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)

We recently developed rat fibroblast cell lines that stably overproduce high levels of the beta 1 form of protein kinase C (PKC). These cells display several disorders in growth control and form small microscopic colonies in agar. In the present study we demonstrate that one of these cell lines, R6-PKC3, is extremely susceptible to transformation by an activated human bladder cancer c-H-ras oncogene (T24). Compared with control cell line R6-C1, T24-transfected R6-PKC3 cells yielded a 10-fold increase in the formation of large colonies in agar. Cell lines established from these colonies displayed a highly transformed morphology, expressed the T24-encoded p21 ras protein, continued to express high levels of PKC, and were highly tumorigenic in nude mice. These results provide genetic evidence that PKC mediates some of the effects of the c-H-ras oncogene on cell transformation. Data are also presented suggesting that optimum synergistic effects between c-H-ras and PKC require critical levels of their respective activities. These findings may be relevant to the process of multistage carcinogenesis in tissues containing cells with an activated c-H-ras oncogene.
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PMID:Cells that overproduce protein kinase C are more susceptible to transformation by an activated H-ras oncogene. 247 57

Porcine transforming growth factor 1 and 2 (pTGF-beta 1 and -beta 2) and milk growth factor (MGF) at 1 ng/ml significantly inhibited the proliferation of human lymphocytes induced by anti-CD3 antibodies. In contrast, the anti-CD3-mediated increase of intracellular Ca2+ and the activation and translocation of protein kinase C were not affected by the transforming growth factors.
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PMID:Transforming growth factors beta 1 and beta 2 as well as milk growth factor decrease anti-CD3-induced proliferation of human lymphocytes without inhibiting the anti-CD3-mediated increase of [Ca2+]i and the activation of protein kinase C. 252 86

We have used a previously described retroviral expression vector pMV7-PKC beta 1 to develop derivatives of two rat liver epithelial cell lines, K16 and K22, that stably express about tenfold-higher PKC activity than control cells. Despite these high levels of PKC, these cells did not exhibit gross morphologic changes, anchorage-independent growth, or tumorigenicity. K16PKC-4 and K22PKC-2, two lines with the highest PKC enzyme activity, were studied further in terms of several responses to the phorbol ester tumor promoter TPA. When treated with 100 ng/ml of TPA, the control K16MV7 and K22MV7 cells displayed a slight change in morphology, whereas the K16PKC-4 and K22PKC-2 cells displayed a marked change in morphology. Northern blot analyses demonstrated that TPA induced increased levels of fos, myc, phorbin, and ODC RNAs in control K16MV7 and K22MV7 cells, with maximum induction occurring at about 0.5, 1, 8, and 8 h, respectively. In K16PKC-4 and K22PKC-2 cells, TPA induction of phorbin and ODC RNAs was markedly enhanced, but this was not the case for myc and fos RNAs. In addition, the levels of myc RNA were constitutively higher in both K16PKC-4 and K22PKC-2 cells than in the control cells. Taken together, these results provide direct evidence that PKC plays a critical role in modulating the expression of myc, phorbin, and ODC RNAs. On the other hand, overexpression of PKC beta 1 is not itself sufficient to cause cell transformation.
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PMID:Phenotypic effects of overexpression of PKC beta 1 in rat liver epithelial cells. 253 31

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.
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PMID:Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram. 255 65

It has now become clear that protein kinase C (PKC) plays a fundamental role in cellular growth control in higher eukaryotes. In addition, since PKC has also been shown to be the high-affinity intracellular receptor for several classes of tumor promoters, the study of PKC has also become a central focus of current work in cancer research. We have isolated cDNA clones encoding several forms of this enzyme, and we have used these clones to begin to study in detail the role of PKC in growth control and tumor promotion. The complete primary structure of one of these forms, designated PKC beta 1, exhibits structural and functional characteristics which are shared among all of the currently identified forms of PKC. These include an amino terminal cysteine-rich domain which mediates Ca2+ and phospholipid binding, tumor promoter binding, and membrane association, and a carboxy terminal catalytic domain which possesses serine/threonine protein kinase activity. To further characterize the function of PKC, we have generated a series of rat fibroblast cell lines which stably overexpress a full-length cDNA encoding the beta 1 form of this enzyme. These cell lines contain a 20- to 53-fold increase in PKC activity, and also have an increase in high affinity phorbol ester receptors, relative to control cells. They also exhibit dramatically enhanced morphologic changes in response to treatment with the tumor promoter 12-0-tetradecanoyl phorbol-13-acetate (TPA). These cell lines grow to a higher saturation density in monolayer culture and, when maintained at post-confluence, develop small, dense foci. In contrast to the control cells, which display complete anchorage dependence, the cell lines that overproduce PKC form small colonies in soft agar in the absence of TPA, and larger colonies in the presence of TPA. Thus, the mere overproduction of a single form of PKC is sufficient to confer anchorage independent growth and other growth abnormalities in rat fibroblasts. Taken together, these results provide direct evidence that PKC plays a critical role in normal cellular growth control and that it mediates several, and perhaps all of the cellular effects of the phorbol ester tumor promoters.
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PMID:Structural and functional studies of protein kinase C. 306 83

The expression in human fibroblasts of the beta 2-interferon (IFN-beta 2) gene, which is now recognized to be identical to the gene encoding B-cell differentiation factor BSF-2, is enhanced by several cytokines that affect cell growth (tumor necrosis factor, interleukin 1, platelet-derived growth factor, and beta 1-interferon). We have examined the possibility that IFN-beta 2 gene expression is regulated through activation, by diacylglycerol, of the protein kinase C pathway. The synthetic diacylglycerols 1,2-dioctanoylglycerol (diC8) and 1-oleoyl-2-acetylglycerol strongly enhanced IFN-beta 2, but not IFN-beta 1, gene expression in human fibroblasts (FS-4 strain). An increase in IFN-beta 2 mRNA level was detected within 15 min after addition of diC8 (290 microM) to FS-4 cells and was maximal approximately 20 hr later. An increase in IFN-beta 2 gene transcription was detected within 5 min of addition of diC8, and the rate of transcription was near-maximal by 15-30 min. The enhancement of IFN-beta 2 gene expression by diC8, interleukin 1, or tumor necrosis factor was not prevented by H8, a preferential inhibitor of cAMP- and cGMP-dependent protein kinases, but was blocked by H7, an inhibitor of protein kinase C as well as of cyclic nucleotide-dependent protein kinases. diC8 was found to protect FS-4 cells from the cytopathic effect of vesicular stomatitis virus; this protection was blocked by polyclonal or monoclonal antibodies that neutralize IFN-beta, suggesting that the antiviral effect was due to the secretion of IFN-beta 2 by the diC8-treated fibroblasts. The calcium ionophore A23187 (1-10 microM) also elicited an increase in the level of IFN-beta 2 mRNA in FS-4 fibroblasts; appropriate combinations of A23187 and diC8 had at least an additive effect in enhancing IFN-beta 2 mRNA levels. These results show that protein kinase C-activating or [Ca2+]-elevating agents rapidly increase the expression of the IFN-beta 2 gene in human fibroblasts.
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PMID:Rapid enhancement of beta 2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187. 310 77

We have generated a series of rat fibroblast cell lines that stably overexpress a full-length cDNA encoding the beta 1 form of protein kinase C (PKC). These cell lines contain a 20- to 53-fold increase in PKC activity and exhibit dramatically enhanced morphologic changes following exposure to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA). They grow to a high saturation density in monolayer cultures and, when maintained at postconfluence, develop small, dense foci. In contrast to control cells, which display complete anchorage dependence, PKC-overproducing cells form small colonies in soft agar in the absence of TPA and large colonies in the presence of TPA. Thus, the mere overproduction of a single form of PKC is sufficient to confer multiple growth abnormalities in rat fibroblasts. These results provide direct evidence that PKC plays a critical role in growth control and that it mediates several of the cellular effects of the phorbol ester tumor promoters. They also suggest that the activation of PKC may be of central importance in the process of multistage carcinogenesis.
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PMID:Overproduction of protein kinase C causes disordered growth control in rat fibroblasts. 334 63

We previously reported that the synthesis of NeuAc(alpha 2-3)Gal(beta 1-4)GlcCer (GM3) ganglioside was preferentially enhanced during the differentiation of HL-60 cells into a monocyte/macrophage lineage induced by 12-O-tetradecanoylphorbol-13-O-acetate (TPA). Since exogenously added GM3 ganglioside was shown to be able to induce the differentiation of HL-60 cells into the monocyte/macrophage lineage in a synthetic medium, the functional role of the GM3 ganglioside increase during the differentiation of HL-60 cells has become the subject of much interest. In the present study, we investigated the activity of CMP-NeuAc:lactosylceramide sialyltransferase, which catalyzes the synthesis of GM3 ganglioside from lactosylceramide, in cells undergoing differentiation induced by two different reagents, TPA and 1 alpha,25-dihydroxy-vitamin D3, which induce the differentiation of HL-60 cells into the monocyte/macrophage lineage through different modes of action. We showed that the activation of CMP-NeuAc:lactosylceramide sialyltransferase and the increase in GM3 ganglioside were not related to the differentiated lineage but to the specific action of TPA, i.e. activation of protein kinase C.
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PMID:Activation of CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase during the differentiation of HL-60 cells induced by 12-O-tetradecanoylphorbol-13-acetate. 346 24

Isolation of two protein kinase C (PKC) cDNA clones containing divergent carboxy-terminal sequences suggested a common genetic origin for these cDNAs. Partial characterization of the hPKC beta chromosomal gene provided direct evidence for the existence of two adjacent carboxy-terminal exons (beta 1 and beta 2) that are alternatively spliced to generate two types of hPKC beta sequences. PKC beta 1 and beta 2 mRNAs are expressed in a selective manner in both human hematopoietic cells and bovine brain tissues.
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PMID:Alternative splicing increases the diversity of the human protein kinase C family. 367 94

Phorbol esters upregulate the functional affinity of beta 1 integrin receptors for fibronectin on human neutrophils and other leukocytes. We investigated the ability of phorbol myristate acetate (PMA) to stimulate the human promyelocytic cell line HL-60 to adhere to fibronectin, either in its undifferentiated state (HL60) or after dimethylsulfoxide-induced differentiation along the granulocytic pathway (dHL60). PMA stimulated little adherence of undifferentiated HL60 to fibronectin or to the 120-kD chymotryptic cell-binding domain (CBD) of fibronectin. In contrast, PMA stimulated dHL60 cells to rapidly adhere to both fibronectin- and to CBD-coated plastic. PMA-stimulated dHL60 adherence to fibronectin was largely mediated by both alpha 4 beta 1 and alpha 5 beta 1, whereas PMA-stimulated dHL60 adherence to CBD was largely mediated by alpha 5 beta 1. There was little contribution from beta 2 integrins to PMA-stimulated dHL60 adherence to fibronectin or CBD. The inability of undifferentiated HL60 to adhere to fibronectin and CBD did not result from lack of expression of alpha 4 beta 1 or alpha 5 beta 1 because HL60 and dHL60 express similar amounts of both alpha 4 beta 1 and alpha 5 beta 1 on their surface. In addition, 1 mmol/L Mn2+ induced similar amounts of alpha 5 beta 1-dependent adherence of both HL60 and dHL60, showing that alpha 5 beta 1 on undifferentiated HL60 is capable of binding to its ligand. These data suggest that activation of protein kinase C cannot functionally upregulate these beta 1 integrins on undifferentiated HL60 cells. The development of PMA-stimulated beta 1-dependent adherence after granulocytic differentiation of HL60 cells suggests that the differentiated HL60 cell is a useful model for investigating functional coupling of protein kinase C to beta 1 integrin in myeloid cells.
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PMID:Activation of beta 1 integrin fibronectin receptors on HL60 cells after granulocytic differentiation. 750 54


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