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)

Induction of differentiation in murine erythroleukemia cells (MELCs) involves a protein kinase C (PKC)-mediated step. Vincristine-resistant cells respond more rapidly to hybrid polar/apolar inducers than the parental cells. These vincristine-resistant MELCs contain elevated levels of the beta isozyme of PKC (PKC-beta). Exogenous homologous murine PKC-beta, incorporated into permeabilized MELCs, accelerates induced differentiation. Neither rat PKC-beta, nor mouse PKC-alpha, nor rat PKC-alpha, incorporated into permeabilized MELCs, is effective in altering the kinetics of induced differentiation. This provides direct evidence for a rate-limiting role for this PKC isozyme during N,N'-hexamethylenebisacetamide-mediated induced differentiation of a transformed cell.
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PMID:Introduction of the beta isozyme of protein kinase C accelerates induced differentiation of murine erythroleukemia cells. 235 25

The present study has characterized several aspects of the mouse epidermal protein kinase C (PKC) system and compared phorbol ester-sensitive and -resistant mice. Protein immunoblots of partially purified epidermal PKC preparations from SENCAR and C57BL/6 mice indicated the presence of the gamma-, beta-, and alpha-isozymes of PKC in both strains. Hydroxylapatite chromatography profiles of epidermal PKC isozymes from SENCAR and C57BL/6 mice revealed three major peaks of PKC activity eluting in fractions similar to those observed in chromatograms of brain tissue and corresponding to PKC-gamma, -beta, and -alpha. Further analyses of hydroxylapatite chromatography fractions revealed that PKC-gamma and -beta were present in approximately similar proportions and were much more abundant than PKC-alpha. This distribution of epidermal PKC isozymes was similar in both strains. After a single topical application of 3.4 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) to SENCAR mouse epidermis, total PKC activity in the cytosol fraction decreased rapidly to about 50% of control within 15 min and was accompanied by an increase (approximately 150% of control) of PKC activity in the membrane fraction. At 4 h, PKC activities were significantly lower than the control levels and remained downregulated through 96 h with a maximal decrease (to approximately 25-30% of the control) in both cytosol and membrane fractions at h. PKC activity returned to control levels by 168 h. Ca++/phospholipid-independent kinase activity was the same as control levels at 15 min, 1 h, and 4 h after TPA treatment but was elevated above control levels at 24 h, 48 h, and 96 h, and by 168 h returned essentially to control levels. No differences were found in the magnitude or kinetics of TPA-induced translocation and downregulation of total PKC or appearance of Ca++/phospholipid-independent kinase activity between SENCAR, DBA/2, and C57BL/6 mice. Scatchard analyses using a two binding site model revealed that the apparent Kd and Bmax values for binding of PDBu to epidermal cytosol and membrane fractions were similar between SSln, SENCAR, DBA/2, and C57BL/6 mice. The present results demonstrate for the first time that mouse epidermis contains significant amounts of the three major PKC isozymes that are present in brain, especially PKC-gamma. In addition, topical application of a promoting dose of TPA did not lead to complete loss of PKC activity in either the membrane or cytosol fractions of mouse epidermis. In conclusion, no differences were observed between phorbol ester-sensitive and -resistant mice in any aspect of epidermal PKC examined.
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PMID:Partial characterization of epidermal protein kinase C in mice sensitive or resistant to phorbol ester. 237 71

Normal human melanocytes, unlike malignant melanomas, require the presence of phorbol ester for growth in culture. Because protein kinase C (PKC) represents the intracellular receptor for phorbol esters, we investigated a possible correlation between expression of PKC and tumor progression in the melanocytic system. The results failed to show expression of PKC-alpha, -beta or -gamma in normal human melanocytes. However, PKC-alpha was expressed in primary and metastatic melanomas; even though antisense oligodeoxynucleotides targeted against different mRNA regions of human PKC-alpha, and H7, an inhibitor of PKC, did not display significant growth-inhibitory effects. A similar pattern of expression was detected with respect to the expression of cAMP-dependent protein kinase (PKA). Normal human melanocytes did not reveal expression of either of the known catalytic or regulatory subunits of human PKA, whereas primary and metastatic melanomas demonstrated expression of the PKA-specific subunits C alpha and RI alpha.
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PMID:Differential expression of protein kinase C and cAMP-dependent protein kinase in normal human melanocytes and malignant melanomas. 239 22

A set of complementary DNAs (cDNAs) that encode the complete 672-amino acid sequence for mouse protein kinase C (PKC) type alpha have been isolated from a mouse Swiss 3T3 cDNA library. Extensive rescreening of this cDNA library only resulted in the isolation of clones of the same PKC species, indicating that Swiss 3T3 fibroblasts express exclusively PKC-alpha. This enzyme is encoded by two different mRNAs that exhibit a substantial heterogeneity in their 3'-noncoding regions. This heterogeneity could have been derived from alternative splicing of the pre-mRNAs or be due to differential usage of the polyadenylation motif. The expression of PKC mRNA in fibroblasts is very low and it is not influenced by treatment with the tumor promoter 12-O-tetradecanoyl-13-phorbol-acetate.
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PMID:Molecular cloning of mouse protein kinase C (PKC) cDNA from Swiss 3T3 fibroblasts. 246 25

During rat liver regeneration induced by carbon tetrachloride administration, the protein kinase C alpha subspecies was activated in a heterogeneous fashion, a higher number of hepatocytes expressing the protein kinase C alpha subspecies being detected in the pericentral zone than in the periportal zone. This zonal heterogeneity became maximal at 24 h after the treatment. The distribution of hepatocytes expressing the protein kinase C alpha subspecies was roughly coincident with that of hepatocytes exhibiting DNA synthesis. These results suggest that protein kinase C may play a crucial role in liver regeneration.
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PMID:Heterogeneous activation of protein kinase C during rat liver regeneration induced by carbon tetrachloride administration. 277 86

An early consequence of stimulation of T cells via their Ag receptor is the activation of protein kinase C (PKC). It has recently been shown that PKC activity resides in a family of homologous proteins. Inasmuch as T cells are phenotypically and functionally heterogeneous, we examined the possibility that this heterogeneity may be reflected in differential expression of message for PKC isoenzyme genes. RNA from six leukemic T cell lines was probed for PKC-alpha, -beta, and -gamma message before and after activation. These studies revealed significant differences among these lines. None expressed mRNA for PKC-gamma. Whereas all cells possessed message for PKC-alpha, there was consistent variability in the level expressed. The greatest heterogeneity was seen with PKC-beta. Two cell lines, HUT 78 and HPB-ALL, did not hybridize with the beta probe under any conditions tested. We subsequently used these PKC-beta negative cells to study the role of this isoenzyme in mediating some of the effects seen with phorbol esters that directly bind to and activate PKC. Our results indicate that PKC-beta, which is expressed in some T cells, is not necessary for PMA-induced CD3 or CD4 internalization, IL-2 production, or acquisition of the p55 chain of the IL-2 receptor.
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PMID:Heterogeneity of protein kinase C isoenzyme gene expression in human T cell lines. Protein kinase C-beta is not required for several T cell functions. 278 92

The KG-1 myeloid leukemia cell line differentiates into macrophages in response to 12-O-tetradecanoylphorbol 13-acetate (TPA), while its spontaneous variant, the KG-1a cell line, is resistant to the differentiative effects of TPA. To determine the mechanism underlying these differential responses to TPA, experiments were performed to determine the relative numbers of TPA binding sites, protein kinase C (PKC) enzyme activity levels, PKC translocation responses and PKC gene expression in these cell lines. KG-1a cells exhibited 40% fewer high affinity binding sites for TPA than KG-1 cells. Although PKC translocation from cytosol to the membrane fraction was observed in both cell types, total PKC activity, measured in vitro using type III-S histone as substrate, was reduced by 70% in KG-1a cells. These biochemical differences between the parental line and the phorbol ester non-responsive variant were correlated with the depressed level of PKC-beta RNA abundance in KG-1a cells. Both lines expressed PKC-alpha RNA at comparable levels. Chronic exposure to TPA resulted in down-regulation of PKC enzyme activity in both cell lines, and a selective decrease in PKC-beta RNA transcripts in both cell types. In contrast, chronic TPA treatment had no effect on the levels of PKC-alpha RNA in KG-1 and KG-1a cells. Our results indicate a correlation between the level of PKC-beta expression and the responsiveness of myeloid lineage precursor cells to the differentiative effects of TPA.
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PMID:Differential responsiveness to phorbol esters correlates with differential expression of protein kinase C in KG-1 and KG-1a human myeloid leukemia cells. 279 38

In a previous study we demonstrated that 13-hydroxyoctadecadienoic acid (13-HODE), a 15-lipoxygenase metabolite of linoleic acid is incorporated into epidermal phosphatidyl 4,5-bisphosphate (PtdIns 4,5-P2) and released as 13-HODE-containing-diacylglycerol (13-HODE-DAG). In vitro, 13-HODE-DAG was shown to selectively inhibit epidermal total protein kinase C (PKC-beta) activity. To determine whether these observations are relevant in vivo, guinea pigs were made essential fatty acid deficient (EFAD) by feeding them a basal diet supplemented with 4% hydrogenated coconut oil for 8 wk. Tissue levels of putative 13-HODE-DAG, protein kinase C (PKC) isozymes and tissue hyperproliferation were determined in the epidermal preparations from skin of control safflower oil-fed guinea pigs, those fed EFAD diet and those fed EFAD diet followed by the control diet for 2 wk. Our data revealed that cutaneous 13-HODE and 13-HODE-DAG were significantly lower in EFAD animals than in safflower-fed controls. These reductions were associated with both elevated epidermal hyperproliferation and elevated expressions and activities of PKC-alpha and beta-isozymes. Refeeding the animals with safflower oil for 2 wk replenished tissue levels of 13-HODE-DAG, which inversely correlated with the selective down regulation of PKC-beta expression and activity and the reversal of hyperproliferation. In contrast, although, the expression and activity of PKC-alpha was elevated in the epidermis of the EFAD guinea pigs, this elevated PKC-alpha expression was not down regulated after refeeding the safflower oil diet to the animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nutritional modulation of guinea pig skin hyperproliferation by essential fatty acid deficiency is associated with selective down regulation of protein kinase C-beta. 747 53

Transforming growth factor (TGF)-beta mediates matrix production in both mesangial and vascular smooth muscle cells. Both TGF-beta and phorbol-12-myristate-13-acetate (PMA) exert both positive and negative effects on mitogenesis in these as well as other cell types. Phorbol esters act through stimulation of protein kinase C (PKC) and are among the most potent tumor promoters known. The present study was conducted to determine if the growth inhibitory effect of TGF-beta parallels that of the phorbol esters and whether this effect of TGF-beta is dependent on activation of PKC. We show that, in vascular smooth muscle cells stimulated to divide by the addition of the serum component basic fibroblast growth factor (bFGF), TGF-beta1 inhibits mitogenesis in a dose-dependent manner, by a maximum of 79% when applied at a concentration of 1 ng/ml. Furthermore, the inhibitory effect on mitogenesis of either TGF-beta1 or PMA, when added four hours after bFGF, are 71% and 84% respectively. Both TGF-beta1 and PMA cause translocation of celllular PKC with similar time courses, while neither PKC-alpha nor PKC-betaII are increased in quantity in response to TGF-beta1. In addition, down-regulation of PKC by 24 hours incubation with PMA abolishes TGF-beta's inhibitory effect in bFGF-stimulated cells. We conclude that (i) the signaling pathway utilized by TGF-beta resulting in inhibition of mitogenesis parallels that of PMA, and (ii) the inhibitory effect of TGF-beta1 on bFGF-induced mitogenesis is partially due to activation of PKC. These data suggest that TGF-beta may be an endogenous activator of the growth-inhibitory pathway of PKC, and, since cellular differentiated functions generally occur when the cells are proliferation-inhibited, PKC may be a modulator of extracellular matrix deposition.
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PMID:TGF-beta and phorbol esters inhibit mitogenesis utilizing parallel protein kinase C-dependent pathways. 747 59

The distribution of six isoforms of protein kinase C (PKC) in seromucous acinar cells of rat submandibular gland was examined and their translocation from the cytosolic- to the membrane fraction after different stimuli investigated. Western blotting, immunostaining with isoform-specific antibodies and scanning densitometry showed that PKC-alpha and epsilon were distributed fairly evenly between the cytosol and membranes in resting cells, while isoforms- beta, delta and zeta were all predominantly localized (over 80%) in membranes. PKC-gamma was not detected. PKC-alpha was mobilized to the membrane fraction by the phorbol ester, TPA, but not by the phosphoinositide-coupled agonists carbachol, methoxamine and substance P (SP). PKC-epsilon was translocated by TPA and carbachol but not by SP or methoxamine. Biochemical assay of total PKC confirmed that cytosolic enzyme activity was significantly reduced by TPA and carbachol to 29% and 75% respectively of control levels. These results suggest that muscarinic regulation of the mucosecretory response in the rat submandibular gland may be mediated by the PKC-epsilon isoform.
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PMID:Distribution and translocation of isoforms of protein kinase C in rat submandibular acinar cells. 747 51


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