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

Inhibitors of protein phosphatases 1/2A (okadaic acid and calyculin A) exhibited differential cytotoxicity toward three human leukemia cell lines, in an increasing order of resistance, HL60 less than HL60/ADR less than K562 cells. Cytotoxicity of the toxins was associated with marked mitotic arrest of the cells, characterized by chromatid scattering/overcondensation and abnormal mitotic spindles. In all cases, calyculin A was more potent than okadaic acid. Protein phosphorylation experiments in intact cells revealed that HL60/ADR, the adriamycin-resistant variant, showed a higher overall phosphorylation of nuclear proteins than the drug-sensitive parental HL60, and that phorbol ester (protein kinase C activator) and calyculin A appeared to more specifically stimulate phosphorylation of p66 and p60, respectively. It was suggested that the toxins might be useful in delineating mechanisms underlying certain properties of cancer cells (such as multidrug resistance, mitosis and differentiation) related to protein phosphorylation/dephosphorylation reactions.
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PMID:Comparative effects of protein phosphatase inhibitors (okadaic acid and calyculin A) on human leukemia HL60, HL60/ADR and K562 cells. 132 92

Stimulation of the activity of protein kinase C by pretreatment of cells with phorbol esters was tested for its ability to inhibit signaling by four members of the insulin receptor family, including the human insulin and insulin-like growth factor-I receptors, the human insulin receptor-related receptor, and the Drosophila insulin receptor. Activation of overexpressed protein kinase C alpha resulted in a subsequent inhibition of the ligand-stimulated increase in antiphosphotyrosine-precipitable phosphatidylinositol 3-kinase mediated by the kinase domains of all four receptors. This inhibition varied from 97% for the insulin receptor-related receptor to 65% for the Drosophila insulin receptor. In addition, the activation of protein kinase C alpha inhibited the in situ ligand-stimulated increase in tyrosine phosphorylation of the GTPase-activating protein-associated p60 protein as well as Shc mediated by these receptors. The mechanism for this inhibition was further studied in the case of the insulin-like growth factor-I receptor. Although the in situ phosphorylation of insulin-receptor substrate-1 and p60 by this receptor was inhibited by prior stimulation of protein kinase C alpha, the in vitro tyrosine phosphorylation of these two substrates by this receptor was not decreased by prior stimulation of the protein kinase C alpha in the cells that served as a source of the substrates. Finally, the insulin-like growth factor-I-stimulated increase in cell proliferation was found to be inhibited by prior activation of protein kinase C alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of protein kinase C alpha inhibits signaling by members of the insulin receptor family. 754 65

Recently the cDNA for two different forms of TNF receptor, with gene products of molecular masses of 60 and 80 kDa, have been cloned. In the present report, we investigated the effects of phorbol ester and dibutyryl cAMP on the regulation of the transcript for each type of TNF receptor in U-937 cells. Our results indicate that exposure of these cells to either phorbol ester or dibutyryl cAMP increases the steady state mRNA levels of the 80 kDa form. This effect is dose- and time-dependent. The induction of the p80 receptor transcript by PMA and dibutyryl cAMP was additive suggesting independent mechanisms of induction. Under identical conditions, both agents failed to induce the transcript for the p60 form of the TNF receptor. As demonstrated by actinomycin D pulse-chase experiment, the mRNA for the p80 receptor was found to be highly stable with an approximate half-life of 16 h. No significant change in the half-life was observed when cells were treated with phorbol ester. The mechanisms by which phorbol ester and dibutyryl cAMP induce the upregulation of p80 receptor mRNA appear to be different. Induction of receptor transcript by cycloheximide suggests the presence of a labile repressor protein. Interestingly, the effect of cycloheximide on the induction of the p80 mRNA was found to be additive with that of dibutyryl cAMP but not with phorbol ester. 1-(5-Isoquinolinylsufonyl)-2-methylpiperazine (H7) and N[2-(methylamino) ethyl]-5-isoquinolinesulfonamide (H-8), inhibitors of protein kinase C and protein kinase A, respectively, both inhibited the phorbol ester-mediated induction of the p80-transcript but not that mediated through dibutyryl cAMP. Since dibutyryl cAMP undergoes intracellular dissociation into cAMP and butyric acid, we found that exposure of cells to sodium butyrate alone could induce p80 mRNA in a dose-dependent manner, thus suggesting the role of histone hyperacetylation. Furthermore forskolin treatment, an intracellular inducer of cAMP, increased the receptor transcript level whereas isobutylmethylxanthine, an inhibitor of phosphodiesterase, had no effect. Interestingly, while the p80 form of the TNF receptor mRNA levels was elevated by both phorbol ester and dibutyryl cAMP, only dibutyryl cAMP increased the TNF binding; phorbol ester treatment decreased the binding activity. Thus, our results demonstrate that the genes for the two forms of TNF receptors are differentially regulated. Furthermore, the mechanism of regulation by PMA differs from that by dibutyryl cAMP.
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PMID:Regulation of two forms of the TNF receptors by phorbol ester and dibutyryl cyclic adenosine 3',5'-monophosphate in human histiocytic lymphoma cell line U-937. 768 79

Incubation of B chronic lymphocytic leukemia (B-CLL) cells with phorbol esters resulted in the phosphorylation of three Triton-soluble, heat-stable, acidic proteins with apparent M(r) of 80 KDa, 60 KDa and 43 KDa. The characteristics of the three proteins suggested that they could be related to the myristoylated, alanine-rich, C-kinase substrate (MARCKS). p80 was immunoprecipitated with an antibody against the N-terminal peptide of MARCKS. p43 co-migrated with mouse MRP/Mac-MARCKS (MARCKS-related protein). p60 is the most prominent substrate of protein kinase C in B-CLL cells.
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PMID:Phosphorylation of the MARCKS family of protein kinase C substrates in human B chronic lymphocytic leukemia cells. 776 46

In the present studies, insulin was found to stimulate in a rat hepatoma cell line (called FAO cells) the tyrosine phosphorylation of the 60-kilodalton p21ras GTPase-activating protein (GAP)-associated protein called p60. Surprisingly, the tyrosine phosphorylation of this protein was also almost equally stimulated by an activator of protein kinase C (PKC), the phorbol ester phorbol 12-myristate 13-acetate (PMA). The tyrosine phosphorylation of p60 induced by either agent correlated with the formation of the GAP-p60 complex in situ and an increase in the ability of p60 to directly bind to the SH2 domain of GAP in vitro. Several lines of evidence indicated that the PMA-induced tyrosine phosphorylation of p60 occurred through a different mechanism than that induced by insulin. First, the stimulation of tyrosine phosphorylation of p60 by maximal concentrations of the two agents was almost additive. Second, down-regulation of PKC or pretreatment with a specific inhibitor of PKC abolished the ability of PMA to stimulate tyrosine phosphorylation of p60 but had no effect on the insulin stimulation. And third, long-term pretreatment with insulin abolished the insulin response but did not affect the response to PMA. The PMA effect did seem to be mediated via a tyrosine kinase, since it was blocked by quercetin, an inhibitor of tyrosine kinases. These results indicate that both PMA and insulin can equally stimulate in FAO cells the tyrosine phosphorylation of p60 and its association with GAP, although these two agents seem to act via different signaling systems.
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PMID:Activation of protein kinase C stimulates the tyrosine phosphorylation and guanosine triphosphatase-activating protein association of p60 in rat hepatoma cells. 783 79

Staurosporine, an inhibitor of protein kinase C, is commonly used to inhibit the growth factor-induced signal transduction pathway at the post-receptor level. In this report, we examined the effect of staurosporine on the constitutive expression of tumor necrosis factor (TNF) receptors in K562, a human erythroblastoid leukemic cell line. Exposure of these cells to staurosporine enhanced cell surface expression of TNF receptors by almost 7-fold in a dose- and time-dependent fashion. Maximum induction occurred at a concentration of 20 nM of the agent for 16 h at 37 degrees C. Induction of the TNF receptor was found to be temperature-dependent. No induction was observed at 22 or at 4 degrees C, suggesting the role of cell metabolism. Scatchard analysis indicated an increase in receptor number without any change in receptor affinity. TNF receptors were induced by staurosporine on a wide variety of human cells of both epithelial (primarily p60 receptors) and myeloid (mainly p80 receptor) origin. Receptor-specific antibodies showed that both TNF receptors were induced. The induction was abolished by inhibitors of protein synthesis, thus suggesting the de novo synthesis of the receptor. Furthermore, we found that staurosporine had no effect on the internalization or shedding of the receptor, but it induced the mRNA for both forms of the TNF receptor. Inhibitors of tyrosine kinases had no effect on the induction of TNF receptors. Modulation of the receptor number by staurosporine correlated with the enhancement of antiproliferative effects of TNF against different tumor cells. Thus, overall these results indicate that protein kinase C may be involved in the signal transduction of TNF not only at the postreceptor level but also at the receptor level.
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PMID:Staurosporine induces the cell surface expression of both forms of human tumor necrosis factor receptors on myeloid and epithelial cells and modulates ligand-induced cellular response. 814 8

It is well known that interferon-gamma (IFN-gamma; type II) potentiates various responses of human tumor necrosis factor (TNF) in a wide variety of cells and that this potentiation is accompanied by the up-regulation of TNF receptor synthesis. In the present studies we examined the regulation of TNF receptors by type I and type II IFNs in a hepatocellular carcinoma cell line, HEP G2. Exposure of these cells to IFN-gamma led to a decrease in TNF receptor number (4029 vs. 2719 sites/cell) without any change in the receptor affinity (0.96 nM vs. 1.1 nM). The effect was time and dose-dependent. Like IFN-gamma, IFN-alpha and IFN-beta (type I) down-modulated the TNF receptors on these cells. The effect of IFNs on the TNF receptors was inhibited by staurosporin, a protein kinase C (PK-C) inhibitor. Furthermore, by the use of receptor-specific antibodies, we found that the IFN-dependent decrease was primarily due to the p60 form of the TNF receptor. Our results presented are the first to demonstrate that IFNs can also down-modulate TNF receptors in certain cells and that this effect is mediated through PK-C.
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PMID:Both type I and type II interferons down-regulate human tumor necrosis factor receptors in human hepatocellular carcinoma cell line Hep G2. Role of protein kinase C. 827 22

Teleost nonspecific cytotoxic cells (NCC) initiate various cell triggering responses following receptor-target cell interactions. A putative receptor protein on NCC may alternatively initiate signalling processes following crosslinkage by homologous anti-receptor mab 5C6. In the present study, we demonstrated that binding to this receptor by mab 5C6 produced increased levels of expression of cytoplasmic src family proto-oncogene kinases lck, fyn and src. The phosphorylated isoforms of each kinase were approximately the same molecular weight (p60). Unlike their mammalian T-cell and natural killer (NK) cell counterparts, NCC p56lck did not autophosphorylate on tyrosine residues. This was determined by a lack of Western blot reactivity of teleost p56lck with anti-phosphotyrosine specific antibodies PT-66 or 4G10. Additional evidence for this lack of tyrosine phosphorylation was shown by experiments treating mab 5C6 activated NCC with sodium orthovanadate. This protein tyrosine phosphatase inhibitor did not affect levels of p56lck autophosphorylation. Mab 5C6 activated NCC were also examined to determine if levels of protein kinase C (PKC) expression were affected during triggering responses. Maximum increased PKC levels occurred 5-10 min following binding. The NCC receptor-activated PKC consisted of a 60,000 M(r) isoform and a 30,000 M(r) homologue equivalent to the mammalian PKC catalytic subunit. Not all kinases examined, however, were affected by mab 5C6 binding. Levels of expression of c-myc and cdc2p34 did not change following NCC activation. This is the first study of NK-like cells in cold-blooded vertebrates regarding the expression of these vital intermediary transducing kinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoclonal antibody binding to a receptor on nonspecific cytotoxic cells (NCC) increases the expression of proto-oncogene kinases and protein kinase C. 856 7

Incubation of B-chronic lymphocytic leukemia (B-CLL) cells with phorbol esters resulted in the phosphorylation of two major PKC substrates, MARCKS (myristoylated, alanine-rich C kinase substrate) and MRP (MARCKS-related protein), and of a third protein, with an apparent m.w. of 60,000 that was the most prominent protein kinase C substrate in these cells. p60 phosphorylation was time and PMA dose dependent, and was induced by cell-permeable diacylglycerol, but not by inactive phorbol esters. Two-dimensional electrophoretic analysis of the protein phosphorylation pattern from the B cell line CESS demonstrated the identity between the p60 protein expressed in this cell line and that expressed in B-CLL cells. p60 was purified from CESS cells and peptide microsequencing of this protein revealed that it was lymphocyte-specific protein 1 (LSP1), that is here characterized as the most prominent protein kinase C substrate in B cells.
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PMID:Characterization and purification of a protein kinase C substrate in human B cells. Identification as lymphocyte-specific protein 1 (LSP1). 859 17

Inhibition of insulin receptor signaling by high glucose levels and by TNF-alpha was recently observed in different cell systems. The aim of the present study was to characterize the mechanism of TNF-alpha-induced insulin receptor inhibition and to compare the consequences of TNF-alpha- and hyperglycemia-induced insulin receptor inhibition for signal transduction downstream from the IR. TNF-alpha (0.5-10 nM) and high glucose (25 mM) showed similar rapid kinetics of inhibition (5-10 min, > 50%) of insulin receptor autophosphorylation in NIH3T3 cells overexpressing the human insulin receptor. TNF-alpha effects were completely prevented by the phosphotyrosine phosphatase (PTPase) inhibitors orthovanadate (40 microM) and phenylarsenoxide (35 microM), but they were unaffected by the protein kinase C (PKC) inhibitor H7 (0.1 mM), the phosphatidylinositol-3 kinase inhibitor wortmannin (5 microM), and the thiazolidindione troglitazone (CS045) (2 microgram/ml). In contrast, glucose effects were prevented by PKC inhibitors and CS045 but unaffected by PTPase inhibitors and wortmannin. To assess effects on downstream signaling, tyrosine phosphorylation of the following substrate proteins of the insulin receptor was determined: insulin receptor substrate-1, the coupling protein Shc, focal adhesion kinase (FAK125), and unidentified proteins of 130 kD, 60 kD. Hyperglycemia (25 mM glucose) and TNF-alpha showed analogous (> 50% inhibition) effects on tyrosine phosphorylation of insulin receptor substrate-1, Shc, p60, and p44, whereas opposite effects were observed for tyrosine phosphorylation of FAK125, which is dephosphorylated after insulin stimulation. Whereas TNF-alpha did not prevent insulin-induced dephosphorylation of FAK125, 25 mM glucose blocked this insulin effect completely. In summary, the data suggest that TNF-alpha and high glucose modulate insulin receptor-signaling through different mechanisms: (a) TNF-alpha modulates insulin receptor signals by PTPase activation, whereas glucose acts through activation of PKC. (b) Differences in modulation of the insulin receptor signaling cascade are found with TNF-alpha and high glucose: Hyperglycemia-induced insulin receptor inhibition blocks both insulin receptor-dependent tyrosine phosphorylation and dephosphorylation of insulin receptor substrate proteins. In contrast, TNF-alpha blocks only substrate phosphorylation, and it does not block insulin-induced substrate dephosphorylation. The different effects on FAK125 regulation allow the speculation that long-term cell effects related to FAK125 activity might develop in a different way in hyperglycemia- and TNF-alpha-dependent insulin resistance.
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PMID:Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. 861 80


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