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)

Adriamycin has a wide variety of biological actions on susceptible cells, several of which may be integrally involved in cytotoxicity. In this paper, we present evidence that one of the alterations in cell function that occurs in the presence of Adriamycin is an elevation in the production of diacylglycerol. The effect is rapid, reaches a peak within 10 min of exposure of Sarcoma 180 cells to Adriamycin, and can thus be classified among the earliest alterations that occur in cells damaged by Adriamycin. Concomitant with the rise in diacylglycerol is an increase in cytosolic protein kinase C activity. Although Adriamycin does not appear to modulate the activity of this enzyme by direct binding, drug-exposed Sarcoma 180 cells have a 56% increase in intrinsic cytosolic protein kinase C (PKC) activity, with no change in the activity of the membrane form. Experiments with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate suggest that the PKC effect is linked to Adriamycin action, since activation of the enzyme by short 12-O-tetradecanoylphorbol-13-acetate exposure enhances Adriamycin's cytotoxicity as well as its ability to provoke DNA damage (measured by alkaline elution). Likewise, down-regulation of PKC by extended 12-O-tetradecanoylphorbol-13-acetate exposure partially protects the cells from Adriamycin-induced cytotoxicity as well as from DNA damage. Thus, the ability of cells to be injured by Adriamycin appears to be correlated with the activity of PKC. Multidrug-resistant subline Sarcoma 180A10 cells have the same total quantity of membrane-recruitable PKC as the sensitive parent Sarcoma 180 cells, as determined by [3H]phorbol-12,13-dibutyrate binding. However, the resistant cells have a significantly higher intrinsic PKC activity and an altered ability to translocate the enzyme to the cell surface. Taken together, the results raise the possibility that cell signaling mechanisms, particularly those involving protein kinase C, may play an important role in mediating the biological action of the anticancer drug Adriamycin.
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PMID:Protein kinase C in adriamycin action and resistance in mouse sarcoma 180 cells. 281 14

We have examined phosphatidylinositol turnover and C-kinase distribution in a flat cellular ras-resistant cell line (C11) derived from Kirsten murine sarcoma virus (Ki-MSV) transformed NIH/3T3 cells (DT). This cell type has been shown to express high levels of the p21 Ki-ras gene product yet is resistant to the transforming effects of this protein. Our data indicate that C11 cells have reduced levels of total C-kinase activity when compared to NIH/3T3 cells and do not retain the ability to phosphorylate the growth associated 80-kDa C-kinase substrate either in vivo or in vitro. Furthermore, whilst the steady state levels of diacylglycerol and the sum of inositol phosphates are elevated in DT cells, in C11 cells these levels are reduced to an amount equivalent to that seen in NIH/3T3 cells. These data indicate a correlation between a protein kinase C dependent pathway and resistance to transformation by ras.
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PMID:Reduced protein kinase C activity in a ras-resistant cell line derived from Ki-MSV transformed cells. 283 May 75

Both cytoplasmic and membrane-bound protein kinase C activities are increased in: Harvey-Sarcoma Virus, infected thyroid epithelial cells. The cytoplasmic kinase C increase is found in the chromatographic fraction eluted at lower salt concentration (100 mM NaCl-S100), while the more acidic protein fraction eluted at higher salt concentration (35 mM NaCl-S350) is virtually absent. Although the cytoplasmic S100 fraction from the control and ras-virus infected cells display a comparable PBt2 binding activity, they are different in the Ca+2-dependence and the TPA down regulation. In addition, the membranes from the control and ras-virus infected cells are different phosphate acceptors in place of the H1 histones.
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PMID:Protein kinase C activities are increased in rat thyroid epithelial cells expressing v-ras genes. 284 29

The PTH receptor has been cloned and shown to activate both adenylate cyclase and phospholipase C. Evidence exists that both signaling pathways are important for mediating the net physiological effects of this hormone on bone remodeling. We have shown previously that UMR-106 osteoblastic sarcoma cells express two calcium-signaling P2 purinergic receptors, a P2U and a unique P2T receptor. Neither receptor modulates PTH receptor-mediated activation of adenylate cyclase. We now report that stimulation of either P2 receptor will, however, potentiate the magnitude of the calcium signal observed after subsequent addition of human (h) PTH-(1-34) to fluo-3-loaded UMR-106 cells. Results from experiments with staurosporine and phorbol 12-myristate 13-acetate argue against a role for protein kinase C as a mediator of this potentiating effect of P2 receptor ligands. The P2 receptor-mediated intracellular calcium elevation itself cannot account for the potentiating mechanism, because addition of ionomycin will not replicate the effect of P2 receptor ligands on hPTH-(1-34) signaling. Addition of EGTA after exposure to P2 ligands does not prevent the potentiation of hPTH-(1-34), indicating that P2 ligands potentiate the release of intracellular calcium after PTH receptor stimulation. Inositol trisphosphate production is potentiated in response to hPTH-(1-34) after first priming [3H]inositol-labeled cells with a P2 agonist. We conclude that UMR-106 cells express PTH receptors that are capable of activating adenylate cyclase, but may be unable to activate phospholipase C until cells receive a signal as a consequence of P2 receptor activation. The nature of the signal is unclear, but appears not to be mediated by either calcium or protein kinase C.
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PMID:P2 purinergic receptors potentiate parathyroid hormone receptor-mediated increases in intracellular calcium and inositol trisphosphate in UMR-106 rat osteoblasts. 766 69

We investigated the role of reactive oxygen intermediates and protein kinase C in the induction of expression of the c-jun gene in human ML-2 leukemic cells and normal human DET-551 fibroblasts by comparing the effects of exposure to either ionizing radiation or H2O2 in the presence or absence of appropriate inhibitors. In these cell types, the radiation- and H2O2-mediated increase in c-jun mRNA levels could be prevented by pretreatment of the cells with N-acetylcysteine, an antioxidant, or H7, an inhibitor of protein kinase C and protein kinase A, but not by HA1004, a specific inhibitor of protein kinase A and G. These results suggest a role for protein kinase C and reactive oxygen intermediates in the induction of c-jun gene expression in both normal and tumor cells. We also investigated potential differences in c-jun gene expression induced by radiation or H2O2 in normal and tumor cells by examining steady-state c-jun mRNA levels in a number of human fibroblast, leukemia, melanoma, sarcoma and carcinoma cell types. We observed heterogeneity in the steady-state level of c-jun mRNA in both the untreated normal and tumor cells and in such cells exposed to ionizing radiation or to H2O2. Exposure to radiation produced a varied response which ranged from little or no induction to an increase in the steady-state level of the c-jun mRNA of more than two orders of magnitude. Exposure to H2O2 gave a pattern similar to that of ionizing radiation. The basis for the differential induction in response to these agents may be attributable to either cell lineage or genetic heterogeneity or a combination of these two parameters.
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PMID:Heterogeneity in c-jun gene expression in normal and malignant cells exposed to either ionizing radiation or hydrogen peroxide. 772 34

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and mRNA levels were significantly reduced in FRTL-5 cells transformed with the Kirsten-Moloney sarcoma virus (KiMol); these cells have lost thyrotropin dependence and express high levels of p21ras. FRTL-5 cells, transformed with a temperature-sensitive mutant of the v-K-ras oncogene (Ats cells: 33 degrees C, permissive; 39 degrees C, nonpermissive), showed significant reduction of HMG-CoA reductase expression when exposed to 33 degrees C. In KiMol cells, as well as in Ats cells at 33 degrees C, the transcription driven by cAMP-responsive element was probed by measuring chloramphenicol acetyl transferase (CAT) levels after transfection with a chimeric plasmid containing the reporter gene linked to the rat reductase promoter. Basal CAT activity in KiMol cells transfected with wild-type promoter was lower than in FRTL-5 cells but was increased by forskolin to the levels attained in thyrotropin-stimulated FRTL-5 cells. Forskolin failed to increase CAT activity in KiMol cells transfected with the plasmid harboring a reductase promoter in which the cAMP-responsive element octamer was mutated to a nonpalindromic sequence. The effect of v-K-ras could be mimicked in FRTL-5 cells by tetradecanoyl phorbol acetate and reverted in KiMol and Ats cells, expressing active Ras protein, by increasing intracellular cAMP and/or by protein kinase C inhibition. The data are consistent with the contention that v-K-ras, through protein kinase C and depletion of intracellular cAMP, is inhibitory for the protein kinase A pathway. This is the first demonstration that active v-K-ras down-regulates HMG-CoA reductase expression.
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PMID:Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in FRTL-5 cells. II. Down-regulation by v-K-ras oncogene. 779 8

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse fibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-receptors results in receptor dimerization and subsequent activation of tyrosine kinase activity in the cytoplasmic protein domain, autophosphorylation of the receptor being the first event in the transduction cascade. Before the ligand-receptor complex is internalized and degraded, receptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphorylation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentration of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited by the PDGF-receptor association are phosphatidylinositol-3'-kinase, ras-GTPase-activating protein, phospholipase C-gamma, serine-threonine kinase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear factors such as c-fos and c-myc genes and dephosphorylation of c-jun occurs, V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studied as a model system for the autocrine stimulation of the PDGF receptor.
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PMID:Platelet derived growth factor/tyrosine kinase receptor mediated proliferation. 822 Jan 10

Interleukin-6 (IL-6) activation of the immediate-early gene junB has been shown to require both a tyrosine kinase and an unknown 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7)-sensitive pathway. Here we report the identification and characterization of an IL-6 immediate-early response element in the junB promoter (designated JRE-IL6) in HepG2 cells. The JRE-IL6 element, located at -149 to -124, contains two DNA motifs, an Ets-binding site (EBS) (CAGGAAGC) and a CRE-like site (TGACGCGA). Functional studies using variously mutated JRE-IL6 elements showed that both motifs were necessary and sufficient for IL-6 response of the promoter. The EBS of the JRE-IL6 element (JEBS) appears to bind a protein in the Ets family or a related protein which could also form a major complex with the EBSs of the murine sarcoma virus long terminal repeat or human T-cell leukemia virus type 1 long terminal repeat. The CRE-like site appears to weakly bind multiple CREB-ATF family proteins. Despite the similarity in the structure between the JRE-IL6 element and the polyomavirus enhancer PyPEA3, composed of an EBS and an AP1-binding site and known to be activated by a variety of oncogene signals, JRE-IL6 could not be activated by activated Ha-Ras, Raf-1, or 12-O-tetradecanoylphorbol-13-acetate. We show that IL-6 activates JRE-IL6 through an H7-sensitive pathway that does not involve protein kinase C, cyclic AMP-dependent kinase, Ca(2+)- or calmodulin-dependent kinases, Ras, Raf-1, or NF-IL6 (C/EBP beta). The combination of JEBS and the CRE-like site appears to form the basis for the selective and efficient response of JRE-IL6 to IL-6 signals, but not to signals generated by activated Ha-Ras, Raf-1, or protein kinase C.
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PMID:Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. 838 18

In this report we describe the time-dependent effects of PIXY321 (a synthetic hybrid cytokine) treatment (500 and 750 micrograms/m2/day for 14 days) on six sarcoma patients. Blood was taken prior to PIXY321 injection (day 0), on days 1, 7, and 14 of treatment, and 7 days posttreatment (day 21). The number of isolated monocytes quadrupuled by day 7 and sustained a significant increase through day 14. There were significant increases in the percentage of circulating monocytes relative to total mononuclear cells on days 1 and 7 of therapy. There were no significant changes in monocyte cell surface antigens (15 checked), suggesting that the increase in monocyte numbers was not due to increased numbers of immature monocytes. The basal activity of the monocytes was not markedly altered during treatment; however, they were primed for significantly increased phorbol 12,13-dibutyrate-stimulated superoxide anion production and endotoxin-stimulated release of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) on days of 1 and 7 of therapy. There was a significant increase of IL-1 beta mRNA levels (unstimulated cells) on days 1 and 7, but TNF-alpha mRNA levels increased significantly on day 1 only. Consistent with the increase in superoxide anion production, there were increases in monocyte protein kinase C (PKC) levels on all days of therapy. There was a significant increase in PKCII beta mRNA only on the first day of treatment. All significant changes in monocyte number and function produced by PIXY321 infusion were reversible, as there were no sustained effects on day 21 (7 days after therapy). These results indicate that the effects of PIXY321 may be mediated through up-regulation of PKC resulting in monocytes primed for increased functional activity in response to an appropriate second stimulus.
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PMID:The in vivo effects of PIXY321 therapy on human monocyte activity. 839 Oct 53

Cells transformed by Kirsten murine sarcoma virus (Ki-MSV) have basal adenylate cyclase activity (AC) higher than control cells and comparable level of forskolin-stimulated AC activity. Moreover, a higher protein kinase C (PKC) activity was found to be present in the transformed cells. The molecular mechanism underlying the increase of AC activity was investigated. Our findings strongly suggest that this biochemical event is due to a marked decrease of the alpha i negative control of the enzyme, even though the alpha i of transformed cells appears to possess fully functional domains interacting with both the effector enzyme and the agonist-activated receptor.
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PMID:ras oncogene-induced transformation of a rat seminal vesicle epithelial cell line produces a marked increase of adenylate cyclase and protein kinase C activities. 840 95


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