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)

Thrombin is a potent mitogen for mesangial cells and stimulates PDGF B-chain gene expression in these cells. It also activates phospholipase C (PLC) resulting in an increase in cytosolic Ca2+ and diacylglycerol (DAG) that are the physiological activators of protein kinase C (PKC). Immunoprecipitation of specific PKC isotypes from thrombin-stimulated mesangial cells with subsequent measurement of their enzymatic activity shows activation of Ca(2+)-dependent PKC alpha and Ca(2+)-independent PKC zeta in a time dependent manner. Optimum activation of both of these isozymes was obtained at 60 minutes. PKC alpha activity increased 83% over basal while activity of PKC zeta increased 104%. Prolonged exposure of mesangial cells to phorbol myristate acetic acid (PMA) inhibited the enzymatic activity of PKC alpha but not PKC zeta. This inhibition of PKC alpha had no effect on thrombin-induced DNA synthesis but abolished PDGF B-chain gene expression induced by thrombin. These data provide the first evidence that PKC alpha activation is necessary for thrombin-induced PDGF B-chain gene expression but not for thrombin-induced DNA synthesis.
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PMID:PKC alpha regulates thrombin-induced PDGF-B chain gene expression in mesangial cells. 758 54

We have investigated the roles of tyrosine kinase and protein kinase C activity in interleukin-1 beta-induced interleukin-6 production, using the U373 human astrocytoma cell line as a model system for astrocytes. Compounds known to inhibit tyrosine kinases were tested for effects on interleukin-6 production in U373 cells stimulated with interleukin-1 beta. Complete to nearly complete inhibition of interleukin-1 beta-induced interleukin-6 production was observed with the flavonoids genistein and quercetin, the bisindole alkaloids staurosporine and K-252a, or the tyrphostin AG879. Herbimycin A was a potent inhibitor but did not induce complete inhibition at saturating dose. Calphostin C, an inhibitor of protein kinase C, also completely inhibited interleukin-6 production. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate induced interleukin-6 production, and treatment with a combination of this phorbol ester and interleukin-1 produced synergistic stimulation. Prolonged exposure to phorbol ester eliminated subsequent stimulation by phorbol ester but only partially decreased interleukin-1-induced interleukin-6 and had no effect on the activities of selected inhibitors including calphostin C. We conclude that tyrosine kinase activity is essential for interleukin-1-induced interleukin-6 production in U373 astrocytoma cells and that activity of a phorbol ester-insensitive, atypical protein kinase C isozyme may also be involved.
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PMID:Tyrosine kinase activity is essential for interleukin-1 beta--stimulated production of interleukin-6 in U373 human astrocytoma cells. 759 43

We have previously shown that protein phosphorylation plays an important role in the sorting and assembly of tight junctions. We have now examined in detail the role of protein kinases in intercellular junction biogenesis by using a combination of highly specific and broad-spectrum inhibitors that act by independent mechanisms. Our data indicate that protein kinase C (PKC) is required for the proper assembly of tight junctions. Low concentrations of the specific inhibitor of PKC, calphostin C, markedly inhibited development of transepithelial electrical resistance, a functional measure of tight-junction biogenesis. The effect of PKC inhibitors on the development of tight junctions, as measured by resistance, was paralleled by a delay in the sorting of the tight-junction protein, zona occludens 1 (ZO-1), to the tight junction. The assembly of desmosomes and the adherens junction were not detectably affected, as determined by immunocytochemical analysis. In addition, ZO-1 was phosphorylated subsequent to the initiation of cell-cell contact, and treatment with calphostin C prevented approximately 85% of the phosphorylation increase. Furthermore, in vitro measurements indicate that ZO-1 may be a direct target of PKC. Moreover, membrane-associated PKC activity more than doubled during junction assembly, and immunocytochemical analysis revealed a pool of PKC zeta that appeared to colocalize with ZO-1 at the tight junction. A preformed complex containing ZO-1, ZO-2, p130, as well as 330- and 65-kDa phosphoproteins was detected by coimmunoprecipitation in both the presence and absence of cell-cell contact. Identity of the 330- and 65-kDa phosphoproteins remains to be determined, but the 65-kDa protein may be occludin. The mass of this complex and the incorporation of ZO-1 into the Triton X-100-insoluble cytoskeleton were not PKC dependent.
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PMID:Regulated assembly of tight junctions by protein kinase C. 759 83

The redistribution of protein kinase C (PKC) isoforms between the cytosolic and plasma membrane fractions of stimulated human polymorphonuclear leukocytes (PMN) was analysed by means of western blotting with antibodies against PKC beta I, beta II and Zeta. Treatment of PMN with 1 microM formyl-methionyl-leucyl-phenylalanine (fMLP) induced a rapid (5-10 sec) and sustained (at least 10 min) increase in the membrane association of PKC beta I, beta II, and the two immunoreactive proteins (76-81 kDa) recognized by the antibody directed against PKC zeta. Optimal translocation of PKC isoforms to the plasma membrane occurred in the presence of 10(-6) M fMLP and was not associated with a detectable fall in cytosolic PKC. In the absence of external calcium, the translocation of all PKC isoforms induced by fMLP was rapid (5 sec) but the membrane association of PKC was lost within one minute. Unlike fMLP, phorbol myristate acetate (PMA) induced a concentration-dependent translocation of the PKC isoforms, which persisted in the membrane in the absence of external calcium. These data provide the first evidence of redistribution of PKC isoforms by a chemoattractant. They further indicate that external calcium plays a crucial role in the persistence of the membrane association of PKC beta I, beta II and zeta induced by formyl peptides.
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PMID:Redistribution of protein kinase C isoforms in human neutrophils stimulated by formyl peptides and phorbol myristate acetate. 762 81

The spontaneously immortalized human skin keratinocytes HaCaT contain protein kinase C (PKC) alpha, -delta, -epsilon, and -zeta. All PKC isoenzymes except PKC zeta are down-regulated by TPA as well as by bryostatin. However, with PKC delta, bryostatin but not TPA was found to be much less effective at high concentrations than at low ones. PKC delta expression at the protein and mRNA level is significantly suppressed in HaCaT cells I-7 and II-4, which are transfected with mutated c-Ha-ras. The expression of the other isoenzymes remains essentially unchanged in the ras-transfected cells compared to normal ones. PKC delta is lost when growing HaCaT cells in a medium obtained from the cultivation of ras-transfected cells ("ras-conditioned" medium). The factor secreted into the medium by the ras-transfected cells that is responsible for this effect appears to be TGF alpha, since the action of ras-conditioned medium on PKC delta expression can be overcome by the addition of an anti-TGF alpha antibody. Moreover, treatment of HaCaT cells with TGF alpha suppresses selectively the expression of the PKC isoenzyme delta.
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PMID:Loss of protein kinase C delta from human HaCaT keratinocytes upon ras transfection is mediated by TGF alpha. 762 46

Cellular sensitivity to cis-diamminedichloroplatinum(II) (cDDP) can be regulated by protein kinase C (PKC) signal transduction pathway. Activators of PKC were shown to enhance the sensitivity of human ovarian carcinoma 2008 cells to cDDP. We have examined whether or not the PKC signal transduction pathway is affected during development of resistance by tumor cells to cDDP. A 2-fold decrease in PKC activity was observed in cDDP-resistant ovarian carcinoma 2008/C13*5.25 cells compared with the drug-sensitive 2008 cells. Subcellular distribution studies revealed a reduction in both cytosolic and particulate PKC activities in 2008/C13*5.25 cells. The pattern of PKC isoform expression was compared in cDDP-sensitive and -resistant cell lines by Western blot analysis with isoform-specific antibodies to PKC. The parental cells expressed PKC alpha, -epsilon, and -zeta isoforms. The abundance of PKC alpha decreased significantly in 2008/C13*5.25 cells, whereas the amount of PKC epsilon increased moderately in the resistant variant, with no alteration in PKC zeta content. Therefore, a reduction in PKC alpha and/or an increase in PKC epsilon expression may be associated with the drug-resistant phenotype.
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PMID:Comparison of protein kinase C activity and isoform expression in cisplatin-sensitive and -resistant ovarian carcinoma cells. 763 71

The structure of protein kinase C zeta (PKC zeta) is unusual with respect to other PKCs, as it lacks the C2 domain and possesses only one zinc finger region. Consequently, PKC zeta can not be activated by diacylglycerol or phorbol esters and is not downregulated by prolonged treatment by phorbol esters nor blocked by commonly utilized PKC inhibitors. In this study, we have explored the idea that PKC zeta might participate in proliferative pathways. Our findings show that marked overexpression of mammalian PKC zeta does not alter the growth characteristics of NIH 3T3 cells, nor induces cellular transformation. Furthermore, mammalian PKC zeta does not potentiate the transforming ability of oncogenes such as ras, sis and the muscarinic receptor m1. In this context, PKC zeta or its dominant negative mutant do not affect MAP kinase activation by oncogenes or growth factors. Taken together, our findings demonstrate that mammalian PKC zeta does not directly participate in signaling pathways involved in oncogenic transformation.
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PMID:Overexpression of mammalian protein kinase C-zeta does not affect the growth characteristics of NIH 3T3 cells. 763 44

The human parainfluenza virus type 3 P protein is an RNA polymerase subunit involved in both transcription and replication during the life cycle of the virus. Our laboratory has recently shown that the P protein is phosphorylated both in vitro and in vivo by the cellular protein kinase C (PKC) isoform zeta and that this phosphorylation is essential for viral replication. To identify the site(s) of phosphorylation, we have used CNBr cleavage, phosphoamino acid analysis, and two-dimensional tryptic peptide mapping of the in vitro and in vivo phosphorylated P protein. We demonstrate that when bacterially expressed unphosphorylated P is labeled in vitro with either commercial PKC or purified recombinant PKC zeta P protein has one major phosphorylation site. By site-directed mutagenesis of PKC consensus sites in the P protein, the primary phosphorylation site is found to be Ser 333. The same site appeared to be modified when viral P protein was phosphorylated in vitro by the PKC packaged within the virion and in the P protein of progeny virion labeled in vivo.
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PMID:Human parainfluenza virus type 3 phosphoprotein: identification of serine 333 as the major site for PKC zeta phosphorylation. 764 59

The requirement of protein kinase C zeta (zeta PKC) for maturation of X. laevis oocytes in response to insulin, p21ras, and phosphatidylcholine-hydrolyzing phospholipase C has recently been shown. Here we present experimental evidence demonstrating that activation of zeta PKC is not only necessary but also sufficient by itself to activate maturation in oocytes and to produce deregulation of growth control in mouse fibroblasts. Furthermore, by using a dominant kinase-defective mutant of zeta PKC, we confirm that this kinase is required for mitogenic activation in oocytes and fibroblasts. These results permit us to propose zeta PKC as a critical step downstream of p21ras in mitogenic signal transduction.
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PMID:Protein kinase C zeta isoform is critical for mitogenic signal transduction. 768 66

We investigated the ras p21 membrane localization and the expression and activation of protein kinase C (PKC) isozymes in activated ras oncogene-containing tumors and assessed whether these events were related to tumor growth. We used 7,12-dimethylbenz[a]anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted SENCAR mouse skin tumors, which were shown to contain Ha-ras oncogene activated by point mutation at codon 61, as an in vivo model for these studies. Compared with levels in epidermis, highly elevated levels of membrane-bound Ha-ras p21 were observed in growing tumors, which also showed strong expression and membrane translocation of PKC zeta and beta II and weak expression of PCK alpha. However, when ras p21 membrane localization was blocked in vivo in growing tumors by lovastatin, opposite results were evident. Compared with saline-treated animals, in which tumor growth continued, lovastatin-treated animals had significantly inhibited tumor growth, which led to tumor regression with concomitant inhibition of Ha-ras p21 membrane localization. These regressing tumors from lovastatin-treated animals also showed a decrease in the expression and membrane translocation of PKC zeta and beta II but increased expression of PKC alpha. Taken together, our results indicate that ras p21 membrane localization and the expression and activation of PKC zeta, beta II, and alpha may be the critical events in the regulation of the growth of tumors that contain activated ras oncogenes.
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PMID:Inhibition of ras p21 membrane localization and modulation of protein kinase C isozyme expression during regression of chemical carcinogen-induced murine skin tumors by lovastatin. 772 42


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