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)

Bacterial lipopolysaccharide (LPS) modulates expression of a variety of genes in macrophages, and additionally activates viral promoters including the HIV-1 LTR. The HIV-1 LTR driving the luciferase reporter gene was stably transfected into the murine macrophage cell line, RAW264. In stably transfected cells, luciferase activity was LPS-dependent. As little as 0.01 ng/ml LPS was sufficient to increase luciferase activity over basal levels with maximal stimulation resulting in a 10- to 20-fold response. The cells also responded to human and murine tumour necrosis factor (TNF alpha). Endogenous TNF alpha was not involved in LPS responses, since pretreatment with alpha-TNF alpha antibody did not affect activation. Induction of HIV-1 LTR activity by LPS occurred independently of phorbol myristate acetate (PMA) sensitive protein kinase C (PKC), since depletion of PKC by prolonged exposure to PMA blocked TNF alpha and PMA responses but was not able to abolish LPS action on these cells. Taxol (5-20 micrograms/ml), a chemotherapeutic agent which mimics LPS action on macrophages, was also able to increase expression of the reporter gene driven by the HIV-1 LTR. However, lower doses of taxol that were not sufficient to trans-activate the LTR or to induce TNF alpha expression were cytotoxic to RAW264 cells suggesting that the cytotoxic and LPS-like activities of taxol were not linked. This cell line provides a convenient method for detecting LPS-like activity and is a useful tool for examining LPS and TNF alpha signalling pathways.
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PMID:RAW264 macrophages stably transfected with an HIV-1 LTR reporter gene provide a sensitive bioassay for analysis of signalling pathways in macrophages stimulated with lipopolysaccharide, TNF-alpha or taxol. 758 58

Taxol has been known to block cell division by stabilizing microtubules with promising anticancer activity. However, taxol has distinct cell cycle-independent effects. Recently, this novel drug has been shown to provide a second signal for murine macrophage activation to tumoricidal activity via L-arginine-dependent nitric oxide (NO) synthesis. To investigate the mechanism of taxol-induced NO synthesis, we evaluated the ability of protein kinase C (PKC) inhibitors such as staurosporine (STSN) or polymyxin B to block taxol-induced effects. Taxol alone had only a small effect, whereas taxol in combination with rIFN-gamma markedly increased NO synthesis in a dose-dependent manner. STSN and polymyxin B decreased NO synthesis, which had been induced by rIFN-gamma plus taxol. Furthermore, prolonged incubation of the cells with phorbol ester, which down-regulates PKC activity, abolished synergistic cooperative effect of taxol with rIFN-gamma on NO synthesis. Synergy between IFN-gamma and taxol was mainly dependent on taxol-induced TNF-alpha secretion because not only the increase of inducible NO synthase (iNOS) gene expression by rIFN-gamma plus taxol was associated with the increased expression of TNF-alpha gene but also taxol-induced NO production was decreased by the treatment of anti-murine TNF-alpha neutralizing Abs. STSN and polymyxin B potently inhibited taxol-induced TNF-alpha secretion and TNF-alpha gene expression as well as iNOS gene expression by rIFN-gamma plus taxol. However, rIFN-gamma plus TNF-alpha-induced NO synthesis was not blocked by STSN or polymyxin B. This result indicates that TNF-alpha-induced signaling for induction of NO synthesis is not dependent on PKC activation, and further suggests that the point at which TNF-alpha acts on the NO synthesis from rIFN-gamma-primed macrophages lies next to the point of PKC activation. In conclusion, the present results strongly suggest that the capacity of taxol to increase NO synthesis from rIFN-gamma-primed macrophages is the result of taxol-induced TNF-alpha secretion via the signal transduction pathway of PKC activation.
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PMID:Involvement of protein kinase C during taxol-induced activation of murine peritoneal macrophages. 775 87

Macrophages play a crucial role in inflammation and host defense, in part, by secreting metabolites of arachidonic acid (20:4). Bacterial lipopolysaccharides (LPS) are poor agonists of the 20:4 cascade, but do have the capacity to prime macrophages for greatly increased 20:4 metabolism upon subsequent stimulation with activators of protein kinase C (PKC). The microtubule-stabilizing agent, taxol, mimics many of the effects of LPS in macrophages. We demonstrate in this study that taxol, like LPS, primes murine peritoneal macrophages for an enhanced release of 20:4 in response to both phorbol 12-myristate 13-acetate (PMA) and zymosan. Taxol and LPS, when used at maximum concentrations, acted additively to prime macrophages for PMA-stimulated release of 20:4, suggesting that the two agents signal through different pathways. Interestingly, agents that stimulate the depolymerization of microtubules, colchicine and nocodazole, also primed macrophages for an enhanced release of 20:4 in response to PMA, however, they did not prime when zymosan was the stimulus. We conclude that agents that disrupt the microtubule network prime resident peritoneal macrophages for enhanced release of 20:4.
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PMID:Microtubule-active agents mimic lipopolysaccharides in priming macrophages for enhanced arachidonic acid metabolism. 873 91

Protein kinase C (PKC) influences cellular sensitivity to cis-diamminedichloroplatinum(II) (cDDP). We have investigated whether the PKC signal transduction pathway is affected during the development of cellular resistance to cDDP. Activators of PKC, such as phorbol 12,13-dibutyrate (PDBu), enhanced the sensitivity of human small cell lung cancer H69 cells to cDDP by 2-fold but had no effect on the sensitivity of cDDP-resistant H69 cells (H69/CP) to cDDP. The maximum sensitization was achieved with 10 nM PDBu and blocked by down-regulation of PKC with higher concentrations of PDBu (1 microM) or bryostatin 1 (0.1 microM). PKC activity was decreased significantly in H69/CP cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cDDP. A modest decrease in PKC activity was also observed in etoposide-resistant H69 (H69/VP-16) cells but not in Taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells. H69 cells expressed conventional PKC alpha and-beta, novel PKC delta, atypical PKC zeta and-iota, and novel/atypical PKC mu. A decrease in cPKC alpha and-beta and an increase in nPKC delta were associated with the cDDP-resistant phenotype. The abundance of aPKC zeta or-iota was unaffected. H69/ VP-16 cells also displayed a reduction in cPKC beta and an increase in nPKC delta. Taxol-resistant H69 cells had no alteration in the expression of any of the PKC isozymes. Thus, a reduction in cPKCs and an increase in nPKC may be associated with cDDP resistance.
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PMID:Characterization of the protein kinase C signal transduction pathway in cisplatin-sensitive and -resistant human small cell lung carcinoma cells. 893 Apr

Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian cancers. Although the primary target of paclitaxel is microtubules, its efficacy exceeds that of conventional microtubule-disrupting agents, suggesting that it may have additional cellular effects. Previously, we demonstrated that paclitaxel can induce interleukin-8 (IL-8) gene expression at the transcriptional level in subsets of human ovarian cancer lines. In this as well as the previous report, we present evidence that this ability is not linked to the lipopolysaccharide pathway of IL-8 gene induction. The present study identifies the cis-acting elements and trans-acting factors involved in this induction by transfecting DNA constructs containing the 5'-flanking region of the IL-8 gene linked to the chloramphenicol acetyltransferase reporter gene into paclitaxel-responsive and nonresponsive ovarian cancer cells (responsiveness refers to the IL-8 response). Paclitaxel only activated the IL-8 promoter in responsive cells. The AP-1 and NF-kappaB binding sites in the IL-8 promoter are required for activation by paclitaxel; in contrast, a C/EBP site required for IL-8 promoter activation in other cell types is not involved. Gel shift assays demonstrate that paclitaxel causes a marked increase in protein binding to the NF-kappaB and AP-1 consensus binding sequences in the paclitaxel-responsive ovarian cells, but not the nonresponsive cells. The induction of NF-kappaB and AP-1 binding is reduced by the addition of protein kinase C inhibitors and cyclic AMP effector, respectively. These results demonstrate a molecular mechanism for cell-specific paclitaxel-induced IL-8 gene expression which may have clinical relevance.
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PMID:Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in the interleukin-8 promoter. 927 87

Telomerase is a specialized ribonucleoprotein polymerase that adds hexanucleotides (TTAGGG) onto human chromosomal ends. The expression of telomerase activity has been associated with cell immortalization and the malignant phenotype in most cancers. How the telomerase activity is regulated in cancer cells is presently not known. In this work, the effects of cell cycle blockers, DNA damaging agents, TopII inhibitors and proteins kinase inhibitors on the telomerase activity were examined in cultured nasopharyngeal carcinoma cells NPC-076. Agents which interfere with tubulin assembly (Taxol and vinblastine) and agents which arrest cells at S phase (methotrexate and 5-fluorouracil) did not inhibit telomerase activity of treated cells. Agents which damage DNA (cisplatin, methyl methanesulfonate, and UV radiation) and TopII inhibitors (etoposide and daunorubicin) also did not inhibit telomerase activity of treated cells. Among the protein kinase inhibitors examined, no significant inhibition of telomerase activity was observed with cells treated with quercetin, H-89, or herbimycin A. On the other hand, two protein kinase C (PKC) inhibitors (bisindolylmaleimide I and H-7) were found to produce a big inhibition of telomerase activity in treated cells. Staurosporine produced a moderate inhibition, and sphingosine had a small inhibitory effect. The inhibition of telomerase activity by PKC inhibitors appears to be specific since the treated cells were mostly viable (i.e., greater than 75%) and still retained significant levels of protein synthesis capability. These results implicate that protein kinase C is involved in the regulation of telomerase activity in vivo.
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PMID:Inhibition of telomerase activity by PKC inhibitors in human nasopharyngeal cancer cells in culture. 943 77

The p34cdc2 kinase is a highly regulated serine-threonine kinase that, when complexed with cyclins A and B, controls cell entry into mitosis. Recently, premature activation of p34cdc2 was shown to be required for apoptosis induced by a wide variety of agents. Here, we show that Taxol induced p34cdc2 kinase activity with a peak at 6 h in human breast carcinoma MCF-7 cells. We subsequently observed that the activation of CPP32/Yama protease as well as the cleavage of its substrate poly(ADP-ribose) polymerase occurred 9 h after Taxol treatment. Olomoucine, a potent p34cdc2 inhibitor, effectively prevented Taxol-induced p34cdc2 kinase activation and subsequent apoptosis. Furthermore, the treatment of cells with cyclin B1-specific antisense oligonucleotide also blocked Taxol-induced apoptosis, suggesting that cyclin B1-associated p34cdc2 kinase plays an important role in the induction of apoptosis by Taxol. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a protein kinase C activator, was found to exert strong protection against Taxol-induced cell death in MCF-7 cells. TPA inhibited Taxol-mediated activation of p34cdc2 kinase by preventing the dephosphorylation of the Tyr-15 residue on p34cdc2 without altering the levels of Cdc2 and cyclin B1. In contrast, the ability of Taxol to enhance tubulin polymerization was not inhibited by TPA. These findings suggest that modulation of protein kinase C signaling can protect against Taxol-induced cell death by inhibiting p34cdc2 kinase activation.
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PMID:Taxol-induced p34cdc2 kinase activation and apoptosis inhibited by 12-O-tetradecanoylphorbol-13-acetate in human breast MCF-7 carcinoma cells. 943 85

Taxol, a microtubule stabilizing agent, has been extensively investigated for its antitumor activity. The cytotoxic effect of taxol is generally attributed to its antimicrotubule activity and is believed to be cell cycle dependent. Herein, we report that taxol induces hyperphosphorylation and reorganization of the vimentin intermediate filament in 9L rat brain tumor cells, in concentration- and time-dependent manner. Phosphorylation of vimentin was maximum at 10(-6) M of taxol treatment for 8 h and diminished at higher (10(-5) M) concentration. Enhanced phosphorylation of vimentin was detectable at 2 h treatment with 10(-6) M taxol and was maximum after 12 h of treatment. Taxol-induced phosphorylation of vimentin was largely abolished in cells pretreated with staurosporine and bisindolymaleimide but was unaffected by H-89, KT-5926, SB203580, genistein, and olomoucine. Thus, protein kinase C may be involved in this process. Hyperphosphorylation of vimentin was accompanied by rounding up of cells as revealed by scanning electron microscopy. Moreover, there was a concomitant reorganization of the vimentin intermediate filament in the taxol-treated cells, whereas the microtubules and the actin microfilaments were less affected. Taken together, our data demonstrate that taxol induces hyperphosphorylation of vimentin with concomitant reorganization of the vimentin intermediate filament and that this process may be mediated via a protein kinase C signaling pathway.
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PMID:Taxol induces concomitant hyperphosphorylation and reorganization of vimentin intermediate filaments in 9L rat brain tumor cells. 949 10

Anticancer drugs have been explored by means of random screening and demonstrated to be active against not only hematologic malignancies but also some solid tumors. Recent progress in the field of molecular biology has identified many new molecular targets for anticancer drugs. In this review, for example, signal-transduction pathways, which are influenced by newer agents like the taxanes (paclitaxel [Taxol] and docetaxel [Taxotere]) and the protein kinase C activator gnidimacrin, are evaluated. Efforts under way to integrate these new compounds into clinical trials are discussed.
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PMID:Overcoming drug resistance in lung cancer. 951 19

Phorbol ester-like protein kinase C (PKC) activators, such as 12-O-tetradecanoylphorbol-13-acetate, and perturbation of some growth factor receptors have been reported to alter the cytotoxicity of cis-diamminedichloroplatinum(II) (CDDP). To study the mechanism of this alteration, we have examined the effect of CDDP per se on PKC isozymes. The SKBR-3 human breast carcinoma cell line exhibits at least six different PKC isozymes (PKC alpha, betaI, betaII, delta, epsilon, and zeta). After exposure to 10-100 microM CDDP for 3 h, only PKC epsilon translocated from the plasma membrane to the nuclear membrane and to the cytosolic fraction. This translocation was observed in a time- and dose-dependent manner by Western blot and confocal microscopy. CDDP also decreased the mobility of PKC epsilon in the nuclear membrane fraction, an effect that was blocked by protein phosphatase 2A, suggesting drug-mediated isozyme phosphorylation. This translocation and phosphorylation were also induced by the cisplatin analogue carboplatin but not with the anticancer agents Adriamycin and Taxol. Antisense oligodeoxynucleotides against PKC epsilon down-regulated isozyme content, blocked drug-induced translocation, and reduced cisplatin-mediated cytotoxicity 3-fold compared to that of sense-treated cells. Antisense PKC epsilon also decreased SKBR-3 cell sensitivity to carboplatin but not to Adriamycin and Taxol. These data support a role for PKC epsilon translocation and phosphorylation on CDDP-mediated toxicity.
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PMID:Protein kinase C epsilon translocation and phosphorylation by cis-diamminedichloroplatinum(II) (CDDP): potential role in CDDP-mediated cytotoxicity. 956 54


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