Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phorbol esters cause long term activation of protein kinase C (PKC) and frequently the down-regulation of PKC protein levels in mammalian cells. Mammalian PKC-gamma, -delta, and -eta down-regulated in response to phorbol esters when expressed in Schizosaccharomyces pombe. However, PKC-epsilon does not down-regulate in S. pombe, in contrast to the behavior of this isotype in mammalian cells. Co-expression of PKC-gamma or -delta with PKC-epsilon in S. pombe renders PKC-epsilon susceptible to down-regulation. A protein kinase defective form of PKC-delta does not down-regulate efficiently in S. pombe but, like PKC-epsilon, is susceptible when co-expressed with PKC-gamma or full-length PKC-delta. Thus, down-regulation is a consequence of the catalytic function of certain PKC isotypes with other isotypes being affected in trans. PKC down-regulation parallels a striking accumulation of vesicles in S. pombe, suggesting a direct relationship between these events.
 ...
PMID:Protein kinase C (PKC)-induced PKC down-regulation. Association with up-regulation of vesicle traffic. 785 35

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)
 ...
PMID:Developmental expression of protein kinase C isozymes in oligodendrocytes and their differential modulation by 4 beta-phorbol-12,13-dibutyrate. 786 20

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.
 ...
PMID:The identification of four protein kinase C isoforms in human glioblastoma cell lines: PKC alpha, gamma, epsilon, and zeta. 793 20

Changes in neocortical immunoreactivity (ir) for muscarinic acetylcholine receptors (mAChRs), protein kinase C gamma (PKC gamma), microtubule-associated protein 2 (MAP-2), and the calcium-binding protein parvalbumin (PARV) induced by the performance of a one-trial passive shock avoidance (PSA) task were studied in young adult male Wistar rats. In experiment I, four groups of animals were formed: three control groups (N, naive; H, habituated but nonshocked; and S, habituated and shocked), and a fully trained group (T, habituated and shocked, followed by a retention trial 24 hr after the footshock). Compared to naive animals, the H, S, and T animals all revealed enhanced cortical ir for mAChRs, PKC gamma, and MAP-2 in discrete subsets of cortical neurons in layers 2, 3, and 5, while no changes were found for PARV. The neurons displaying enhanced levels of ir are of the pyramidal and nonpyramidal cell type and are arranged in a columnar manner. Immunofluorescent double-labeling experiments for mAChR, PKC gamma, and MAP-2 revealed that individual cortical neurons localized within the columns display enhanced ir for all three functionally related proteins. Compared to naive animals, all experimental groups revealed significant increases in the total size of cortical areas showing enhanced ir (H, S, and T over N). A further significant increase is found in animals receiving a footshock over nonshocked animals (S over H, respectively). The retention trial, however, did not induce a further increase (T over S). In some of the animals the patterns appeared to be lateralized, in either the left or right hemisphere. In order to test the role of cholinergic innervation in the induction of enhanced mAChR-ir, unilateral lesions of the nucleus basalis magnocellularis (nbm) were performed in experiment II. Apparently, an intact cholinergic innervation from the nbm is not required for the occurrence of the aforementioned columnar patterns. However, when the enhanced columnar patterns in the sensory areas of the cortex are cholinergically deprived, clear deficits in PSA performance are observed. These results indicate that although ACh is not a prerequisite for the induction of enhanced ir for mAChRs in cortical cells, such neurons demand cholinergic neurotransmission for optimal retention of the shock experience. The alterations in ir for coexpressed mAChR, PKC gamma, and MAP-2 in a discrete subset of cholinoceptive cortical neurons arranged in characteristic patterns most likely represent part of the neuronal substrate involved in functional cortical plasticity related to PSA training.
 ...
PMID:Passive avoidance training induces enhanced levels of immunoreactivity for muscarinic acetylcholine receptor and coexpressed PKC gamma and MAP-2 in rat cortical neurons. 795 Mar 10

The regulatory domain of protein kinase C gamma (PKC gamma) contains the following functional elements which can interact with lipids: the pseudosubstrate motif within the first variable region (V1), cysteine-rich domains, Cys1 and Cys2 which contain zinc and bind phorbol dibutyrate (PDBu)/diacylglycerol, and the calcium-dependent lipid binding domain (CaLB). The function of individual or combined segments of the regulatory domain was investigated, using glutathione S-transferase (GST) fusion proteins and mixed micellar or liposomal assays. GST-Cys1 and GST-Cys2 bound PDBu with comparable affinity (Kd = 14-17 nM). GST-Cys1Cys2 yielded a protein with a PDBu binding affinity of 3.4 nM, in the presence of calcium, similar to that of intact PKC gamma (Kd = 2.6 nM). The phosphatidylserine (PS) dependence of PDBu binding was highly cooperative for all fusion proteins tested with Hill numbers (n) lying in the range of 3.5-4.8, similar to values obtained for intact PKC gamma. While Hill numbers were similar under all conditions, the PS concentration necessary for half-maximal PDBu binding was dependent upon the nature and presence of divalent cations. The PS requirement was lowest in the presence of calcium for GST-Cys1, GST-Cys2, and GST-Cys1Cys2 (Km for PS = 11, 14, and 12 mol %, respectively) but still significantly above the value for intact PKC gamma (5.4 mol %). The data establish Cys1 and Cys2 as independent PDBu binding domains that are modulated by divalent cations. While PDBu binding affinity to a GST-V1Cys1 fusion protein (Kd = 36 nM) was comparable to that of GST-Cys1, the CaLB domain dramatically reduced PDBu binding affinity of GST-Cys2CaLB (Kd = 912 nM). This effect of the CaLB domain on PDBu binding to Cys2 suggests that PDBu/diacylglycerol binding to native PKC gamma may occur at Cys1 and that the Cys2 domain may serve another regulatory function.
 ...
PMID:The regulatory region of protein kinase C gamma. Studies of phorbol ester binding to individual and combined functional segments expressed as glutathione S-transferase fusion proteins indicate a complex mechanism of regulation by phospholipids, phorbol esters, and divalent cations. 805 Oct 84

Protein kinase C isoenzymes can be subdivided into two classes, based on their requirement for calcium. Protein kinase C-alpha, beta I, -beta II, and -gamma are calcium dependent, whereas protein kinase C-gamma, -epsilon, -zeta, -eta, and -theta are calcium independent. We have examined the expression, translocation, downregulation, and activation of calcium-dependent and -independent protein kinase C isoenzymes in human skin keratinocytes and fibroblasts. Human keratinocytes and fibroblasts expressed protein kinase C-alpha, -delta, -epsilon, and -zeta mRNA and protein, whereas protein kinase C-eta (L) was detected only in keratinocytes. Protein kinase C-beta I, -beta II, -gamma, and -theta were not detected in either cell type. The protein kinase C activators 12-0-tetradecanoylphorbol 13-acetate and bryostatin-1 (50 nM, for 5 min) induced translocation of protein kinase C-alpha and -epsilon cytosol to membrane in both keratinocytes and fibroblasts. 12-0-tetradecanoylphorbol 13-acetate and bryostatin-1, for 18 h, induced complete downregulation (i.e., loss) of protein kinase C-alpha and -epsilon in keratinocytes, but only partial downregulation was observed in fibroblasts. The subcellular distribution of protein kinase C-delta, -zeta or protein kinase C-eta, in keratinocytes or fibroblasts, did not change in response to 12-0-tetradecanoylphorbol 13-acetate or bryostatin-1. These data indicate differential expression, subcellular distribution, and regulation of protein kinase C isoenzymes in human skin cells.
 ...
PMID:Translocation and downregulation of protein kinase C isoenzymes-alpha and -epsilon by phorbol ester and bryostatin-1 in human keratinocytes and fibroblasts. 807 2

In this study we explored the pattern of protein kinase C (PKC) isozyme selectivity of the bryostatins, a unique class of PKC activators that induce only a subset of the typical phorbol ester responses and antagonize those phorbol ester-mediated responses that they themselves fail to induce. The binding properties of individual recombinant PKC isozymes that had been expressed in insect cells, isolated, and reconstituted in Triton X-100/phosphatidylserine mixed micelles were determined. [3H]Bryostatin 1 showed lower affinity for PKC-beta 1 and -gamma, compared with PKC-alpha, -delta, -epsilon, and -eta. This pattern contrasts with that observed for other PKC ligands. These latter assays were conducted with isozymes reconstituted in phosphatidylserine, conditions that unfortunately do not permit quantitation of bryostatin 1 binding under equilibrium conditions. Using delta 19,20-bryostatin 10 and delta 19,20-isobryostatin 10, we could distinguish the respective roles of ligand and lipid in the pattern of selectivity. When isozymes were reconstituted in phosphatidylserine vesicles, delta 19,20-bryostatin 10 and delta 19,20-isobryostatin 10 showed similar affinities for PKC-alpha and -gamma, similarly to the phorbol esters. However, in the mixed micellar system, PKC-gamma showed a significantly lower binding affinity, as had been observed for bryostatin 1. These results suggest that the unique pattern of biological responses to the bryostatins does not represent a unique pattern of isotype recognition. Furthermore, the lipid environment of PKC plays an important role in determining the binding selectivity for individual isozymes.
 ...
PMID:Binding of [26-3H]bryostatin 1 and analogs to calcium-dependent and calcium-independent protein kinase C isozymes. 807 99

The involvement of protein kinase C (PKC) in the mechanism of chemotaxis and invasiveness of human melanoma has been studied in 6 clones of 665/2 cell line characterized by a different integrin profile, differentiation grade and in vitro invasive ability. The levels of total protein kinase C activity revealed a direct correlation with the chemotactic and invasive ability of these clones. Protein kinase C inhibitors, sphingosine and staurosporine, reduced chemotaxis and invasiveness of the highly invasive clone 2/60, while 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) was ineffective. Immunofluorescence analysis revealed high levels of protein kinase C alpha in clone 2/60, while the less invasive clone 2/21 expressed low levels of protein kinase C alpha and beta, but surprisingly appreciable levels of protein kinase C gamma. Downregulation with phorbol 12-myristate 13-acetate (TPA) did not affect invasiveness of clone 2/60 unless the compound was present during the assay. H7 strongly increased invasiveness of clone 2/21 and was able to reverse the inhibitory effect of TPA on clone 2/60. Preliminary experiments showed higher levels of diacylglycerol in clones with lower protein kinase C, suggesting a constitutive downregulation of the enzyme in low invasive clones. Our results support a role for protein kinase C in the invasion process, but point out the complexity of the mechanism which might involve the proteolytic fragment of the enzyme, protein kinase M.
 ...
PMID:Effect of protein kinase C inhibitors on invasiveness of human melanoma clones expressing different levels of protein kinase C isoenzymes. 815 65

The protein kinase C (pkc) enzymes are a family of serine-threonine protein kinases, each encoded by a distinct and separate gene. The chromosomal locations of human PRKCA, PRKCB, and PRKCG have previously been established. We now report that PRKCD, a novel member of the pkc gene family, maps to human chromosome 3. The chromosomal location of Pkcd has also been determined in the mouse by analysis of recombination frequency in an interspecific panel of backcross mice. We find that the locus encoding pkcd resides proximal to nucleoside phosphorylase (Np-2) and Tcra on mouse chromosome 14 in a region syntenic with human 3p.
 ...
PMID:Assignment of the protein kinase C delta polypeptide gene (PRKCD) to human chromosome 3 and mouse chromosome 14. 818 19

Human immunodeficiency virus 1 (HIV-1) and its purified proteins activate target cell functions. Because protein kinase C (PKC) plays a crucial role in signal transduction and there is a molecular heterogeneity of PKC, we compared the effect of recombinant HIV-1 gp120 and phorbol ester (PMA) on PKC isozymes in monocytic U937 cells, with isozyme-specific antibodies using flow cytometry. All PKC isozymes except PKC-gamma were present in U937 cells. Both PMA and HIV-1 gp120 increased levels of calcium-dependent and -independent PKC isozymes. The most striking change was observed in PKC-zeta isozymes levels. This study for the first time demonstrates that HIV-1 gp120 affects calcium-independent PKC isozymes in U937 cells.
 ...
PMID:Human immunodeficiency virus-1 recombinant gp120 induces changes in protein kinase C isozymes--a preliminary report. 820 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>