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)

Increased protein kinase C (PKC) activity in malignant breast tissue and positive correlations between PKC activity and expression of a more aggressive phenotype in breast cancer cell lines suggest a role for this signal transduction pathway in the pathogenesis and/or progression of breast cancer. To examine the role of PKC in the progression of breast cancer, human MCF-7 breast cancer cells were transfected with PKC-alpha, and a group of heterogenous cells stably overexpressing PKC-alpha were isolated (MCF-7-PKC-alpha). MCF-7-PKC-alpha cells expressed fivefold higher levels of PKC-alpha as compared to parental or vector-transfected MCF-7 cells. MCF-7-PKC-alpha cells also displayed a substantial increase in endogenous expression of PKC-beta and decreases in expression of the novel delta- and eta-PKC isoforms. MCF-7-PKC-alpha cells displayed an enhanced proliferative rate, anchorage-independent growth, dramatic morphologic alterations including loss of an epithelioid appearance, and increased tumorigenicity in nude mice. MCF-7-PKC-alpha cells exhibited a significant reduction in estrogen receptor expression and decreases in estrogen-dependent gene expression. These findings suggest that the PKC pathway may modulate progression of breast cancer to a more aggressive neoplastic process.
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PMID:MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. 770 98

We have used immunocytochemical analyses to characterize the subcellular distribution of protein kinase C (PKC)-alpha, -beta I, -beta II, -gamma, -delta, -epsilon, -zeta, and -eta in NIH 3T3 fibroblasts that overexpress these different PKC isozymes. Immunofluorescence studies and Western blotting with antibodies specific for individual isoforms revealed that before activation the majority of the PKCs are not membrane-bound and are diffusely distributed throughout the cytoplasm. In addition, a fraction of PKC-delta and -eta appears membrane-bound and concentrated in the Golgi apparatus. Activation of each isozyme's kinase activity (with the exception of PKC-zeta) by treatment of these cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate results in isozyme-specific alterations of cell morphology, as well as in a rapid, selective redistribution of the different PKC isozymes to distinct subcellular structures. Within minutes after 12-O-tetradecanoylphorbol-13-acetate treatment, PKC-alpha and -epsilon concentrate at cell margins. In addition, PKC-alpha accumulates in the endoplasmic reticulum, PKC-beta II associates with actin-rich microfilaments of the cytoskeleton, PKC-gamma accumulates in Golgi organelles, and PKC-epsilon associates with nuclear membranes. Our results demonstrate that each activated PKC isozyme specifically associates with a particular cellular structure, presumably containing the substrate for that isozyme. These findings support the hypothesis that PKC substrate specificity in vivo is mediated, at least in part, by the restricted subcellular locale for each PKC isozyme and its target protein.
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PMID:Immunocytochemical localization of eight protein kinase C isozymes overexpressed in NIH 3T3 fibroblasts. Isoform-specific association with microfilaments, Golgi, endoplasmic reticulum, and nuclear and cell membranes. 773 Mar 83

Effects of insulin of levels of mRNA encoding protein kinase C (PKC)-alpha, PKC-beta, PKC-epsilon and PKC-theta were examined by ribonuclease protection assay in primary cultures of rat adipocytes in vitro, and in rat adipose tissue and gastrocnemius muscle in vivo. In all cases, insulin increased the levels of PKC-alpha mRNA and PKC-beta mRNA, and, in muscle, insulin also increased the level of PKC-theta mRNA. PKC-epsilon mRNA levels, on the other hand, were not altered significantly. Insulin also stimulated the apparent translocation of PKC-alpha, -beta, -epsilon and -theta, to the membrane fractions of adipocytes, adipose tissue and gastrocnemius muscles, and, in some instances, total PKC levels were diminished, e.g. PKC-alpha and PKC-beta in cultured adipocytes in vitro and/or whole adipose tissue in vivo, and PKC-alpha and PKC-theta in the gastrocnemius muscle. Thus, insulin-induced increases in PKC mRNA may have been partly compensatory in nature to restore PKC levels following translocation and proteolytic losses. However, much more severe depletion of PKC-alpha and PKC-beta by phorbol ester treatment in cultured rat adipocytes in vitro resulted in, if anything, smaller increases in PKC-alpha mRNA and PKC-beta mRNA, and it therefore appears that insulin effects on PKC mRNA levels were not simply due to decreases in respective PKC levels. In addition, effects of insulin, particularly on PKC-beta mRNA, could not be attributed to increased glucose metabolism, which alone decreased PKC-beta mRNA in cultured adipocytes in vitro. We conclude that insulin-induced translocation and degradation of PKC-alpha, PKC-beta and PKC-theta are attended by selective increases in their mRNAs. This mechanism of increasing mRNA may be important in maintaining PKC levels during the continued action of insulin.
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PMID:Insulin increases mRNA levels of protein kinase C-alpha and -beta in rat adipocytes and protein kinase C-alpha, -beta and -theta in rat skeletal muscle. 775 64

Spontaneously apoptotic U937 cells from exponentially growing cell cultures were enriched on discontinuous Percoll density gradients. Increased PKC-beta and reduced PKC-zeta expression were detected in apoptotic cells by Western blotting. Using confocal microscopy, changes in the level of PKC isoenzymes were confirmed and in addition alterations in the subcellular location of PKC isoenzymes were detected in apoptotic cells compared with nonapoptotic cells. The data indicate that the expression of specific PKC isoenzymes is modulated during apoptosis and that PKC-beta and PKC-zeta may play specific roles in the regulation of the apoptotic program.
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PMID:Changes in protein kinase C isoenzyme expression associated with apoptosis in U937 myelomonocytic cells. 779 79

The localization of PKC subspecies alpha, beta, gamma, epsilon and zeta was studied immunocytochemically in the rabbit retina. Conventional, Ca(2+)-sensitive PKC subtypes alpha, beta, gamma were all localized in different neuronal populations. The zeta-subspecies, which does not require Ca2+ for activation, was colocalized with PKC-alpha. PKC-epsilon, which is independent of Ca2+ and DAG, was colocalized with PKC-beta. Some populations of neurons, including cone bipolar cells, contained none of the PKC-subspecies studied. These results imply a cellular segregation of different signaling pathways in mammalian retina.
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PMID:Localization of protein kinase C subspecies in the rabbit retina. 782 69

Myelin gene expression in normal oligodendrocytes (OLG) depends on developmentally regulated protein kinase C (PKC) enzyme activity (Asotra and Macklin: J Neurosci Res 34:571-588, 1993). We studied the developmental expression of the Ca(++)-dependent PKC-alpha, -beta 1, -beta II and -gamma isozymes, and the Ca(++)-independent PKC-delta, -epsilon, -zeta and -eta isozymes in enriched rat brain OLG cultures. In A2B5+ O-2A progenitors, only PKC-delta, PKC-epsilon and PKC-zeta were detected immunocytochemically. In 04+ proligondendrocytes, PKC-beta I, -delta and -zeta were expressed moderately and low levels of PKC-alpha and -epsilon were detected. GD3+ OLG, GC+ OLG and MBP+ OLG showed increased levels of PKC-alpha, -beta I, -delta and -zeta isozymes. PKC-beta II, -gamma and -eta were poorly expressed in OLG. On immunoblots, PKC-alpha was present early and increased continually up to 18 days but PKC-beta I increased until 12 days in cultured OLG. High levels of PKC-delta, PKC-epsilon and PKC-zeta, the most abundant PKC isozymes in OLG, were maintained up to 12 days and were then slightly reduced. Interestingly, relatively high levels of PKC-alpha, PKC-beta I, PKC-beta II, PKC-gamma and PKC-epsilon isozymes were detected in purified myelin membrane although greater levels of PKC-delta were found in OLG than in purified myelin. Thus, most of the PKC isozymes found in cultured OLG were also present in myelin, although at different levels. Treatment with 50 nM 4 beta-phorbol-12,13-dibutyrate (PDB) caused a delayed downregulation of PKC-delta levels after 8 hr without modulating the expression of other PKC isozymes in 1-day OLG; in the 3-day-old and 6-day-old OLG, PDB downmodulated PKC-beta I, -delta and epsilon isozymes with only a minor effect on PKC-alpha and no reduction in PKC-zeta. Induction or downmodulation of individual PKC isozymes by phorbol esters appears to depend on the differentiation state of OLG. These data suggest that PKC-beta I, -delta and -epsilon isozymes have an important function in different cellular events of OLG differentiation. We conclude that the PKC-dependent modulation of myelin gene expression in OLG results predominantly from the Ca(++)-dependent PKC-beta I isozyme activity and the CA(++)-independent PKC-delta and PKC-epsilon activitives in a cell differentiation state-dependent manner.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Developmental expression of protein kinase C isozymes in oligodendrocytes and their differential modulation by 4 beta-phorbol-12,13-dibutyrate. 786 20

The profiles of the calcium-dependent protein kinase C (PKC) isozymes alpha, beta, and gamma were examined in subcellular fractions from Fischer 344 rat liver during the early stages (48 h, 96 h, 7 d, and 60 d) of diethylnitrosamine (DEN)-induced carcinogenesis, using the Solt-Farber "resistant hepatocyte" model (DEN-2-acetylaminofluorene-partial hepatectomy; DEN-AAF-PH), and then related to the presence of focal or nodular gamma-glutamyl transpeptidase (GGT)-positive morphologic changes in the liver. After DEAE and hydroxyapatite column chromatography, two peaks, immunologically identified as PKC-alpha and -beta isoforms, were detected in the liver of normal (alpha/beta ratio = 4.0) and treated rats. In DEN-AAF-PH hepatocarcinogenesis an increase in PKC-alpha expression was found after PH (+43 +/- 19% at 48 h, alpha/beta ratio = 5.1; +125 +/- 25% at 96 h, alpha/beta ratio = 4.8), whereas the PKC-beta isoform appeared less significantly modified (+11 +/- 3% at 48 h and +89 +/- 17% at 96 h). Seven and 60 days after PH, a marked increase in the PKC-alpha (+96 +/- 20% and +150 +/- 48%, respectively) and PKC-beta isoforms (+158 +/- 41%, alpha/beta ratio = 3.1 and +130 +/- 26%, alpha/beta ratio = 4.4, respectively), occurred along with the appearance of GGT-positive altered hepatic foci and nodules in the liver sections. Sham hepatectomy caused PKC-alpha and -beta isoform activities similar to those of normal controls. In contrast, saline-AAF-PH-treated rats had downregulation of PKC-alpha after PH (alpha/beta ratio = 1.8 at 96 h), possibly due to the mitoinhibitory effect of the carcinogen AAF on normal uninitiated hepatocytes. Immunohistochemical analysis with monoclonal antibodies to PKC-alpha and -beta revealed diffuse positive cytoplasmic signals in GGT-positive foci and nodules in rat liver. Taken together, these preliminary results, using the Solt-Farber model of liver carcinogenesis, suggest a role for PKC in tumor promotion. They also suggest that the PKC-alpha isoform may play a specific role in clonal expansion of DEN-initiated hepatocytes after PH.
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PMID:Analysis of calcium-dependent protein kinase C isoforms in the early stages of diethylnitrosamine-induced rat hepatocarcinogenesis. 790 65

Levels of protein kinase C (PKC) isoforms in eight human glioblastoma cell lines and two normal human glial cell cultures were determined. Earlier studies identified PKC-alpha and PKC-gamma in these cell lines but PKC-beta was not present. In this study, PKC-epsilon and PKC-zeta are demonstrated immunologically in these cell lines and also in two normal human glial cell cultures. Protein kinase C-delta was not present. When levels of the four isoforms in the tumor cells were compared to levels in the normal cells, no increase was observed in PKC-alpha or PKC-gamma, but PKC-epsilon was elevated three to 30 times in six of the eight tumors, and PKC-zeta was elevated approximately two times in all of the tumors. Incubation of cell line A172 with phorbol ester for 6 hours resulted in a 48-fold maximum increase in the nuclear PKC-epsilon and a sevenfold increase in the plasma membrane fraction with no change in the cytoplasmic fraction. A similar incubation for 4 hours produced a 0.5- to onefold increase of PKC-zeta in cytoplasmic, nuclear, and plasma membrane fractions. Other researchers have shown that overexpression of PKC-epsilon in fibroblasts results in tumorigenesis, and that blocking PKC-zeta function inhibits deoxyribonucleic acid synthesis. These data suggest that alteration in the expression of PKC-epsilon and PKC-zeta could be a factor in the conversion of normal glial cells to glioblastomas.
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PMID:The identification of four protein kinase C isoforms in human glioblastoma cell lines: PKC alpha, gamma, epsilon, and zeta. 793 20

Our laboratory recently reported that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] rapidly increases the breakdown of membrane phosphoinositides, raises intracellular calcium concentration ([Ca2+]i), and translocates protein kinase C (PKC) from the cytosolic to the particulate fraction of Caco-2 cells. In the present experiments, we found that Caco-2 cells contained predominantly the alpha- and zeta-isoforms of PKC, with minimally detectable amounts of PKC-beta and -epsilon by Western blotting. 1,25(OH)2D3 and the PKC activator 12-O-tetradecanoylphorbol 13-acetate (TPA) each caused time-dependent translocations of PKC-alpha, but not PKC-zeta. TPA treatment of these cells for 24 h induced a significant concentration-dependent downregulation of PKC-alpha, but not PKC-zeta. Since PKC inhibits phospholipase C-induced mobilization of Ca2+ in other cells, we examined the effects of staurosporine and H-7, PKC inhibitors, and TPA on 1,25(OH)2D3-stimulated increase in [Ca2+]i. As previously demonstrated by our laboratory, 1,25(OH)2D3 caused a biphasic increase in [Ca2+]i, with an initial elevation (transient phase) followed by a sustained increase (plateau phase). We previously demonstrated that the transient phase is mediated, at least in part, by an increase in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] stimulated by the secosteroid. Acute pretreatment with staurosporine or H-7 caused a significant stimulation, whereas acute TPA pretreatment caused a significant inhibition of the 1,25(OH)2D3-induced increase in the transient phase of [Ca2+]i. Preincubation of Caco-2 cells with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxy-methyl ester (BAPTA-AM) abolished both the rise in [Ca2+]i and the increase in particulate-associated PKC-alpha stimulated by 1,25(OH)2D3. Moreover, downregulation of PKC-alpha by chronic TPA treatment significantly augmented the transient phase of the 1,25(OH)2D3-stimulated rise in [Ca2+]i but had no effect on the 1,25(OH)2D3-induced change in Ins(1,4,5)P3 concentration. Furthermore, in these PKC-alpha downregulated cells staurosporine no longer increased the secosteroid-stimulated transient rise in [Ca2+]i. These results indicate that 1,25(OH)2D3, which increases [Ca2+]i and diacylglycerol, activates PKC-alpha, but not PKC-zeta. The alpha-isoform, in turn, limits the secosteroid-stimulated rise in [Ca2+]i, at a step distal to Ins(1,4,5)P3 accumulation in Caco-2 cells.
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PMID:1,25(OH)2 vitamin D3 activates PKC-alpha in Caco-2 cells: a mechanism to limit secosteroid-induced rise in [Ca2+]i. 794 45

We have studied effects of ferric transferrin (FeTF), ferric lactoferrin (FeLF), ferric complexes of pyridoxal- or salicylaldehyde-isonicotinoyl hydrazone, (Fe-PIH, Fe-SIH), and ferric ammonium citrate (FAC) on expression of protein kinase C (PKC) mRNA transcripts in a variety of cultured cell lines. FeTF supported an increase of PKC-beta mRNA transcripts in T-lymphoblastoid (CCRF-CEM; Jurkat), B-lymphoblastoid (Daudi; Raji), promyelocyte (HL-60), erythroleukemia (K562), and monocyte (U937) cell lines. By contrast, FeLF, Fe-PIH, and Fe-SIH did not support an increase of PKC-beta mRNA transcripts in any of these cell lines. Furthermore, FAC supported an increase of PKC-beta mRNA transcripts in HL-60, K562, and U937 cells only. Preincubation of cells with desferrioxamine (DF), a cell-permeable iron chelator, abolished the increments of PKC-beta mRNA observed in response to FeTF or FAC. In contrast to results with PKC-beta, neither FeTF nor FAC caused an increase of PKC-alpha transcripts in any cell line. To locate iron-responsive DNA regulatory elements of the PKC-beta gene, we prepared genetic constructs containing various portions of the human PKC-beta 5'-flanking DNA linked to the firefly luciferase gene. Constructs were cotransfected with the neomycin resistance plasmid, Pwl-neo, into HRE H9 cells, and stable transfectants were selected in G418. Treatment with FeTF of transfectants bearing chimeric gene constructs with 2,200 bp of the PKC-beta 5'-flanking region increased luciferase activity and mRNA transcripts 2.5-fold. This increase was blocked by DF. Neither luciferase activity nor mRNA increased with FeTF in stable transfectants bearing constructs with 342 bp or 587 bp of the PKC-beta 5'-flanking region. These data provide direct confirmation that iron is involved in regulation of PKC-beta but not PKC-alpha gene expression in many cell lines. The form in which iron is presented to these cell lines appears to affect its availability for this function, and cells vary in their capabilities to use nontransferrin iron to support PKC-beta gene expression. Finally, transcriptional upregulation of PKC-beta by FeTF is mediated by DNA sequences located between -2200 bp and -587 bp in the 5'-flanking region of the human PKC-beta gene.
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PMID:Regulation of protein kinase C (PKC) expression by iron: effect of different iron compounds on PKC-beta and PKC-alpha gene expression and role of the 5'-flanking region of the PKC-beta gene in the response to ferric transferrin. 794 5


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