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 somatic muscle of Ascaris suum is principally under the excitatory control of neuromuscular junction transmitter, acetylcholine (ACh). However, it has recently been shown that neuropeptides also play an important role in the motor-nervous system and one of these, AF3 (AVPGVLRFamide), also contracts muscle. The events which trigger contraction to ACh and AF3 would appear to be different, with ACh activating a nicotinic acetylcholine receptor whilst the response to AF3 is most likely to involve a G-protein coupled receptor negatively coupled to adenylate cyclase. In order to further elucidate differences in the cellular signalling pathways through which ACh and AF3 elicit muscle contraction, we investigated the actions of protein kinase C inhibitors, tamoxifen and chelerythrine, on the dorsal somatic muscle strip of A. suum. Contractions in response to 1 microM AF3 were potentiated by 17% in the presence of 10 microM tamoxifen (P < 0.05; n = 8); however, contractions in response to 10 microM ACh were markedly inhibited (tamoxifen IC50 44 +/- 18 microM; n = 6). Tamoxifen also blocked muscle cell depolarizations to 5 microM ACh (IC50 4 +/- 1 microM; n = 6) and 1 microM levamisole (IC50 14 +/- 6 microM; n = 4). This was unlikely to be a non-specific effect on the membrane as hyperpolarizations to 10 microM GABA were unaffected (93% of control with 10 microM tamoxifen; n = 6; P > 0.05). However, another inhibitor of mammalian protein kinase C, chelerythrine, did not affect the response either to ACh or AF3 (n = 6).
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PMID:The inhibitory action of tamoxifen on the contraction of Ascaris suum somatic muscle in response to acetylcholine. 1063 28

The effect of tamoxifen on oxyhemoglobin-mediated cerebral vasoconstriction was examined. Tamoxifen caused a concentration-dependent relaxation of cerebral artery preparations contracted with oxyhemoglobin and phorbol myristate acetate with the IC(50) values 0.66+/-0.1 and 1.1+/-0.1 microM, respectively. In cerebrovascular smooth muscle cells, oxyhemoglobin and phorbol myristate acetate induced protein kinase C activation, which was 220+/-7% and 203+/-8% of control, respectively. The increase in protein kinase C activity was prevented by tamoxifen. The results suggest that the ability of tamoxifen to reverse vasoconstriction is mediated, at least in part, via inhibition of protein kinase C.
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PMID:Effects of tamoxifen on oxyhemoglobin-induced cerebral vasoconstriction. 1070 22

Tamoxifen inhibits bone resorption by disrupting calmodulin-dependent processes. Since tamoxifen inhibits protein kinase C in other cells, we compared the effects of tamoxifen and the phorbol ester, phorbol myristate acetate, on osteoclast activity. Phorbol esters stimulate bone resorption and calmodulin levels four-fold (k0.5 = 0.1-0.3 microM). In contrast, tamoxifen inhibited osteoclast activity approximately 60% with an IC50 of 1.5 microM, had no apparent effect on protein kinase C activity in whole-cell lysates, and reduced protein kinase C alpha recovered by immunoprecipitation 75%. Phorbol esters stimulated resorption in a time-dependent manner that was closely correlated with a similar-fold increase in calmodulin. Protein kinase C alpha, beta, delta, epsilon, and zeta were all down-regulated in response to phorbol ester treatment. Tamoxifen and trifluoperazine inhibited PMA-dependent increases in bone resorption and calmodulin by 85 +/- 10%. Down-regulation of protein kinase C isoforms by phorbol esters suggests that the observed increases in bone resorption and calmodulin levels are most likely due to a mechanism independent of protein kinase C and dependent on calmodulin. In conclusion, the data suggest that protein kinase C negatively regulates calmodulin expression and support the hypothesis that the effects of both phorbol esters and tamoxifen on osteoclast activity is mediated by calmodulin.
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PMID:Tamoxifen inhibits phorbol ester stimulated osteoclastic bone resorption: an effect mediated by calmodulin. 1120 83

The tumor-promoting phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) cooperates with c-Src overexpression to transform rat fibroblasts. TPA transforms c-Src-overexpressing cells by depleting the delta isoform of protein kinase C (PKCdelta). Tamoxifen, which has both estrogen-mimetic and estrogen-antagonist properties, has been widely used to improve the prognosis of breast cancer patients. However, with extended use, there is an increased risk for endometrial and other cancers that can be observed within 10 years of treatment. We report here that tamoxifen, similar to TPA, cooperates with c-Src overexpression to transform 3Y1 rat fibroblasts. Tamoxifen induced both DNA synthesis and anchorage-independent cell proliferation in c-Src-overexpressing, but not in parental, 3Y1 rat fibroblasts. Tamoxifen also induced an association between c-Src and PKCdelta that resulted in the tyrosine phosphorylation and down-regulation of PKCdelta. These phenotypes were not induced by estrogen, indicating that the effect of tamoxifen was in addition to any estrogen-mimetic effects. Thus, in addition to the hyperplasia-inducing capability of an estrogen-mimetic, tamoxifen has an additional tumor-promoting capability similar to that of TPA. The dual tumor-promoting capability of both estrogen- and TPA-mimetic properties for tamoxifen may contribute to the increased incidence of endometrial cancers observed in the relatively short exposure period of <10 years.
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PMID:Novel tumor-promoting property of tamoxifen. 1133 Dec 47

Tamoxifen (TAM) has been used in the treatment of breast cancer for over a decade. The observed clinical efficacy of TAM has been attributed to both growth arrest and induction of apoptosis within the breast cancer cells. Although the primary mechanism of action of TAM is believed to be through the inhibition of estrogen receptor (ER), research over the years has indicated that additional, non-ER-mediated mechanisms exist. These include modulation of signaling proteins such as protein kinase C (PKC), calmodulin, transforming growth factor-beta (TGFbeta), and the protooncogene c-myc. Recent studies, including those from our laboratory, have implicated the role of caspases and mitogen-activated protein kinases (MAPK), including c-Jun N-terminal kinase (JNK) and p38 in TAM-induced apoptotic signaling. Oxidative stress, mitochondrial permeability transition (MPT), ceramide generation as well as changes in cell membrane fluidity may also play important roles in TAM-induced apoptosis. These various signaling pathways underlying TAM-induced apoptosis will be reviewed in this article.
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PMID:Mechanisms of tamoxifen-induced apoptosis. 1159 37

The effects of zearalenone (ZEA), an estrogenic mycotoxin produced by Fusarium fungi, on bovine neutrophils were investigated in vitro using chemiluninescence, a bactericidal parameter. ZEA suppressed luminol-dependent, phorbol 12-myristate 13-acetate (PMA)-elicited chemiluminescence in a dose-dependent manner at concentrations of 10(-4) M and 10(-5) M. No significant suppression was observed at concentrations lower than 10(-6) M. The possible mode ofaction of 10(-4) M ZEA on the cell activity was investigated with special reference to intracellular Ca2+ ([Ca2+]i) release and estrogen receptors. The 10(-4) M ZEA treatment significantly impaired [Ca2+]i release. When pretreated with a low dose (10(-6) M) of PMA, the cells resisted the ZEA-induced chemiluminescence suppression. However, pretreatment of the cells with the estrogen receptor blockers Tamoxifen and ICl 182,780 (both at 10(-6) M) did not annul the suppressive ZEA action. Considering that PMA is an activator of protein kinase C (PKC), a signal transducing enzyme, and in association with a rise in [Ca2+]i causes cytosolic PKC to shift to the plasma membrane where the activated PKC triggers a varied array of cellular responses, the pharmacological dose of ZEA might have suppressed chemiluminescence by hindering the release of [Ca2+]i and the PKC shift. The results of pretreatment with estrogen receptor blockers, however, did not support the suggestion that the ZEA treatment affected the cells via estrogen receptor pathways.
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PMID:Suppressive effect of zearalenone, an estrogenic mycotoxin, on bovine neutrophil chemiluminescence. 1193 9

We tested the hypothesis that Tamoxifen (TMX), an inhibitor of protein kinase C (PKC), augments the cytotoxicity of photodynamic therapy (PDT) treatment of human (U87) and (U25ln) glioma cells. U87 and U25ln glioma cells were plated and treated with PDT using Photofrin as the sensitizer. Cells were treated with Photofrin at various doses and with various optical (632 nm) irradiation intensities 24 h later. Cells were also treated with Photofrin at a fixed dose alone and with various doses of Tamoxifen and subjected to laser treatment 24 h later. Tumor response was tested using the (3-94,5-dimethyl-2-yl)-2,5-diphenyl-tetrazolium (MTT) method. Total toxicity of U87 cells was achieved with PDT at all doses of Photofrin (1, 2.5, 5, 10 microg/ml) with irradiation densities equal to or greater than 200 mJ/cm2. Using an irradiation intensity of 100 mJ/cm2, U87 and U25ln cells were killed in a Photofrin dose-dependent manner. Significant cytotoxicity was detected with Photofrin doses of 5 microg/ml (p < 0.05) and 10 microg/ml (p < 0.001). Tamoxifen at a dose of 500 microg/ml and higher, significantly increased the toxicity of the PDT response with 5 microg/ml Photofrin and 100 mJ/cm2 (p < 0.05). In summary, our data demonstrate that Tamoxifen significantly enhances the Photofrin PDT activity of U87 and U25ln human glioma cells.
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PMID:Tamoxifen increases photodynamic therapeutic response of U87 and U25ln human glioma cells. 1194 27

17 beta-Estradiol (E(2)) regulates growth plate cartilage cells via classical nuclear receptor mechanisms, as well as by direct effects on the chondrocyte membrane. These direct effects are stereospecific, causing a rapid increase in protein kinase C (PKC) specific activity, are only found in cells from female rats and are mimicked by E(2)-bovine serum albumin (BSA), which cannot penetrate the cell membrane. E(2) and E(2)-BSA stimulate alkaline phosphatase specific activity and proteoglycan sulfation in female rat costochondral cartilage cell cultures, but traditional nuclear receptors do not appear to be involved. This study examined the effect of the anti-estrogen tamoxifen on these markers of chondrocyte differentiation; the gender-specificity of tamoxifen's effect on PKC, if tamoxifen has an effect on vitamin D metabolite-stimulated PKC, which is mediated via specific membrane receptors (1,25-mVDR; 24,25-mVDR) and whether the effect of tamoxifen is mediated by nuclear estrogen receptors. Tamoxifen dose-dependently inhibited the effect of E(2)-BSA on PKC, alkaline phosphatase and proteoglycan sulfation in confluent cultures of female resting zone (RC) cells and growth zone (GC) (prehypertrophic/upper hypertrophic zones) cells, suggesting that its action is at the membrane and not cell maturation-dependent. Neither the estrogen receptor (ER) antagonist ICI 182780 nor the ER agonist diethylstilbesterol affected E(2) or E(2)-BSA-stimulated PKC in female chondrocytes. Tamoxifen also inhibited the increase in PKC activity due to 1 alpha,25-(OH)(2)D(3) or 24R,25-(OH)(2)D(3) in growth plate cells derived from either female or male rats. Inhibition of PKC by tamoxifen may be a general property of membrane receptors involved in rapid responses to hormones.
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PMID:Tamoxifen elicits its anti-estrogen effects in growth plate chondrocytes by inhibiting protein kinase C. 1198 87

Tamoxifen (TAM) is a well-tolerated compound in the treatment of breast cancer and is primarily considered to act by competition with estrogen receptors (ER). Here we investigated the in vitro efficacy and potentially underlying mechanisms of TAM in established cell lines of squamous cell carcinomas of the head and neck (SCCHN). Using proliferation and apoptosis assays the antitumor activity of TAM in five SCCHN and the breast carcinoma line MCF-7 (positive control) was determined. MCF-7 was more sensitive to low-dose TAM (below 1 microM), whereas SCCHN showed significant growth inhibition at higher TAM concentrations (5-10 microM). Growth curve analysis and apoptosis assays were indicative for a cytostatic effect of low-dose TAM and high-dose TAM led to cell loss by apoptosis in sensitive SCCHN. In order to further characterize the observed antitumor effects we determined the amount of steroid hormone receptors with the dextran-coated charcoal method and immunocytochemistry. In addition, production of transforming growth factor (TGF-)-alpha, -beta1 and -beta2 was measured by ELISA, and protein kinase C (PKC) activity was assessed with a radioligand assay. Except MCF-7, none of the SCCHN lines was positive for ER. TAM caused decreased TGF-alpha and increased TGF-beta levels in MCF-7, but not in SCCHN supernatants. Furthermore, the antiestrogen reduced PKC activity in MCF-7, but not in SCCHN. In the present in vitro system, the observed antitumor activity of high-dose TAM in SCCHN cannot be explained by estrogen antagonism, alterations of TGF-alpha/beta levels or decreased PKC activity.
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PMID:Effects of tamoxifen on human squamous cell carcinoma lines of the head and neck. 1204 64

Tamoxifen, the antioestrogenic drug prescribed for long-term, low-dose therapy of breast cancer, induces retinopathy. This study evaluates the effects of tamoxifen on the human retinal pigment epithelial cell line D407, attempting to identify the underlying mechanisms on tamoxifen-induced retinopathy and the involvement of cellular membranes in the cytotoxic action mechanism. We demonstrate that the tamoxifen-induced decrease in the cell growth of the D407 cell line results from pyknosis and cell cycle arrest rather than from necrosis. Furthermore, D407 cells influence the lipid composition of both plasma membrane and intracellular membranes in response to tamoxifen. Tamoxifen increases the physical order of the lipid bilayer. We observed a compensatory decrease in the cholesterol content of the plasma membrane which results in an increase of the plasma membrane fluidity. In intracellular membranes the phosphatidylcholine content is reduced to 50% of the controls. This reduction may be related to the formation of a second messenger via phospholipase pathway and sustained activation of protein kinase C. Since increased plasma membrane fluidity as well as sustained activation of protein kinase C influence the rod outer segments binding and/or ingestion by retinal pigment epithelial cells, our results suggest that membrane-mediated pathways contribute to the tamoxifen-induced retinopathy.
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PMID:Tamoxifen induces changes in the lipid composition of the retinal pigment epithelium cell line D407. 1219 56


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