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)

The signaling pathway of protein kinase C (PKC) is known to play a role in mediating the action of various cytokines. Here we examined the signal transduction pathway of PKC activation and the role of PKC isoforms in interleukin-1beta (IL-1beta)-mediated cyclooxygenase-2 (COX-2) expression in human pulmonary epithelial cell line (A549). The tyrosine kinase inhibitors (genistein and tyrphostin AG126) and phosphatidylcholine-phospholipase C inhibitor (D-609) prevented IL-1beta-induced prostaglandin E(2) (PGE(2)) release and COX-2 expression, whereas U-73122 (a phosphatidylinositol-phospholipase C inhibitor) and propranolol (a phosphatidate phosphohydrolase inhibitor) had no effect. The PKC inhibitors (Go 6976 and Ro 31-8220) and NF-kappaB inhibitor, pyrrolidine dithiocarbamate, also attenuated IL-1beta-induced PGE(2) release and COX-2 expression. Western blot analysis using PKC isoenzyme-specific antibodies indicated that A549 cells expressed PKC-alpha, -gamma, -iota, -lambda, -zeta, and -micro. IL-1beta caused the translocation of PKC-gamma but not other isoforms from cytosol to the membrane fraction. Moreover, the translocation of PKC-gamma was inhibited by genistein or D-609, but not by U-73122. IL-1beta caused the translocation of p65 NF-kappaB from cytosol to the nucleus as well as the degradation of IkappaB-alpha in cytosol. Furthermore, the translocation of p65 NF-kappaB was inhibited by genistein, Go 6976, Ro 31-8220, or pyrrolidine dithiocarbamate. These results indicate that in human pulmonary epithelial cells, IL-1beta might activate phosphatidylcholine-phospholipase C through an upstream tyrosine phosphorylation to elicit PKC activation, which in turn initiates NF-kappaB activation, and finally induces COX-2 expression and PGE(2) release. Of the PKC isoforms present in A549 cells, only activation of PKC-gamma is involved in regulating IL-1beta-induced responses.
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PMID:Involvement of protein kinase C-gamma in IL-1beta-induced cyclooxygenase-2 expression in human pulmonary epithelial cells. 1061 76

MS-153, (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline, is a new neuroprotective drug. Recent data in the literature suggest that it inhibits glutamate accumulation occurring during ischemia and the translocation of protein kinase C gamma (PKC gamma). The present study was undertaken to prove the hypothesis that MS-153 blocks neuroreceptors and ion channels involved in glutamate accumulation. Neurons isolated from rat dorsal root ganglia and frontal cortex were used for recording channel currents by the whole-cell patch clamp technique. The effects of bath-applied MS-153 were examined on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels and high voltage-gated calcium channels of dorsal root ganglion neurons, and channels activated by glutamate, N-methyl-D-aspartate (NMDA), kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxarole propionic acid (AMPA), gamma-aminobutyric acid (GABA) and acetylcholine (ACh) in cortical neurons. MS-153 at a concentration of 300 microM had no effect on either tetrodotoxin-sensitive or tetrodotoxin-resistant sodium channels. High voltage-gated calcium channels were either suppressed or not affected by 1-300 microM MS-153. The variable blocking effect of MS-153 was due to the variable activity of intracellular components in individual neurons, especially that of PKC, whose translocation is known to be inhibited by MS-153. When 100 nM phorbol 12-myristate-13-acetate (PMA) was applied to neurons, MS-153 suppressed the calcium channel current more frequently. Calphostin C (0.5 microM), a specific PKC inhibitor, applied intracellularly via recording patch pipette, completely abolished MS-153 suppression of the calcium channel current. Currents induced by glutamate, NMDA, kainate, AMPA, GABA or ACh were not affected by MS-153 at 300 microM. It was concluded that MS-153 inhibited high voltage-gated calcium channels through interactions with PKC, thereby preventing massive release of glutamate from nerve terminals in ischemic conditions.
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PMID:Ion channel modulation as the basis for neuroprotective action of MS-153. 1066 44

Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) have the restricted consensus sequence V/I/xYxxL/V, but may be more broadly defined by the sequence V/I/L/SxYxxL/V/I/S. If one includes the ITIM of CTLA-4, then the sequence becomes psixYxxpsi, where psi represents amino acids with nonpolar side chains. Aside from their presence in various inhibitory molecules, ITIMs are also found on many activating receptors and pathways. ITIMs with the restricted consensus sequence occur on IL-4Ralpha, IL-3Rbeta type II, gp130 cytokineR, OB-R (leptinR), LIF-Rbeta TNF-RI, G-CSF-R, PDGF-R, Blk, Ctk/Ntk, Lsk, Zap-70, PKB/RACalpha, PKC-alpha, PKC-beta, PKC-gamma, PKC-delta, PKC-zeta, PKC-epsilon, PKC-eta, PKC-phi, PKC-mu, calmodulin-dependent kinase IIdelta, SLP-76-associated protein, FYN-binding protein, Shc binding protein, RasGRF2, CDC25 homologue, Jak2, Jak3, PLCbeta1, and PLCbeta3. If ITIMs are defined by a broader consensus sequence, the list of ITIMs on activating molecules becomes even larger. In some instances, these ITIMs have been shown to associate with inhibitory phosphatases. Whether these ITIMs on activating receptors/pathways are necessary and sufficient for negative control of activating events and for immunologic tolerance is not yet known. In some instances, ITIMs on coinhibitory receptors are also required for appropriate negative regulation. By studying events leading to negative control during activation and to immunologic tolerance, it should be possible to discern the balance between antigen receptor-based negative events and coinhibition.
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PMID:Immunoreceptor tyrosine-based inhibitory motifs on activating molecules. 1087 92

To determine the presence of protein kinase C (PKC) isozymes in the septal olfactory epithelium of mice (mSOE), western blotting and immunohistochemistry were performed using antibodies against PKC isozymes. With the exception of PKC-betaI, all of the PKC isozymes were detected in the whole lysate of septal tissue layer and apparent molecular weights for each isoform were found. PKC-alpha, PKC-gamma and PKC-epsilon were detected in the olfactory glandular cells of the lamina propria, and PKC-betaI and PKC-betaII were located in the microvillar cells. Neither novel PKC nor atypical PKC was detected in olfactory glandular cells or microvillar cells, except for PKC-epsilon. PKC-lambda was localized in the mucous layer of the mSOE. Meanwhile, PKC-delta and PKC-xi were distributed in the receptor cells in the mSOE. These data demonstrate the isoform-specific expression of PKC in mSOE and suggest a role for the novel and atypical types of PKC in olfactory transduction.
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PMID:Cellular distribution of isozymes of protein kinase C in septal olfactory epithelium of mice. 1087 81

Protein kinase C (PCK) is a family of isoforms that are implicated in subcellular signal transduction. The authors investigated the distribution of several PKC isoforms (PKC-alpha, PKC-beta, PKC-gamma, PKC-delta, and PKC-epsilon) within major cerebellar cell types as well as cerebellar projection target neurons, including Purkinje neurons, cerebellar nuclear neurons, and secondary vestibular neurons. PKC-alpha, PKC-beta, PKC-gamma, PKC-delta, and PKC-epsilon are found within the cerebellum. Of these isoforms, PKC-gamma and PKC-delta are highly expressed in Purkinje cells. PKC-gamma is expressed in all Purkinje cells, whereas the expression of PKC-delta is restricted to sagittal bands of Purkinje cells in the posterior cerebellar cortex. In the lower folia of the uvula and nodulus, Purkinje cell expression of PKC-delta is uniformly high, and the sagittal banding for PKC-delta expression is absent. Within the cerebellar nuclei, PKC-delta-immunolabeled axons terminate within the medial aspect of the caudal half of the ipsilateral interpositus nucleus. PKC delta-immunolabeled axons also terminated within the caudal medial and descending vestibular nuclei (MVN and DVN, respectively), the parasolitary nucleus (Psol), and the nucleus prepositus hypoglossi (NPH). PKC-gamma-immunolabeled axons terminated in all of the cerebellar nuclei as well as in the lateral and superior vestibular nuclei and the MVN, DVN, Psol, and NPH. The projection patterns of PKC-immunolabeled Purkinje cells were confirmed by lesion-depletion studies in which unilateral uvula-nodular lesions caused depletion of PKC-immunolabeled terminals ipsilateral to the lesion in the vestibular complex. These data identify circuitry that is unique to cerebellar-vestibular interactions.
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PMID:Regional and cellular distribution of protein kinase C in rat cerebellar Purkinje cells. 1105 91

We have previously shown that the antinociceptive effects produced by the delta opioid-selective agonist deltorphin II are preserved in mu-opioid receptor (MOR)-deficient mice. We have now investigated rewarding effects and physical dependence produced by deltorphin II in these animals. Wild-type and MOR-deficient mice were implanted with a cannula into the third ventricle and deltorphin II was administered centrally. The rewarding effects induced by deltorphin II were then investigated using the place preference paradigm. Wild-type mice showed place preference for the compartment previously associated with deltorphin II and this effect was not observed in MOR-deficient mice. In a second experiment, mice received a chronic perfusion of deltorphin II over 6 days, via an Alzet minipump connected to the intraventricular cannula, and withdrawal was precipitated by naloxone administration. Wild-type animals showed a moderate but significant incidence of several somatic signs of withdrawal. This withdrawal response was suppressed in MOR-deficient mice. Analysis of the immunoreactivity levels of PKC-alpha, PKC-beta (I and II) and PKC-gamma isozymes in the cerebral cortex of mice infused chronically with deltorphin II showed a significant up-regulation of all these isozymes in the soluble fraction in wild-type but not in MOR-deficient mice. In conclusion, mu-opioid receptors, which are not involved in deltorphin II antinociception, appear to mediate the effects of chronic deltorphin II on rewarding responses, physical dependence and adaptive changes to PKC.
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PMID:Lack of dependence and rewarding effects of deltorphin II in mu-opioid receptor-deficient mice. 1113 13

Halogenated aromatic hydrocarbon including polychlorinated biphenyls (PCBs) are persistent and bioaccumulative environmental toxicants. Although health effects associated with exposure to these chemicals, including motor dysfunction and impairment in memory and learning, have been identified, their molecular site of action is unknown. Previous study from this laboratory demonstrated that, while ortho PCBs perturbed intracellular signaling mechanisms including Ca2+ homeostasis, receptor-mediated inositol phosphate production and translocation of PKC, non-ortho PCBs did not. Since PKC signaling pathway is implicated in the modulation of motor behavior, as well as learning and memory, and the roles of PKC are isoform-specific, we have now studied the effects of two structurally distinct PCBs on isoforms of PKC in cerebellar granule cell culture model. Cells were exposed to 2,2'-dichlorobiphenyl (ortho PCB; 2,2'-DCB) or 4,4'-dichlorobiphenyl (non-ortho PCB; 4,4'-DCB) for 15 min, respectively, and subsequently fractionated and immunoblotted against the selected PKC monoclonal antibodies (alpha, gamma, delta, epsilon, lambda, iota). While 2,2'-DCB induced a translocation of PKC-alpha [cytosol (% control): 54 +/- 12 at 25 microM and 66 +/- 10 at 50 microM; membrane (% control): 186 +/- 37 at 25 microM and 200 +/- 48 at 50 microM] and -epsilon [cytosol (% control): 92 +/- 12 at 25 microM and 97 +/- 15 at 50 microM; membrane (% control): 143 +/- 23 at 25 microM and 192 +/- 24 at 50 microM] from cytosol to membrane fraction in a concentration-dependent manner, 4,4'-DCB had no effects. 2,2'-DCB induced translocation of PKC-alpha was blocked by pretreatment with sphingosine, suggesting a possible role of sphingolipid pathway. Although reports on implication of PKC-gamma with learning and memory are relatively extensive, the expression of this particular isoform in the primary cerebellar granule cells was below the detectable level. PKC-delta, -lambda and -iota were present in these cells, but were not altered by PCB exposure. These results suggest that the effects of 2,2'-DCB on PKC is isoform-dependent and PKC-alpha as well as PKC-epsilon may be target molecules for ortho-PCBs in neuronal cells.
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PMID:Possible molecular targets of halogenated aromatic hydrocarbons in neuronal cells. 1116 82

Polyunsaturated fatty acids influence the aetiology of prostate cancer. Their effects on cellular mechanisms regulating prostate tumorigenesis are unclear. Using prostate cancer cells (LNCaP), we determined effects of n-9-OA, n-6-LA, and n-3-EPA on total PKC and its isoforms in relation to cell proliferation and PSA production. PKC-alpha, delta, gamma, iota, mu, and zeta were present in LNCaP cells; PKC-beta, epsilon, eta, and theta isoforms were not. PKC-alpha was detected only in cytosol; PKC-delta, iota, gamma, and mu were present in cytosol and in membranes. Fatty acids increased cell proliferation, total PKC activity and elicited pro-proliferative effects on specific PKC isoforms (PKC-delta and -iota). EPA and LA increased total PKC activity and reduced membrane-abundance of PKC-delta. OA reduced cytosolic and membrane PKC-delta. Only EPA reduced PKC-gamma membrane abundance. Fatty acids enhanced cytosolic PKC-iota abundance but only EPA and to a lesser extent LA increased its membrane content. Changes in PKC-delta, -iota, and -gamma did not affect PSA production.
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PMID:Fatty acid regulation of protein kinase C isoforms in prostate cancer cells. 1135 56

It was previously determined that ANG II and phorbol esters inhibit Kv current in neurons cultured from newborn rat hypothalamus and brain stem in a protein kinase C (PKC)- and Ca2+-dependent manner. Here, we have further defined this signaling pathway by investigating the roles of "physiological" activators of PKC and different PKC isozymes. The cell-permeable PKC activators, diacylglycerol (DAG) analogs 1,2-dioctanoyl-sn-glycerol (1 micromol/l, n = 7) and 1-oleoyl-2-acetyl-sn-glycerol (1 micromol/l, n = 6), mimicked the effect of ANG II and inhibited Kv current. These effects were abolished by the PKC inhibitor chelerythrine (1 micromol/l, n = 5) or by chelation of internal Ca2+ (n = 8). PKC antisense (AS) oligodeoxynucleotides (2 micromol/l) against Ca2+-dependent PKC isoforms were applied to the neurons to manipulate the endogenous levels of PKC. PKC-alpha-AS (n = 4) treatment abolished the inhibitory effects of ANG II and 1-oleoyl-2-acetyl-sn-glycerol on Kv current, whereas PKC-beta-AS (n = 4) and PKC-gamma-AS (n = 4) did not. These results suggest that the angiotensin type 1 receptor-mediated effects of ANG II on neuronal Kv current involve activation of PKC-alpha.
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PMID:ANG II-mediated inhibition of neuronal delayed rectifier K+ current: role of protein kinase C-alpha. 1461 46

Euxanthone, a potent neuritogenic compound isolated from the roots of the medicinal herb Polygala caudata, has recently been shown to induce the differentiation of murine neuroblastoma Neuro 2A (BU-1) cells. In this study, the role of protein kinase C (PKC) and the expression of various PKC isoforms in euxanthone-treated BU-1 cells were examined. mRNA phenotyping using the reverse-transcription polymerase chain reaction (RT-PCR) showed that BU-1 cells express six different PKC isoforms, namely PKC-alpha, -beta, -delta, -epsilon, -lambda, and -zeta. Differential regulation and expression of PKC isoforms was observed in BU-1 cells treated with 100 microM euxanthone. PKC-apha, -beta, -delta, -lambda and -zeta were all up-regulated, with 1.7- to 9.5-fold increase, at around 30 to 60 minutes after euxanthone treatment. The expression level of PKC-epsilon remained relatively constant during the treatment. PKC-gamma, -eta, and -theta were not detected in both untreated and euxanthone-treated BU-1 cells. Staurosporine, a broad spectrum PKC inhibitor, was found to inhibit both spontaneous and euxanthone-induced neuritogenesis in BU-1 cells. A significant reduction of the euxanthone-induced neuritogenic effect was also observed when the PKC isoform-specific inhibitor Go6976 was included in the culture. These results suggest that the euxanthone-induced differentiation of the neuroblastoma BU-1 cells may be mediated through the differential expression of PKC-alpha, -beta, -delta, -lambda and -zeta isoforms.
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PMID:Expression of protein kinase C isoforms in euxanthone-induced differentiation of neuroblastoma cells. 1148 51


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