Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human promyelocytic leukemia cells (HL-60) were treated with several differentiation inducers, then the changes in the activity of cytosolic protein kinase C (PKC) isoforms were examined by hydroxylapatite chromatography and the species of the isoforms were determined immunologically. In three undifferentiated HL-60 cell lines examined, PKC alpha and beta isoforms were present, but PKC gamma isoform was not detected. When the cells were induced by dimethylsulfoxide, dibutyryl cAMP, or nicotinamide to differentiate into granulocytes, these two PKC isoforms each increased to about 2- to 3-fold. When retinoic acid was used as the inducer, in addition to PKC alpha and beta, a third PKC isoform appeared. This isoform was clearly distinct from rat PKC alpha, beta, and gamma, immunologically. This isoform showed a distinctly lower Ca(2+)-requirement (3 microM) than that of PKC alpha or beta (100 microM) and was more dependent on cardiolipin and phosphatidylethanolamine, compared with PKC alpha, beta, and gamma. These results suggest that while the increases in the activities of PKC alpha and beta isoforms are common in the differentiation program initiated by several inducers, including retinoic acid, the emergence of an unclassified PKC isoform is a retinoic acid-specific process.
 ...
PMID:Retinoic acid-specific induction of a protein kinase C isoform during differentiation of HL-60 cells. 156 50

Neutrophils produce reactive oxygen species (superoxide anion [O2-]) via activation of reduced nicotinamide dinucleotide phosphate oxidase. In the intact neutrophil, this enzyme can be activated by increases in cytosolic calcium, protein kinase C, and unsaturated fatty acids such as arachidonic acid, all of which are produced on stimulation by chemotactic peptides like N-formyl-methionyl-leucyl-phenylalanine. Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) do not stimulate the respiratory burst but instead prime the cell for an enhanced response by an appropriate stimulus. We examined the role and potential mechanisms of free fatty acids in stimulating or priming neutrophil O2- production. Except for arachidonic acid, the ability of an unsaturated fatty acid to stimulate O2- production was not correlated with its critical micellar concentration, suggesting that detergent action was not the primary mechanism. Eicosatetraynoic acid, which blocks further arachidonate metabolism by the 5- and 15-lipoxygenases, inhibited O2- production by arachidonic acid. However, eicosatetraenoic acid did not inhibit other unsaturated fatty acid or phorbol ester-induced O2- production, suggesting that the effects of arachidonic acid were mediated at least in part by a metabolite. The same negatively charged, unsaturated fatty acids that directly stimulated O2- production when used in micromolar concentrations also primed neutrophils when added in nanomolar concentrations. The amount of a priming response was independent of chain length or number of double bonds. The magnitude of priming observed in GM-CSF-treated cells could be reconstituted with combinations of arachidonic acid and its lipoxygenase products.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Unsaturated fatty acids and lipoxygenase products regulate phagocytic NADPH oxidase activity by a nondetergent mechanism. 194 May 76

Effects of Ebselen and its analogs (PZ-25, NAT06-123, NAT02-761, NAT02-801, NAT06-099, and NAT06-513) on superoxide anion (O2-) production induced by tetradecanoyl phorbol acetate (TPA) were examined in intact guinea pig polymorphonuclear leukocytes (PMNL). Four compounds having a structure of 1,2 benzoisoselenazol-3-(2H) one (Ebselen, NAT06-123, and NAT02-761) and its sulfur-substituted analog (PZ-25), had a potent inhibitory effect on O2- production as compared with others. Ebselen and NAT06-123 also markedly inhibited nicotinamide adenine dinuclestide phosphate (NADPH) oxidase activity, which is responsible for O2- production in intact cells, and in a particulate fraction prepared from TPA-stimulated PMNL, whereas PZ-25 inhibited this enzyme weakly and NAT02-761 did not. On the other hand, Ebselen and PZ-25 had the same degree of potent inhibitory effect on protein kinase C which was involved in the regulation of NADPH oxidase activation. Thus, it is plausible that inhibition of O2- production in intact PMNL by these compounds were due not only to direct inhibition of NADPH oxidase but also to inhibition of protein kinase C.
 ...
PMID:Mechanism for the inhibitory effect of a seleno-organic compound, Ebselen, and its analogues on superoxide anion production in guinea pig polymorphonuclear leukocytes. 196 95

Phorbol ester-induced promotion of initiated NMRI mouse skin keratinocytes to papillomas could be largely prevented when nicotinamide-like inhibitors of poly(ADP-ribose)polymerase (nicotinamide, benzamide, 3-aminobenzamide) were applied simultaneously with 12-O-tetradecanoylphorbol-13-acetate (TPA). A similar suppression of tumor promotion by nicotinamide analogues was demonstrated in clone 41 JB6 epidermal cells which are promotable by TPA to anchorage-independent growth. The antipromotion effect of nicotinamide analogues, however, does not appear to come about by an inhibition of poly(ADP-ribose)polymerase. Acid analogues of nicotinamide, such as benzoic acid or 3-aminobenzoic acid which do not inhibit the polymerase, showed antipromotion activity similar to that of their corresponding amides. It could also be ruled out that these antipromoters mediate their effect on keratinocytes by a cytostatic action, by scavenging the promoter TPA in a chemical reaction, or by inhibiting protein kinase C. In initiated mouse skin, nicotinamide analogues strongly suppressed TPA-induced accumulation of inflammatory cells and vascular permeability, while epidermal hyperplasia was not significantly affected.
 ...
PMID:Nicotinamide and nicotinamide analogues as antitumor promoters in mouse skin. 213 6

Cocaine and its derivatives blunted responses of neutrophils (cell/cell aggregation, up-regulation of the receptor for C3bi (CR3, CD11b/CD18), generation of superoxide anion (O2-) and degranulation to various stimuli. The order of potency of these agents was the same as that for local anesthesia: tetracaine greater than bupivacaine greater than cocaine greater than lidocaine. Neutrophil aggregation elicited by the chemoattractant FMLP (10(-7) M) was inhibited by cocaine (10 mM) to 13.6 +/- 6% of control (p less than 0.002); the IC50 was approximately 4 mM. Cocaine and the other local anesthetics not only inhibited the upregulation of CR3 and O2- generation, but also blocked degranulation of cytochalasin B-treated cells. Cocaine (10 mM) reduced beta-glucuronidase and lysozyme secretion to 4.3 +/- 0.7 and 13 +/- 2.2% controls, respectively; its IC50 was 4 mM. Local anesthetics added after ligand/receptor engagement (FMLP) interrupted aggregation and halted generation of O2-. Moreover, local anesthetics rapidly inhibited aggregation, O2- generation, and degranulation elicited by PMA (1 microgram/ml) or the Ca ionophore A23187 (10 microM): the effects of cocaine could therefore not be attributed to unique actions at the FMLP receptor. Peak levels of intracellular Ca2+ ([Ca]i) at 5 to 10 s, and levels of [Ca]i 120 s after FMLP in Fura 2-loaded cells were significantly lower in cells treated with lidocaine, findings that could be explained by enhanced 45Ca2+ efflux from neutrophils. In cells loaded with bis(carboxyethyl)carboxyfluorescine (pH indicator) local anesthetics failed to affect the initial FMLP-induced (0 to 15 s) drop of pHi but inhibited the later (120 s) realkalinization of the cytosol (lidocaine, bupivacaine). Most remarkably, autoradiographs of SDS gels prepared from stimulated, 32P-labeled neutrophils treated with local anesthetics showed no difference from resting cells, either with respect to patterns of phosphorylation and dephosphorylation or their kinetics. Labeling of a 47-kDa protein, a component of the reduced nicotinamide-adenine dinucleotide phosphate-oxidase system, was unchanged. The effects of local anesthetics, which blunt neutrophil responses without affecting protein phosphorylation, suggest that protein phosphorylation is an insufficient signal for neutrophil activation. Inasmuch as cocaine and its derivatives affect cell functions at sites distal to activation of protein kinase C, these agents should prove useful in uncoupling protein phosphorylation from functional responses.
 ...
PMID:Cocaine and its derivatives blunt neutrophil functions without influencing phosphorylation of a 47-kilodalton component of the reduced nicotinamide-adenine dinucleotide phosphate oxidase. 216 79

Cultured human epidermal keratinocytes were used as a model system for testing compounds with potential therapeutic effect against hyperproliferative skin disorders. We have investigated whether each test compound caused direct damage to the DNA or inhibited DNA repair and/or seminconservative replication of DNA, as well as its effect on the overall rate of protein synthesis and on expression of specific keratin genes. The following compounds were studied: (a) inhibitors of DNA polymerase alpha [aphidicolin and its derivative aphidicolin glycine], (b) inhibitors of topoisomerases [novobiocin, nalidixic acid, teniposide, etoposide, and 4'-(9-acridylamine) methanesulfon-m-anisidide], (c) modifiers of chromatin structure [sodium butyrate, 3-aminobenzamide, and nicotinamide], (d) inhibitors of calmodulin activation and protein kinase C [chlorpromazine and trifluoperazine]; and (e) drugs used in clinical dermatology [anthralin, fluocinolone acetonide, ketoconazole, and hydroxyurea]. The compounds were tested at concentrations at which they were known from the literature to be effective in their respective actions. Among the groups of compounds studied, the topoisomerase inhibitors were particularly interesting since they caused no detectable damage to DNA but exhibited maximal inhibitory effect on replication combined with minimal inhibition of DNA repair. In addition most of the topoisomerase inhibitors, particularly novobiocin, changed the pattern of gene expression by inhibiting the synthesis of certain keratins and inducing a Mr 67,000 protein in the prekeratin fraction. These properties combined with minimal systemic side effects may encourage the clinical exploration of some topoisomerase inhibitors for antiproliferative therapy of skin disorders.
 ...
PMID:Comparative effects of growth inhibitors on DNA replication, DNA repair, and protein synthesis in human epidermal keratinocytes. 242 88

A 47-kilodalton neutrophil cytosol factor (NCF-47k), required for activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase superoxide (O2-.) production, is absent in most patients with autosomal recessive chronic granulomatous disease (AR-CGD). NCF-47k cDNAs were cloned from an expression library. The largest clone predicted a 41.9-kD protein that contained an arginine and serine-rich COOH-terminal domain with potential protein kinase C phosphorylation sites. A 33-amino acid segment of NCF-47k shared 49% identity with ras p21 guanosine triphosphatase activating protein. Recombinant NCF-47k restored O2-. -producing activity to AR-CGD neutrophil cytosol in a cell-free assay. Production of active recombinant NCF-47k will enable functional regions of this molecule to be mapped.
 ...
PMID:Recombinant 47-kilodalton cytosol factor restores NADPH oxidase in chronic granulomatous disease. 254 47

The mechanism of human interleukin (IL)-1 beta-mediated cytolysis was studied in a human melanoma cell line, A375.6. Purified recombinant human IL-1 beta produced 50% cytocidal activity at 50 pg/ml. A variety of compounds were tested for their ability to interfere with A375.6 lysis. Compounds were added simultaneously with IL-1 beta (100 pg/ml), and tumor cytolysis was measured after 72 hr of culture by release of 125I from DNA of A375.6 cells labeled with [125I]-dUrd. A variety of anti-inflammatory/immunosuppressive agents (including auranofin, chloroquine, cyclosporin A, d-penicillamine) and several cyclooxygenase/lipoxygenase inhibitors (AA-861, BW755c, and indomethacin) lacked protective activity. Similarly, phospholipase inhibitors (mepacrine and 4-bromophenacyl bromide), putrescine, inhibitors of lysosomal activity (chloroquine and NH4Cl), calcium channel blockers (nifedipine and verapamil), calmodulin inhibitors (W-7 and calmidazolium), and inhibitors of ADP ribosylation (nicotinamide and 3-aminobenzamide) were inactive. In contrast, corticosteroids (dexamethasone, hydrocortisone, and paramethasone acetate), tilorone, and protein kinase C inhibitors (1-[5-isoquinolinyl-sulfonyl]-2-methylpiperazine and staurosporine) significantly inhibited IL-1 beta-mediated A375.6 cytolysis. These compounds also interfered with tumor necrosis factor-mediated lysis of A375.6, suggesting common mechanisms of tumor cytotoxicity by these monokines. This model may be useful for delineating intracellular biochemical events integral to IL-1 action.
 ...
PMID:Potent inhibition of interleukin 1 beta-mediated human melanoma (A375.6) lysis by corticosteroids, staurosporine, and tilorone. 262 25

The mammalian cerebellum is built around an array of parasagittal bands of Purkinje cells that can be demonstrated by immunocytochemical staining for the differentiation antigen zebrin II. Climbing and mossy fiber afferents also terminate in bands, and the afferent terminal fields and the Purkinje cell bands are aligned. The convergence of mossy and climbing fiber pathways onto the Purkinje cells, which are the sole output of the cerebellar cortex, is a characteristic feature of cerebellar circuitry. Previous studies showed that when both afferent pathways are activated synchronously there develops a long-term depression of synaptic efficacy at the parallel fiber-Purkinje cell synapse. Two second messenger pathways mediate long-term depression: one involves diacylglycerol and protein kinase C, and the other involves nitric oxide that is generated by a nitric oxide synthase. We have studied the distribution of nitric oxide synthase in the adult mouse cerebellum by using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. NADPH-diaphorase activity is found mainly in the granule and basket cells. Within the granular layer NADPH-diaphorase activity is expressed nonuniformly by patches of granular cells and synaptic glomeruli. The patches are seen in all lobules, are reproducible from individual to individual, and are topographically ordered with respect to the Purkinje cell compartments as revealed by using anti-zebrin II immunocytochemistry. These data imply that nitric oxide-dependent, long-term depression may only involve a subset of mossy fiber/granule cell projections, and that one role for nitric oxide may be to refine cerebellar receptive fields.
 ...
PMID:Compartmentation of NADPH-diaphorase activity in the mouse cerebellar cortex. 752 60

1. In RAW 264.7 macrophages, lipopolysaccharide (LPS) and gamma-interferon (IFN gamma) alone or in combination stimulated the induction of nitric oxide synthase (iNOS) activity and increased the expression of the 130 kDa isoform of NOS. 2. LPS-induced NOS activity was reduced by incubation with CD14 neutralising antibodies and abolished in macrophages deprived of serum. 3. LPS stimulated a small increase in protein kinase C (PKC) activity in RAW 264.7 macrophages which was dependent on the presence of serum. However, IFN gamma did not potentiate LPS-stimulated PKC activity. 4. The protein kinase C inhibitor, Ro-318220, abolished both LPS- and IFN gamma-stimulated protein kinase C activity and the induction of NOS activity. 5. LPS- and IFN gamma-induced NOS activity was reduced by the tyrosine kinase inhibitor genestein. Genestein also reduced LPS-stimulated protein kinase C activity but did not affect the response to the protein kinase C activator, tetradecanoylphorbol acetate (TPA). 6. Nicotinamide, an inhibitor of poly-ADP ribosylation, abolished LPS- and IFN gamma-induced NOS activity. 7. Brefeldin A, an inhibitor of a factor which stimulates nucleotide exchange activity on the 21 kDa ADP-ribosylation factor, ARF, reduced LPS- and IFN gamma-induced NOS activity by approximately 80%. 8. These results suggest the involvement of protein kinase C, tyrosine kinase and poly-ADP ribosylation pathways in the regulation of the induction of nitric oxide synthase in RAW 264.7 macrophages by LPS and IFN gamma.
 ...
PMID:Protein kinase C and tyrosine kinase pathways regulate lipopolysaccharide-induced nitric oxide synthase activity in RAW 264.7 murine macrophages. 753 21


1 2 3 4 5 6 7 8 9 10 Next >>