PMID:Upregulation of N-acetylaspartic acid alters inflammation, transcription and contractile associated protein levels in the stomach and smooth muscle contractility. 1794 58


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