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)

A novel antibiotic tautomycin induced many blebs on the surface of K562 human chronic myeloid leukemia cells, similar to the morphological changes induced by phorbol esters. However, tautomycin did not induce nitroblue tetrazolium reducing activity, when HL60 human promyelocytic leukemia cells were caused to differentiate by quinomycin into mature granulocytes. It did not induce spread of HL60 cells, one of the phenotypes of mature macrophages. In addition, it did not compete with phorbol dibutyrate to bind to the cell surface of K562 cells. However, tautomycin significantly activated protein kinase C (PKC) extracted from K562 cells. These results indicate that tautomycin is a new activator of PKC, distinct from phorbol esters.
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PMID:Induction of morphological change of human myeloid leukemia and activation of protein kinase C by a novel antibiotic, tautomycin. 316 53

When human promyelocytic leukemia cells (HL-60) are induced by phorbol esters to differentiate to macrophages, the process is accompanied by immediate activation of protein kinase C (PK-C) in the cytoplasm and later changes in DNA and RNA synthesis. Although these events are temporarily related, it remains unclear how activation of this protein kinase leads to changes in nuclear transcription. In this study, we find that bryostatin, a macrocyclic lactone which does not induce differentiation of HL-60 cells but activates PK-C, mimics the effects of phorbol esters on protein phosphorylation and PK-C location. Treatment of HL-60 cells with bryostatin stimulates phosphorylation of the surface transferrin receptor and in the cytoplasm of five proteins having the molecular weights of 17-43 kDa over the same time course as that stimulated by phorbol esters. Similarly, prolonged treatment with bryostatin, like that with phorbol esters, causes the loss of all cellular PK-C activity. Unlike the phosphorylation studies, bryostatin treatment, over a 1-100 nM concentration range and for varying lengths of time, did not affect HL-60 c-myc RNA levels, while phorbol ester treatment rapidly decreased c-myc RNA levels. These data suggest that neither the activation of PK-C and the phosphorylation of specific substrates nor the loss of total cellular PK-C activity from HL-60 cells is sufficient to induce marked decreases in c-myc levels and differentiation of HL-60 cells.
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PMID:Bryostatin induces changes in protein kinase C location and activity without altering c-myc gene expression in human promyelocytic leukemia cells (HL-60). 332 77

The bryostatins, macrocyclic lactones isolated on the basis of their antineoplastic activity, activate protein kinase C in vitro and inhibit phorbol ester binding to the enzyme. In intact cells, the bryostatins induce some phorbol ester responses, such as neutrophil activation, but paradoxically they not only fail to induce other responses, e.g., differentiation in HL-60 promyelocytic leukemia cells, but actually block response to the phorbol esters. We compare here bryostatin I and phorbol 12,13-dibutyrate as inhibitors of cell-cell communication in cultured primary mouse epidermal cells. Like phorbol 12,13-dibutyrate, bryostatin I at nanomolar concentrations markedly inhibited cell coupling. It differed from the phorbol esters, however, in that its action was more transient. By 4 h of incubation bryostatin 1 caused little inhibition of coupling. Moreover, coincubation of bryostatin 1 and phorbol 12,13-dibutyrate gave no greater response at this time than that found for bryostatin 1 alone. Time-dependent inhibition of the protein kinase C pathway could account for many of the observed differences between the actions of the phorbol esters and bryostatin 1.
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PMID:Contrasting duration of inhibition of cell-cell communication in primary mouse epidermal cells by phorbol 12,13-dibutyrate and by bryostatin 1. 342 54

Treatment of human promyelocytic leukemia cells (HL-60) with phorbol 12-myristate 13-acetate or phorbol 12,13-dibutyrate (PDBu) caused a rapid decrease in transcription of the c-myc protooncogene. In the continuous presence of PMA or PDBu, the rate of transcription of c-myc decreased to 20% of control within 2 h and was maintained at 20-30% of the control level for the ensuing 24 h. Cell-permeable sn-1,2-dioctanoylglycerol (diC8), a diacylglycerol analogue, also caused a rapid decrease in c-myc transcription. The decrease in the transcription of c-myc induced by diC8 or PDBu was reversible; prolonged exposure of the cells to either agent for periods greater than 2 h was necessary to maintain the transcription of c-myc below the control rate. With both PDBu and diC8, there was a close correlation between the concentration dependence for binding to the phorbol ester receptor and the concentration dependence for inhibition of c-myc transcription. The decrease in transcription of c-myc induced by PDBu or diC8 appeared to be due to a block of elongation of the nascent mRNA beyond exon 1. The results of this study suggest that prolonged stimulation of protein kinase C (Ca2+/phospholipid-dependent enzyme) is required for persistent inhibition of transcription of c-myc in HL-60 cells.
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PMID:Dioctanoylglycerol and phorbol esters regulate transcription of c-myc in human promyelocytic leukemia cells. 342 30

HL-60 promyelocytic leukemia cells were induced to differentiate by 1,25-dihydroxyvitamin D3 (calcitriol) into mature monocytes. Differentiation was assessed by nitro blue tetrazolium dye reduction, nonspecific esterase activity, and DNA synthesis. Terminal differentiation of cultures induced by calcitriol (10 nM) was inhibited by 80% when cells were treated simultaneously with protein kinase inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) (32 microM) and N-[2-guanidinoethyl]-5-isoquinolinesulfonamide hydrochloride (HA1004) (320 microM). The IC50 for inhibition of calcitriol-induced differentiation was approximately 15 microM for H-7 and 170 microM for HA1004. The IC50 values for H-7 and HA1004 antagonism of calcitriol-induced differentiation are quantitatively and relatively correlated to their known action to inhibit protein kinase C activity. Treatment of cells with concentrations of 0-32 microM H-7 or 0-320 microM HA1004 alone did not affect cell growth, differentiation, or trypan blue exclusion. However, higher concentrations of H7 (greater than 32 microM) and HA1004 (greater than 320 microM) were found to be cytotoxic. The data presented suggest that calcitriol-induced differentiation is antagonized by inhibitors of protein kinase and are consistent with the hypothesis that kinase C activity is required for HL-60 cell differentiation.
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PMID:Effects of protein kinase inhibitors 1(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and N-[2-guanidinoethyl]-5-isoquinolinesulfonamide hydrochloride (HA1004) on calcitriol-induced differentiation of HL-60 cells. 342 61

Activity of the Ca2+/phospholipid-dependent protein kinase C has been shown to increase during differentiation of the human promyelocytic leukemia cell line HL-60 by dimethyl sulfoxide and retinoic acid (Zylber-Katz, E., and Glazer, R. I. (1985) Cancer Res. 45, 5159-5164). Antipeptide antibodies were prepared that specifically recognize the alpha, beta, and gamma isozymes of protein kinase C in rat brain cytosol and HL-60 cell extracts. The three isozymes do not share a common tissue distribution pattern. The gamma enzyme is abundant in brain but a relatively minor component in HL-60 cells; the opposite is true for the alpha enzyme. All three isozymes increase at least 2-fold in abundance in HL-60 cells exposed to 1.2% dimethyl sulfoxide for 48 h. The increase in abundance of the alpha and beta isoforms reaches 7- and 5-fold, respectively, by 96 h without further increase in the abundance of the gamma isozyme. Similarly, all three isozymes increase at least 1.5-fold in abundance after 48 h and 3-fold after 96 h with 1 microM retinoic acid. No further increase in the abundance of any of the isozymes is seen between 96 and 144 h of incubation with retinoic acid. The increase in protein kinase C activity is not limited to the cytosolic forms of the enzyme; a parallel increase in membrane-associated protein kinase C is also observed during differentiation. Approximately 10% of total protein kinase C activity is membrane-associated in both control and differentiating cells. These studies provide the first immunochemical evidence that all three protein kinase C isozymes increase during HL-60 cell differentiation, and they suggest that the increase in the isozyme levels may be coordinately regulated.
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PMID:Immunochemical evidence that three protein kinase C isozymes increase in abundance during HL-60 differentiation induced by dimethyl sulfoxide and retinoic acid. 342 43

Treatment of the human promyelocytic leukemia cell line HL-60, with 12-o-tetradecanoylphorbol acetate (TPA) results in the differentiation into macrophage-like cell. A potent inhibitor of protein kinase C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine(H-7), suppressed the proliferation of HL-60 cells and also inhibited TPA-induced cell differentiation of these cells. N-(2-guanidinoethyl)-5-isoquinolinesulfonamide(HA-1004), a weaker analog of H-7, failed to inhibit this TPA-induced cell differentiation. H-7 also inhibited TPA-induced protein phosphorylation in these cells. Thus, protein kinase C-mediated phosphorylation may be involved in the process of TPA-induced HL-60 cell differentiation.
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PMID:1-(5-Isoquinolinesulfonyl)-2-methylpiperazine(H-7), a potent inhibitor of protein kinases, inhibits the differentiation of HL-60 cells induced by phorbol diester. 346 46

Treatment of human promyelocytic leukemia cells (HL-60 cells) with 12-O-tetradecanoylphorbol 13-acetate (TPA) results in terminal differentiation of the cells to macrophage-like cells. Treatment of the cells with TPA induced marked enhancement of the phosphorylation of 28- and 67-kDa proteins and a decrease in that of a 75-kDa protein. When the cells were treated with diacylglycerol, i.e. 50 micrograms/ml 1-oleoyl-2-acetylglycerol (OAG), similar changes in the phosphorylation of 28-, 67-, and 75-kDa proteins were likewise observed, indicating that OAG actually stimulates protein kinase C in intact HL-60 cells. OAG (1-100 micrograms/ml), which we used, activated partially purified mouse brain protein kinase C in a concentration-dependent manner. Treatment of HL-60 cells with 10 nM TPA for 48 h caused an increase by about 8-fold in cellular acid phosphatase activity. Although a significant increase in acid phosphatase activity was induced by OAG, the effect was scant compared to that of TPA (less than 7% that of TPA). After 48-h exposure to 10 nM TPA, about 95% of the HL-60 cells adhered to culture dishes. On the contrary, treatment of the cells either with OAG (2-100 micrograms/ml) or phospholipase C failed to induce HL-60 cell adhesion. Ca2+ ionophore A23187 failed to act synergistically with OAG. In addition, hourly or bi-hourly cumulative addition of OAG for 24 h also proved ineffective to induce HL-60 cell adhesion. Our present results do not imply that protein kinase C activation is nonessential for TPA-induced HL-60 cell differentiation, but do demonstrate that protein kinase C activation is not the sole event sufficient to induce HL-60 cell differentiation by means of this agent.
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PMID:Failure of 1-oleoyl-2-acetylglycerol to mimic the cell-differentiating action of 12-O-tetradecanoylphorbol 13-acetate in HL-60 cells. 393 52

The phorbol diesters are the most potent inducers of differentiation of the promyelocytic leukemia cell line, HL-60. Soluble phorbol diester receptors from HL-60 cells were obtained from the cytosolic fraction and from the particulate fraction by either divalent ion chelation or detergent extraction. The partially purified soluble phorbol diester receptors required exogenous Ca2+ and phospholipid for maximal binding and displayed a dissociation constant (KD) of 8.1 nM for [3H]phorbol 12,13-dibutyrate. Phorbol diester analogues inhibited [3H]phorbol 12,13-dibutyrate binding in a stereospecific manner consistent with their biologic potency. The soluble phorbol diester receptors prepared by all three methods copurified in a constant ratio with the Ca2+/phospholipid-dependent protein kinase C through ammonium sulfate precipitation, DEAE ion exchange, and gel filtration chromatography. Partially purified protein kinase C was directly activated by the phorbol diesters even in the absence of exogenous Ca2+. The ability of a series of phorbol analogues to activate the kinase correlated with their known activity as inducers of cell differentiation. In addition, phorbol diester stimulation altered the phosphate acceptor substrate profile of protein kinase C, at least in part, by alteration of the Michaelis constant (Km). These data suggest that protein kinase C is the phorbol diester receptor and that phorbol diester-induced macrophage maturation of HL-60 cells may be mediated by activation of intracellular protein kinase C.
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PMID:Possible mechanism of phorbol diester-induced maturation of human promyelocytic leukemia cells. 632 56

Effects of DL-palmitoylcarnitine (PC), an inhibitor of calciumactivated, phospholipid-dependent protein kinase (protein kinase C), on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell differentiation were investigated in human promyelocytic leukemia cells (HL-60). TPA caused HL-60 cell adhesion concomitant with morphological changes, and an increase in acid phosphatase activity. The median effective concentration was 1 nM, which corresponded well to the dissociation constant of [3H]TPA binding to the cell extract. [3H]TPA binding to the cell extract was saturable and reversible. The maximal number of [3H]TPA-binding sites was 1.5 pmol/mg protein and a Hill coefficient was unity, indicating noncooperative interactions. PC, but neither palmitic acid nor DL-carnitine, inhibited the TPA-induced cell adhesion and morphological changes with the median inhibitory concentration of 1 microM, whereas a TPA-induced increase in acid phosphatase activity was not affected by 3 microM PC. Addition of PC 1 or 2 days after the addition of TPA was also effective in inhibiting the cell adhesion. Among various acylcarnitines, PC had the largest effect. [3H]TPA binding to the cell extract was not inhibited by PC at the concentration which was effective in inhibiting the TPA-induced cell adhesion. These results indicate that protein kinase C possibly mediates HL-60 cell differentiation induced by TPA.
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PMID:Inhibition by palmitoylcarnitine of adhesion and morphological changes in HL-60 cells induced by 12-O-tetradecanoylphorbol-13-acetate. 632 91


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