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)

12-O-tetradecanoylphorbol-13-acetate (TPA), a phorbol ester that is known as a tumor promoter, induces differentiation of myeloid cells and suppresses their proliferation. We studied the regulation of apoptosis by TPA in human monocytic cell line U937 cells that lack p53. Untreated U937 cells constitutively underwent apoptosis, and TPA enhanced apoptosis in these cells. Further studies showed that TPA increased production of tumor necrosis factor-alpha (TNFalpha) in U937 cells, and exogenously added TNFalpha induced apoptosis. Moreover, the induction of apoptosis by TPA was blocked by anti-TNFalpha antibody. Similar results were obtained in the myeloblastic cell line KY821 cells. We also found that the induction of apoptosis by TPA was increased in cells overexpressed with TNF receptor 1 but not in control cells. Furthermore, TPA failed to induce the production of TNFalpha and apoptosis in cells with either their protein kinase C or mitogen-activated protein kinase pathway blocked. Our results indicate that TPA induces apoptosis, at least in part, through a pathway that requires endogenous production of TNFalpha in U937 cells. Our data also suggest that the induction of apoptosis by TPA occurs through activation of protein kinase C and mitogen-activated protein kinase and TNFalpha is an autocrine-stimulating factor for the induction of apoptosis in these cells.
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PMID:12-O-tetradecanoylphorbol-13-acetate-induced apoptosis is mediated by tumor necrosis factor alpha in human monocytic U937 cells. 1049 85

Several mutations prevent the expression of p53 in the human lymphoblastoid T cell line Jurkat. Restoration of p53 in Jurkat cells had no effect on the cell growth but markedly increased the amount of apoptosis induced by gamma-irradiation. Inhibition of RNA synthesis using 5,6-dichlorobenimidizole riboside had little effect on apoptosis induced by irradiation in the presence of p53 and did not affect the p53-independent apoptotic pathway. Expression of p53 also had no effect on the expression levels of proteins such as Fas, GADD45, Bax, Bcl-2, Bcl-x(L) or p53 induced proteins (PIGS) in resting cells or after irradiation. Activation of protein kinase C by phorbol 12-myristate 13-acetate produced an almost complete inhibition of p53-independent apoptosis following irradiation, whereas no significant effect was observed on the rate of p53-induced apoptosis. Although phorbol 12-myristate 13-acetate strongly induced p21 and stabilised p53 in the resting transfected Jurkat cells, neither apoptosis nor cell arrest was observed. In summary, this work shows that p53 enhances the radiosensitivity of Jurkat cells through an apoptotic process that is triggered by irradiation and is largely independent of RNA synthesis and protein kinase C activation. Apoptosis in p53- negative Jurkat cells is strongly inhibited by PMA indicating that the pathway triggered by p53 may be distinct from apoptotic pathways used in its absence.
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PMID:Contributions of p53 and PMA to gamma-irradiation induced apoptosis in Jurkat cells. 1054 70

The protein kinase C (PKC) signaling pathway plays a key role in tumor cell proliferation, differentiation, and apoptosis. Gastric cancer usually possesses a higher level of PKC activity than normal tissue. We evaluated inhibition of PKC activity in apoptosis induction of gastric cancer cells and the expression profile of apoptosis-related genes. Gastric cancer cells (AGS) were incubated with two highly specific PKC inhibitors (RO-31-8220 and chelerythrine). Cell viability and cell cycle were determined by methyl-tetrazolium (MTT) assay and flow cytometry, respectively. Apoptosis was characterized by acridine orange staining, DNA gel electrophoresis, and flow cytometry. The expression of p53, p21(waf/cip1), c-myc, bcl-2, and bax was determined by western blot. The results showed that both PKC inhibitors hindered cell growth, arrested cells at G0/G1 phase and induced apoptosis. The protein level of p53, p21(waf/cip1), c-myc, and bax was elevated while bcl-2 kept unchanged following drug exposure. In conclusion, PKC inhibitors suppress growth of gastric cancer cells through apoptosis induction and cell cycle quiescence, which may be regulated by differential expression of apoptosis-related genes.
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PMID:Pharmacological inhibition of protein kinase C activity could induce apoptosis in gastric cancer cells by differential regulation of apoptosis-related genes. 1054 53

To examine whether protein kinase C (PKC) and A (PKA) contribute to WAF1 induction by ionizing radiation (IR) in cultured human melanomas, the effect of PK inhibitors 1-(5'-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H7), bisindolylmaleimide (GF) and N-[2(p-dromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H89) on IR-induced WAF1 accumulation was analysed by Western blot analysis. Gamma-ray-induced accumulation of WAF1 showed a peak at 6 Gy in all the cell lines. After gamma-ray irradiation of 6 Gy, a peak of WAF1 accumulation was observed at 6 h in SK-Mel-26, G361 and HM6KO cells, and at 3 h in MeWo cells. In MeWo and SK-Mel-26 cells, the X-ray-induced WAF1 accumulation was decreased by PK inhibitors, GF (PKC inhibitor) or H89 (PKA inhibitor); this did not occur in G361 and HM6KO. In all the cell lines, accumulation of WAF1 induced by X-ray irradiation was suppressed by H7 (PKC and PKA inhibitor). In addition, polymerase chain reaction-single strand conformational polymorphism analysis detected no aberrations in the p53 gene of the four cell lines used. These results suggest that IR-induced WAF1 expression involves PKC and/or PKA activity depending on cell type.
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PMID:Effects of protein kinase inhibitors on radiation-induced WAF1 accumulation in human cultured melanoma cells. 1058 12

Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon neoplasia. Whereas activation is involved in immortalization of neoplastic cells, repression of telomerase permits consecutive shortening of telomeres in a chromosome replication-dependent fashion. This cell cycle-dependent, unidirectional catabolism of telomeres constitutes a mechanism for cells to record the extent of DNA loss and cell division number; when telomeres become critically short, the cells terminate chromosome replication and enter cellular senescence. Although neither the telomere signaling mechanisms nor the mechanisms whereby telomerase is repressed in normal cells and activated in neoplastic cells have been established, inhibition of telomerase has been shown to compromise the growth of cancer cells in culture; conversely, forced expression of the enzyme in senescent human cells extends their life span to one typical of young cells. Thus, to switch telomerase on and off has potentially important implications in anti-aging and anti-cancer therapy. There is abundant evidence that the regulation of telomerase is multifactorial in mammalian cells, involving telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Several proto-oncogenes and tumor suppressor genes have been implicated in the regulation of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2, p21(WAF1), Rb, p53, PKC, Akt/PKB, and protein phosphatase 2A. These findings are evidence for the complexity of telomerase control mechanisms and constitute a point of departure for piecing together an integrated picture of telomerase structure, function, and regulation in aging and tumor development-Liu, J.-P. Studies of the molecular mechanisms in the regulation of telomerase activity.
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PMID:Studies of the molecular mechanisms in the regulation of telomerase activity. 1059 57

In order to obtain additional information on the involvement of protein kinase C (PKC) isoenzymes in the resistance of cells to anticancer drugs and in the induction of apoptosis, we employed antisense oligonucleotides to PKC alpha and PKC zeta, CGP 53506, a new inhibitor of PKC alpha, and cells overexpressing PKC alpha, PKC epsilon and PKC zeta. We found that in HeLa cells which express PKC alpha and zeta, down-modulation of either PKC alpha or PKC zeta with antisense oligonucleotides induced apoptosis. The PKC alpha selective inhibitor CGP 53506 reduced the proliferation rate of PKC alpha overexpressing NIH3T3 cells more than that of wild-type cells and induced apoptosis, indicating that such a PKC alpha inhibitor may be useful in the treatment of tumors overexpressing PKC alpha such as glioblastomas. NIH3T3 cells overexpressing PKC alpha were more resistant, whereas NIH3T3 cells overexpressing PKC epsilon or PKC zeta were more sensitive to treatment with cis-platin, adriamycin or gamma-irradiation compared to parental NIH3T3 wild-type cells. The observed resistance and sensitization corresponded to the extent of apoptosis induced by these treatments. Alterations in the expression of p53, bcl-2 and bax in the PKC isoenzyme overexpressing cells indicate that these proteins may be involved in the different sensitivities of these cells.
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PMID:The involvement of protein kinase C isoenzymes alpha, epsilon and zeta in the sensitivity to antitumor treatment and apoptosis induction. 1062 39

The observations presented in this paper indicate that serum of Dalton's lymphoma (DL) bearing mice contained certain soluble factor(s) that augmented the induction of apoptosis in thymocytes in a time- and dose-dependent manner. DL-ascitic fluid and DL-conditioned medium could also induce apoptosis of thymocytes in vitro, though the magnitude of the same was consistently lower than that induced by serum of DL-bearing mice. It was observed that the interaction of FasL and TNFalpha with their respective receptors could trigger apoptosis in thymocytes. Elucidation of the signal transduction mechanism revealed involvement of protein tyrosine kinase, protein kinase C and ser/thr phosphatases with concomitant increase in the level of protein products of apoptosis associated genes p53, bax, bad, fas and fas ligand and cleavage of N-terminal 23 kDa fragment of Bcl-2 that exhibited Bax-like death effector properties. Further, we report, for the first time, the ability of thymosin alpha-1, an immunopotentiating thymic hormone, to antagonize apoptosis in thymocytes induced by factors present in serum of DL-bearing mice. The underlying mechanism of tumor serum induced apoptosis inhibition by thymosin alpha-1 was also analyzed. The signal transduction cascade evoked by thymosin alpha-1 involves activation of protein kinase C with a decrease in the level of protein products of proapoptotic genes like bax and bad and increase in the protein products of bcl-2 gene.
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PMID:Mechanism of thymocyte apoptosis induced by serum of tumor-bearing host: the molecular events involved and their inhibition by thymosin alpha-1. 1068 4

The development of human cancers is frequently associated with inactivation of the p53 tumour suppressor protein triggering cell cycle arrest or apoptosis in response to cellular stress. The p53 protein has been identified as a transcription factor with sequence-specific DNA binding properties. The DNA-binding activity is cryptic but can be modulated through the C-terminal region of the p53 protein by several different stimuli, including phosphorylation by casein kinase II (CKII), protein kinase C (PKC) or binding of the C-terminal monoclonal antibody PAb421. Monoclonal antibodies to the C-terminal region of p53 protein are able to activate the latent form of p53 and induce binding to DNA. To characterise such antibodies, we used a combination of the PEPSCAN ELISA procedure and a newly developed non-radioactive gel shift assay. Monoclonal antibodies from the Bp53 series displayed higher affinities for the human, rat and mouse p53 proteins than did the conventional antibody PAb421. In addition, these antibodies were able to activate the sequence-specific DNA binding functions in latent forms of p53 protein and, in contrast to PAb421, they were able to recognise both PKC phosphorylated and PKC non-phosphorylated forms of p53 protein. Our monoclonal antibodies recognising post-translationally modified target epitopes in the C-terminal region of p53 protein might assist the development of more effective molecules for p53-based cancer therapy.
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PMID:Precise characterisation of monoclonal antibodies to the C-terminal region of p53 protein using the PEPSCAN ELISA technique and a new non-radioactive gel shift assay. 1072 51

It was found in our previous study that oxidative modification LDL (Ox-LDL) could stimulate the proliferation of cultured human arterial smooth muscle cells (SMC). Yet, the mechanism responsible for the SMC proliferation induced by Ox-LDL is not clear. Proliferating cell nuclear antiger (PCNA), P53 and P27 are the key regulatory factors of cell replication. In order to observe the effects of Ox-LDL on cell cycling phase and PCNA, P53, P27 and c-erb B-2 expression in SMC, we used the flow cytometric method in the present study on the proliferation of cultured human SMC induced by Ox-LDL. The results showed a relation between the Ox-LDL mediated SMC proliferation and the cycling phase shifting. The relative number of S phase cells in the Ox-LDL group was higher than that of the control group (22.9% vs 15.7%). Ox-LDL mediated SMC proliferation was accompanied with the increasing expression of PCNA. The percentage of specific PCNA positive FITC cells in the Ox-LDL group was significantly higher than that of the control group (12.6% vs 6.5%). PMA, an activitor of protein kinase C (PKC), stimulated SMC proliferation and increased the PCNA exression in cultured SMC, while the PKC inhibitor, F109203X, significantly decreased the PCNA expression in SMC (PCNA positive cells 13.4% vs 0.4%). No changes were observed in the expression of P53, P27 and c-erb B-2 in the cultured proliferating SMC induced by Ox-LDL. In all, the results suggest that the OX-LDL mediated SMC proliferation is related to increasing S Phase Cells and involved in the PCNA expression which might undergo the PKC cellular signal transduction pathway.
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PMID:[Effect of Ox-LDL on cell cycling phases and PCNA, P53, P27 and c-erbB-2 expression in cultured human arterial smooth muscle cells]. 1074 36

The predominant pathway for the repair of O(6)-methylguanine in DNA is via the activity of an alkyltransferase protein that transfers the methyl group to a cysteine acceptor site on the protein itself. This review article describes recent studies on this alkyltransferase. The protein repairs not only methyl groups but also 2-chloroethyl-, benzyl- and pyridyloxobutyl-adducts. It acts on double-stranded DNA by flipping the O(6)-guanine adduct out of the DNA helix and into a binding pocket. The free base, O(6)-benzylguanine, is able to bind in this pocket and react with the cysteine, rendering it an effective inactivator of mammalian alkyltransferases. The alkylated form of the protein is rapidly degraded by the ubiquitin/proteasomal system. Some tumor cells do not express alkyltransferase despite having an intact gene. Methylation of key sites in CpG-rich islands in the promoter region are involved in this silencing and a change in the nuclear localization of an enhancer binding protein may also contribute. The alkyltransferase promoter contains Sp1, GRE and AP-1 sites and is slightly inducible by glucocorticoids and protein kinase C activators. There is a complex relationship between p53 and alkyltransferase expression with p53 mediating a rise in alkyltransferase in response to ionizing radiation but having no clear effect on basal levels. DNA adducts at the O(6)-position of guanine are a major factor in the carcinogenic, mutagenic, apoptopic and clastogenic actions of methylating agents and chloroethylating agents. Studies with transgenic mice in which alkyltransferase levels are increased or decreased confirm the importance of this repair pathway in protecting against carcinogenesis. Alkyltransferase activity in tumors protects them from therapeutic agents such as temozolomide and BCNU. This resistance is abolished by O(6)-benzylguanine and this drug is currently in clinical trials to enhance cancer chemotherapy by these agents. Studies are in progress to reduce the toxicity of such therapy towards the bone marrow by gene therapy to express alkyltransferases with mutations imparting resistance to O(6)-benzylguanine at high levels in marrow stem cells. Several polymorphisms in the human alkyltransferase gene have been identified but the significance of these in terms of alkyltransferase action is currently unknown.
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PMID:Repair of O(6)-alkylguanine by alkyltransferases. 1076 20


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