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)

Dexamethasone stimulated 15-PGDH activity in HEL cells in a time and concentration dependent manner. Increase in 15-PGDH activity by dexamethasone was found to be accompanied by an increase in enzyme synthesis as revealed by Western blot and [35S]methionine labeling studies. In addition to dexamethasone, other anti-inflammatory steroids also increased 15-PGDH activity in the order of their glucocorticoid activity. Among sex steroids only progesterone increased significantly 15-PGDH activity. 12-0-Tetradecanoylphorbol-13-acetate (TPA) also induced the synthesis of 15-PGDH but inhibited the enzyme activity. It appears that TPA caused a time dependent inactivation of 15-PGDH by a protein kinase C mediated mechanism.
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PMID:Regulation of synthesis and activity of NAD(+)-dependent 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) by dexamethasone and phorbol ester in human erythroleukemia (HEL) cells. 205 13

We have studied factors controlling message levels for the neuronal growth- and plasticity-associated protein, GAP-43. Following exposure of PC12 cells to various effectors, cytoplasmic RNA was isolated and analyzed by Northern transfer and autoradiography using a GAP-43 cDNA probe. Induction by NGF is apparent after 3 hr exposure and reaches maximal levels at 24 hr. Beyond 24 hr, levels remain constant in the continued presence of NGF. Induction is insensitive to variations in culture conditions, such as plating density or substrate, which influence NGF-induced neurite outgrowth. Other inducers, in order of decreasing efficacy, are FGF, dBcAMP, TPA, K+, and EGF. Insulin and retinoic acid are ineffective. Dexamethasone partially inhibited basal expression as well as induction by NGF, FGF, dBcAMP, and TPA. The methyltransferase inhibitor 5'-S-(2-methyl-propyl)adenosine completely inhibited induction by NGF, FGF, and dBcAMP. Inhibition of protein synthesis by cycloheximide partially decreased induction by NGF, FGF, and TPA but slightly enhanced dBcAMP induction. Complete down-regulation of protein kinase C by chronic TPA treatment completely eliminated the TPA response but slightly enhanced induction by NGF. These findings and the results of additivity experiments in which cells were stimulated with various combinations of NGF, dBcAMP and TPA suggest that NGF induction of GAP-43 RNA (1) does not involve activation of protein kinase C but (2) may be mediated partially via activation of protein kinase A.
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PMID:Factors influencing GAP-43 gene expression in PC12 pheochromocytoma cells. 213 63

Dexamethasone treatment of the Jurkat T77 cell clone inhibited the enhancing effect of 12-O-tetradecanoylporbol-13-acetate (TPA) and the calcium ionophore A23187 on the interleukin 2 (IL2) mRNA levels and gene transcription from intact nuclei. Dexamethasone treatment of Jurkat T77 cells inhibited the TPA/A23187-dependent activation of the transcription from the transfected pIL2CAT, containing 600 base pairs of the genomic sequences upstream of the coding region of IL2 gene, including the TPA/calcium responsive cis-regulatory elements and promoter sequences, driving the expression of the chloramphenicol acetyltransferase (CAT) gene. Transfection of either Jurkat T77 cell clone or glucocorticoid-resistant Jurkat cells with a human glucocorticoid receptor cDNA under the transcriptional control of the Rous sarcoma virus long terminal repeat (LTR) (pRShGR alpha) significantly increased or induced, respectively, the dexamethasone-mediated inhibition of the TPA/A23187-dependent expression of pIL2-CAT as well as the enhancing effect on the expression of the cotransfected CAT gene under the control of the mouse mammary tumor virus LTR, as a marker of glucocorticoid receptor action. This suggests a role for the glucocorticoid receptor in mediating the dexamethasone action on IL2 gene expression. To study the cis-regulatory sequence specificity of the dexamethasone-induced interference with the TPA/A23187-mediated T cell activating signals, we studied the effect of the hormone on the regulatory elements contained in the Rous sarcoma virus and human T lymphotropic virus 1 long terminal repeats and the SV40 promoter, which are known to be transcriptionally enhanced by those activating agents. Dexamethasone was unable to interfere with the TPA/A23187-mediated enhancement of these cis-regulatory elements, suggesting that the hormone effect is specific for IL-2 gene sequences. Our data suggest that the dexamethasone-mediated transcriptional inhibition of the IL2 gene is mediated by an interference with the protein kinase C and calcium-mediated trans-activation of the antigen-responsive and T cell-specific elements lying in the 5'-flanking region of the gene.
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PMID:Transcriptional regulation of the interleukin 2 gene by glucocorticoid hormones. Role of steroid receptor and antigen-responsive 5'-flanking sequences. 215 67

Activated macrophages kill several types of tumor cells in vitro, whereas non-activated macrophages lack this capacity. We, however, observed that non-activated macrophages efficiently kill F9 teratocarcinoma as well as other teratocarcinoma cell lines. Dexamethasone, a glucocorticoid known to prevent macrophage activation, did not perturb the killing of F9 teratocarcinoma cells. Neither tumor necrosis factor alpha, nor the reactive oxygen intermediates, i.e. hydrogen peroxide, superoxide anion, and hydroxyl radical, nor serine proteases participated in this killing, shown by employing various agents which interfere with their production, secretion, or function. Using acridine orange/ethidium bromide vitality staining, the F9 teratocarcinoma cells were shown to be phagocytized alive by macrophages and subsequently killed intracellularly. Intact lysosomal function is required for the killing of F9 cells, as the lysosomotropic drugs chloroquine and ammonium chloride markedly inhibited this killing without perturbing their engulfment. The signal transduction pathway induced in the macrophages upon interaction with F9 teratocarcinoma cells seems to differ from that induced by macrophage activation. Neither the protein kinase C inhibitors polymyxin B and H-7 [1-(5-isoquinolinylsulfonyl)-2-methyl piperazine] nor the protein kinase C activator phorbol 12-myristate-13-acetate affected the killing of F9 cells. However, chlorpromazine (a powerful inhibitor of calmodulin), dibutyryl cAMP (a cAMP analog), and prostaglandin E2 inhibited the macrophage-mediated killing of F9 cells. In vivo studies indicate that an increased number of macrophages at the F9 tumor inoculation site (the peritoneal cavity) as a result of elicitation by thioglycollate prevents F9 tumor development. Our findings indicate that non-activated macrophages kill teratocarcinoma cells using a mechanism which differs from that employed by activated macrophages in the killing of other tumor cells.
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PMID:Engulfment and intracellular killing of F9 teratocarcinoma cells by non-activated murine macrophages. 227 89

Glucocorticoids inhibit superoxide (O2-) generation by phagocytes through a mechanism that remains unclear. We investigated this effect by using dexamethasone on guinea pig alveolar macrophages. O2- generation was induced either by the calcium ionophore A23187, a potent stimulus of phospholipase A2, or by the protein kinase C activator, phorbol myristate acetate (PMA). Dexamethasone inhibited O2- generation initiated by A23187 by 50-55%. This inhibition required: (a) more than 45 min incubation and was maximal after 2 h; (b) glucocorticoid receptor occupancy; and (c) protein synthesis. The inhibitory effect of dexamethasone could not be explained by an interaction with the respiratory burst enzyme NADPH oxidase since O2- generation was only weakly affected upon PMA stimulation. Lipocortin I, a glucocorticoid inducible and phospholipase A2 inhibitory protein, inhibited O2- generation initiated by A23187 but failed to modulate the respiratory burst activated by PMA. These results were obtained with lipocortin I purified from mouse lungs, human blood mononuclear cells, and with human recombinant lipocortin I. We propose that lipocortin I is capable of inhibiting the activation of NADPH oxidase only when membrane signal transduction involves phospholipase A2. By mimicking the effect of dexamethasone, lipocortin I may extend its potential anti-inflammatory action to the partial control of the formation of oxygen reactive species by phagocytes.
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PMID:Inhibition of O2- generation by dexamethasone is mimicked by lipocortin I in alveolar macrophages. 254 78

We investigated the positive and negative effects of IFN-gamma, PMA, dibutyryl cAMP (Bt2cAMP), dexamethasone and transforming growth factor-beta (TGF-beta) on Fc gamma R subtype expression and phagocytosis of a human monoblast cell line, U937. IFN-gamma increased and Bt2cAMP decreased Fc gamma RI expression determined by a mAb 32.2, whereas PMA and Bt2cAMP increased Fc gamma RII expression determined by a mAb IV-3. Phagocytosis was measured microscopically by counting ingested aggregated human IgG- or BSA-treated ox E (Eo'-IgG or Eo'-BSA). IFN-gamma increased the phagocytosis of Eo'-IgG but not that of Eo'-BSA, and PMA increased the phagocytosis of both Eo'-IgG and Eo'-BSA. Bt2cAMP decreased both basal and IFN-gamma- and PMA-augmented phagocytosis of U937 cells. Dexamethasone also inhibited both basal and IFN-gamma-augmented Fc gamma RI expression and PMA-augmented Fc gamma RII expression and phagocytosis, but did not affect IFN-gamma-augmented phagocytosis of Eo'-IgG. The augmentation of phagocytosis of Eo'-IgG by IFN-gamma thus seems to be due mainly to the increased internalizing process rather than to increased Fc gamma RI expression. TGF-beta slightly decreased Fc gamma R expression. In a study of the participation of protein kinase C (PK-C), it was found that H-7, a PK-C inhibitor, did not inhibit either IFN-gamma- or PMA-enhanced Fc gamma RI and Fc gamma RII expression, respectively, and 1-oleoyl-2-acetylglycerol and N-(6-phenylhexyl)-5-chloro-1-naphthalenesulfonamide, both PK-C activators, did not show any apparent increase in Fc gamma R expression and phagocytosis. These results show that Fc gamma RI and Fc gamma RII expression on U937 cells is regulated by different mechanisms and that IFN-gamma and PMA play their roles in Fc gamma R expression and phagocytosis by different pathways. It is possible that cAMP but not PK-C plays an important role in the regulation of Fc gamma R expression and phagocytosis.
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PMID:Regulation of Fc gamma receptor expression and phagocytosis of a human monoblast cell line U937. Participation of cAMP and protein kinase C in the effects of IFN-gamma and phorbol ester. 255 78

The transcription of the insulin genes in rat pancreatic islets was determined in response to dexamethasone, cholera toxin and Ca2+. Furthermore, the contents of islet insulin mRNA after culture with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (TPA) were assayed by dot-blot analysis. Dexamethasone and cholera toxin stimulated the rates of insulin gene transcription, whereas the withdrawal of Ca2+ and addition of TPA exerted no effects on insulin gene expression. It is concluded that islet cAMP may be one factor regulating the transcription of the insulin gene in response to nutrient secretagogues, whereas Ca2+ and activation of protein kinase C do not serve such a function.
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PMID:Regulation of insulin gene expression by dexamethasone, Ca2+ and a phorbol ester. 307 61

The effect of aniso-osmotic exposure on the level of inducible cyclooxygenase (Cox-2) and on prostanoid synthesis was studied in cultured rat liver macrophages (Kupffer cells). In lipopolysaccharide (LPS)- or phorbol 12-myristate 13-acetate-stimulated Kupffer cells, hyperosmotic (355 mosmol/l) exposure, due to addition of NaCl or impermeant sugars, markedly increased prostaglandin (PG) E2, D2 and thromboxane B2 synthesis in a time- and osmolarity-dependent manner. Increased prostanoid production was observed about 8 h after exposure to LPS in hyperosmotic medium compared to Kupffer cells treated with LPS under normotonic (305 mosmol/l) conditions. A similar stimulatory effect of hyperosmolarity on PGE2 production was also seen when arachidonate was added exogenously. Hyperosmotic stimulation of PGE2 production was accompanied by a strong induction of Cox-2 mRNA levels and an increase in immunoreactive Cox-2, whereas the levels of immunoreactive phospholipase A2 and cyclooxygenase-1 did not change significantly. Dexamethasone, indomethacin and the selective Cox-2 inhibitor, NS-398, abolished the hypertonicity-induced stimulation of PGE2 formation; dexamethasone also prevented the increase in Cox-2 mRNA and protein. The increase of immunoreactive Cox-2 lasted for about 24 h and was also blocked by actinomycin D or cycloheximide, but not by brefeldin A. Tunicamycin or treatment with endoglucosidase H reduced the molecular mass of hypertonicity-induced Cox-2 by 5 kDa. Tunicamycin treatment also suppressed the hypertonicity-induced stimulation of PGE2 production. The hyperosmolarity/LPS-induced stimulation of prostaglandin formation was partly sensitive to protein kinase C inhibition but was not accompanied by an increase in the cytosolic free Ca2+ concentration. The data suggest that osmolarity may be a critical factor in the regulation of Cox-2 expression and prostanoid production in activated rat liver macrophages.
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PMID:Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages. 749 3

Hepatocyte growth factor (HGF) is a multifunctional cytokine with mitogenic, motogenic, morphogenic, and tumor-suppressing activities. Despite the broad spectrum of its biological activities, HGF is most likely the physiological hepatotrophic factor that triggers or modulates liver regeneration. Regulatory mechanisms for HGF production are crucial for understanding the control of liver regeneration. We previously reported that HGF production by human skin fibroblasts is stimulated by a protein kinase C (PKC)-mediated pathway. We determined here whether gene expression and production of HGF in human skin fibroblasts can be induced via activation of a cAMP-mediated pathway. HGF secretion by the cells was markedly stimulated by the cAMP-elevating agents, forskolin, cholera toxin, prostaglandin E2 (PGE2), and 3-isobutyl-1-methylxanthine, as well as by the membrane-permeable cAMP analogues, 8-bromo-cAMP and dibutyryl cAMP. The dose-response curves of induction of HGF secretion by cholera toxin and forskolin were nearly parallel with those of the intracellular cAMP levels. HGF mRNA levels did not significantly increase at 5 and 10 h, but increased considerably 15 h or more after the addition of cholera toxin. Forskolin, 8-bromo-cAMP, and PGE2 also caused appreciable up-regulation of HGF gene expression with a similar time course. Although human skin fibroblasts of various origins secreted variable amounts of HGF, the cAMP-elevating agents and the cAMP analogues caused a very marked increase in HGF production in all of them. The agents also enhanced highly active HGF secretion by MRC-5 human embryonic lung fibroblasts. Dexamethasone and transforming growth factor-beta 1, which inhibit PKC-mediated HGF secretion, down-regulated HGF mRNA expression and HGF production in the cells treated with the cAMP-elevating agents and the cAMP analogues. These results indicate that HGF expression in human skin fibroblasts is stimulated by activation of a cAMP-mediated pathway.
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PMID:Expression of hepatocyte growth factor is up-regulated through activation of a cAMP-mediated pathway. 750 55

1. The involvement of nitric oxide (NO) in the regulation of angiogenesis was examined in the in vivo system of the chorioallantoic membrane (CAM) of the chick embryo and in the matrigel tube formation assay. 2. Sodium nitroprusside (SNP) (0.37-28 nmol/disc), which releases NO spontaneously, caused a dose-dependent inhibition of angiogenesis in the CAM in vivo and reversed completely the angiogenic effects of alpha-thrombin (6.7 nmol/disc) and the protein kinase C (PKC) activator 4-beta-phorbol-12-myristate-13-acetate (PMA) (0.97 nmol/disc). In addition, SNP (28 x 10(-6) M) stimulated the release of guanosine 3'-5'-cyclic monophosphate (cyclic GMP) from the CAM in vitro. 3. In the matrigel tube formation assay, an in vitro assay of angiogenesis, both SNP (1-3 x 10(-6) M) and the cell permeable cyclic GMP analogue, Br-cGMP (0.3-1.0 x 10(-3) M) reduced tube formation. 4. The inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) (3.8-102 nmol/disc) and NG-nitro-L-arginine methylester (L-NAME) (1.3-34.2 nmol/disc) stimulated angiogenesis in the CAM in vivo, in a dose-dependent fashion. D-NMMA and D-NAME on the other hand had no effect on angiogenesis in this system. 5. L-Arginine (10.9 nmol/disc), although it had a modest antiangiogenic effect by itself, was capable of abolishing the angiogenic effects of L-NMMA (34.2 nmol/disc) and of L-NAME (3.8 nmol/disc). 6. Dexamethasone, an inhibitor of the induction of NO synthase, at 0.2-116.1 nmol/disc, stimulated angiogenesis in the CAM, whereas at 348.4-1161 nmol/disc it inhibited this process. Combination of 38.7 nmol/disc dexamethasone with L-NAME (9.3 nmol/disc) resulted in a potentiation of the angiogenic effect of the former. It appears therefore that both the constitutive and the inducible NO synthase may contribute to the NO-mediated inhibition of angiogenesis. 7. Superoxide dismutase (SOD), which prevents the destruction of NO, at 300 i.u./disc had a modest antiangiogenic effect in the CAM, by itself. In addition, SOD, prevented alpha-thrombin (6.7 nmol/disc) and PMA (0.97 nmol/disc) from stimulating angiogenesis in the CAM.8. These results suggest that NO may be an endogenous antiangiogenic molecule of pathophysiological importance.
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PMID:Evidence that nitric oxide is an endogenous antiangiogenic mediator. 751 30


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