EC:2.7.11.13 - FACTA Search

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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)

We investigated the possible relationship between the susceptibility of cells to differentiation induced by phorbol 12-myristate 13-acetate (PMA) and the subcellular translocation of calcium- and phospholipid-dependent protein kinase (protein kinase C) activity from the cytosol to the membrane. These two events were analyzed in a number of human leukemia cell lines, including four cell variants of the promyelocytic cell line HL-60 that exhibit different degrees of susceptibility to PMA-induced differentiation. The phenotype of the differentiated cells was characterized by increased reactivity with monoclonal antibodies against maturation-specific cell surface antigens, increased nonspecific esterase activity, and acquisition of morphological cell maturation. Analysis of the subcellular distribution of protein kinase C activity in each of these cell types revealed that 90% of the kinase activity was present in the cytosolic fraction, with the remaining activity in the membrane fraction. Treatment of the differentiation-susceptible cells with 160 nM PMA resulted, within 5 min after treatment, in a greater than 60% decrease in protein kinase C activity in the cytosolic fraction and a greater than 1500% increase in the activity in the membrane fraction. No such subcellular redistribution of protein kinase C activity was found after treatment of the differentiation-resistant cells. On the basis of these findings, we suggest that the process of subcellular translocation of protein kinase C activity, initiated after the binding of PMA to this kinase, is required for the induction of cell differentiation by this phorbol diester.
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PMID:Translocation of protein kinase C in human leukemia cells susceptible or resistant to differentiation induced by phorbol 12-myristate 13-acetate. 346 70

Carcinogenesis is a multistep process resulting from a complex interaction between multiple factors, both environmental and exogenous. In contract to initiating agents that act by damaging cellular DNA, the primary targets of the phorbol ester tumor promoters are membrane-associated receptors. We have proposed a stereochemical model to explain the interaction of these amphiphilic molecules, and of teleocidin and aplysiatoxin, with this receptor system. The model is consistent with evidence that a complex between protein kinase C and phospholipid is the actual receptor for these compounds. Recent data we have obtained with a compound present in tung oil, 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA), and twelve of its congener's (provided by Y. Ito et al.) are also consistent with our stereochemical model. We have studied phorbol ester receptors in a wide variety of tissue culture cell types. Our data, together with other findings, provide evidence for considerable receptor heterogeneity and this may relate to the pleiotropic effects of these compounds. We have found a case of "masked" receptors in a rat liver cell line and shown that it is due to a cell-associated esterase. Normal human melanocyte cultures contain phorbol ester receptors and this is of particular interest since these cells actually require these or related compounds for optimal growth (in collaboration with M. Eisinger). The receptor studies provide clues to how tumor promoters can, via inductive mechanisms, produce alterations in the structure and function of cell membranes. It is not known, however, how in the multistep carcinogenic process promoters enhance the eventual outgrowth of permanently altered tumor cells. We have found that TPA and teleocidin produce a marked enhancement of transformation of C3H 10T1/2 cells induced by transfection with h-ras human bladder cancer oncogene. These and other results are discussed in terms of the role of alterations in cellular oncogenes and transcriptional enhancer sequences during multistage carcinogenesis.
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PMID:Molecular mechanisms of tumor promotion and multistage carcinogenesis. 609 83

Bryostatin 5 is a macrocyclic lactone which activates protein kinase C (PKC). PKC activation has been implicated in leukemic cell differentiation. We have examined the effect of PKC activation by bryostatin 5 on human acute myeloid cell differentiation in the presence and absence of vitamin D3. In vitro treatment of 20 patient samples of acute myeloid leukemias in a 4 days culture system with 10 nM bryostatin 5 induced strongly adherent macrophage-like cells in all cases. Bryostatin 5 induced a significant (p = 0.00006) increment in esterase activity in a majority of the samples, which was further enhanced by vitamin D3. CD14 expression was significantly (p = 0.035) enhanced with the combination of bryostatin 5 and vitamin D3. Nitroblue tetrazolium (NBT) reducing ability was, however, nearly abolished (p = 0.0007). A loss of CD34 expression occurred during cell culture; this loss was enhanced by vitamin D3, but prevented partly by bryostatin 5. Together these findings indicate that exposure to bryostatin 5 leads to a strong macrophage-like cell differentiation in human myeloid leukemia and that VD3 has an additional effect. These findings strengthen the potential role of bryostatins as possible antileukemic agents.
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PMID:The differentiation inducing effect of bryostatin 5 on human myeloid blast cells is potentiated by vitamin D3. 750 34

The present studies were undertaken to characterize further the potential role of protein kinase C (PKC) in the regulation of apoptosis in HL-60 promyelocytic leukemia cells. The capacity of acute exposure to specific and nonspecific pharmacological inhibitors of PKC to promote apoptotic DNA fragmentation was examined both quantitatively and qualitatively and correlated with effects on cellular differentiation and proliferation. Incubation of HL-60 cells for 6 h with chelerythrine and calphostin C (highly specific inhibitors that act at the regulatory domain) or H7 and gossypol (nonspecific inhibitors that act at the PKC catalytic domain) produced concentration-dependent increases in DNA fragmentation. Induction of DNA fragmentation by chelerythrine, calphostin C, and gossypol was biphasic, resulting in a sharp decline in effect at concentrations above 5 microM, 0.1 microM, and 100 microM, respectively, whereas maximal and more stable effects were observed in response to H7 (100 microM). A 6-h exposure to staurosporine, a nonspecific but potent PKC inhibitor, failed to induce DNA fragmentation at concentrations generally used to achieve maximal inhibition of enzyme activity (e.g., 50 nM) but promoted fragmentation at considerably higher concentrations (e.g., > or = 200 nM). In contrast, 6-h exposures to the nonspecific protein kinase inhibitor hypericin (0.1 to 100 microM) or to the nonspecific inhibitor of protein kinase A, HA1004 (50 microM), were without effect on DNA fragmentation. DNA obtained from cells exposed to chelerythrine (5 microM), calphostin C (100 nM), H7 (50 microM), gossypol (50 microM), and staurosporine (200 nM)--but not hypericin (25 microM)--exhibited clear evidence of internucleosomal DNA cleavage on agarose gel electrophoresis; moreover, these cells exhibited the classical morphological features of apoptosis (cell shrinkage, nuclear condensation, and the formation of apoptotic bodies). All of the PKC inhibitors that induced apoptosis, and one of the inhibitors that did not (hypericin), substantially inhibited HL-60 cell clonogenicity at the concentrations evaluated. None of the agents tested induced cellular maturation as assessed by nonspecific esterase and nitro-blue tetrazolium positivity. DNA fragments obtained from cells exposed to specific and nonspecific PKC inhibitors possessed predominantly 5'-phosphate termini, consistent with the action of a Ca(2+)-/Mg(2+)-dependent endonuclease. Finally, Northern blot analysis revealed that exposure to calphostin C at a concentration that induced apoptosis (100 nM) failed to alter expression of bcl-2, an oncogene known to block apoptosis in both lymphoid and myeloid leukemia cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Induction of apoptotic DNA fragmentation and cell death in HL-60 human promyelocytic leukemia cells by pharmacological inhibitors of protein kinase C. 751 Oct 48

We examined the expression of eosinophilic granules, esterase activity and CD14 in a human eosinophilic cell line, EoL-1. Unstimulated EoL-1 cells were weakly positive for nonspecific esterase, but negative for surface CD14, and contained a few eosinophilic granule-positive cells. A combination of G-CSF and TNF-alpha increased the eosinophilic granule-containing cells, but failed to increase esterase activity or CD14 expression. IFN-gamma alone or in combination with TNF-alpha enhanced nonspecific esterase activity but failed to induce CD14 expression or increase eosinophilic granule-containing cells. dbcAMP increased eosinophilic granule-containing cells, nonspecific esterase activity and CD14 expression. Specific esterase activity was not detected in any circumstances. EoL-1 cells fractionated by density gradients or CD14 expression showed nonspecific esterase activity and CD14 expression in both the eosinophilic granule-positive and negative cell populations. Forskolin and butyrate had a synergistic effect on CD14 induction and protein kinase A was suggested to play a role in dbcAMP-induced CD14 expression. A protein kinase C activator, phorbol 12-myristate 13-acetate, did not increase eosinophilic granules, nonspecific esterase activity or CD14 expression in EoL-1 cells. The results show that EoL-1 cells can express nonspecific esterase and CD14, but the expression is not necessarily restricted to cells which have differentiated into the monocyte/macrophage lineage.
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PMID:Induction of eosinophilic granules, nonspecific esterase activity and CD14 expression in the human eosinophilic leukemia cell line, EOL-1. 752 48

This study examined the role of protein tyrosine kinase (PTK) and protein kinase C (PKC) in the signal transduction pathways for lymphocyte activation through IL-2R to generate LAK cells and through TCR-CD3 to generate CD3-AK cells. Two PTK inhibitors [herbimycin A and genistein (PTK-I)] and two PKC inhibitors [calphositin C and staurosporine (PKC-I)] were used in the experiments. It was found that the primary activation pathway through IL-2R was PTK-dependent; that is, generation of both the IL-2-induced proliferative and the cytotoxic responses was completely abrogated by PTK-I and not by PKC-I. Quite different results were obtained with the alpha CD3-induced CD3-AK cell response. First, the alpha CD3-induced proliferation was only partially inhibited by PTK-I or PKC-I alone. Second, generation of CD3-AK cytotoxic response was primarily PKC-dependent; that is, only PKC-I induced significant inhibition. Genistein was found to reduce protein tyrosine phosphorylation in both LAK cells and CD3-AK cells, indicating that CD3-AK cells were also susceptible to PTK-I treatment. Further studies showed that PTK-I and not PKC-I suppressed perforin mRNA expression and N-2-benzyoxycarbonyl-L-lysine thiobeneylester esterase production in LAK cells, and the opposite was true for CD3-AK cells. These results indicate that different pathways were employed in lymphocyte activation through IL-2R and TCR-CD3. The former pathway is primarily PTK-dependent. Activation through TCR-CD3 is a more complex event.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential requirement of protein tyrosine kinase and protein kinase C in the generation of IL-2-induced LAK cell and alpha CD3-induced CD3-AK cell responses. 753 36

We investigated the effects of insulin, insulin-like growth factor-I (IGF-I), and phorbol 12-myristate 13-acetate (PMA) on neutral cholesteryl esterase activity in cultured rat vascular smooth muscle cells. Insulin and IGF-I at concentrations between 10(-9) mol/L and 10(-6) mol/L significantly decreased neutral cholesteryl esterase activity in growth-arrested vascular smooth muscle cells in a dose-dependent manner but with no influences on the intracellular concentration of 3',5'-adenosine monophosphate (cyclic AMP). Treatment of cells with KT5720 (10(-7) mol/L to 10(-5) mol/L), a specific inhibitor of cyclic AMP-dependent protein kinase, significantly decreased neutral cholesteryl esterase activity in a dose-dependent manner. Incubation of cells for 6 to 12 hours with PMA (10(-9) mol/L to 10(-6) mol/L), an activator of protein kinase C, significantly increased neutral cholesteryl esterase activity in a dose-dependent manner. However, down-regulation of protein kinase C activity by long-term incubation (18 to 48 hours) with PMA resulted in a significant decrease in neutral cholesteryl esterase activity. Treatment of cells with UCN-01 (10(-7) mol/L to 10(-5) mol/L), a specific protein kinase C inhibitor, decreased the enzyme activity in a dose-dependent manner and completely blocked the activation of the enzyme by PMA. When insulin or IGF-I at a concentration of 10(-6) mol/L was present in the medium containing CL 277,082--an inhibitor of acyl coenzyme A:cholesterol acyltransferase--cellular cholesteryl ester content of the cells significantly increased. In contrast, after the treatment with PMA at a concentration of 10(-6) mol/L in the presence of CL 277,082, the net cholesteryl ester content of the cells significantly declined. These data suggest that both insulin and IGF-I may increase cholesteryl ester accumulation in arterial smooth muscle cells by decreasing arterial cholesteryl ester hydrolysis. The data also suggest that neutral cholesteryl esterase is activated not only by cyclic AMP-dependent protein kinase but also by protein kinase C. Thus growth factors may exert their antilipolytic or lipolytic actions specifically by modulating neutral cholesteryl esterase activity in vascular smooth muscle cells. Neutral cholesteryl esterase of vascular smooth muscle cells may be regulated by recholesteryl esterase of vascular smooth muscle cells may be regulated by reversible phosphorylation, with the phosphorylated form being the active form.
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PMID:Effects of insulin, insulin-like growth factor-I, and phorbol esters on neutral cholesteryl esterase activity in cultured rat vascular smooth muscle cells. 766 69

When an H-2d-specific cytotoxic T lymphocytes (CTL) clone, FC1, was incubated in the presence of 10(-7) M phorbol myristate acetate (PMA) for 10-12 hr, the cytolytic activity of the CTL against H-2d target cells was abrogated, but was reversibly restored to the normal level after subsequent incubation of the cells in PMA-free medium for more than 10 hr. These effects of PMA have been reported (Russell, J.H.: J. Immunol. 133, 907-912 (1984)), but the mode of its action has not been fully investigated. Here, we analyzed the biochemical basis of the PMA-induced loss of cytolytic activity. Cycloheximide completely blocked the restoration of the PMA-suppressed cytolytic activity, suggesting that protein synthesis was required in this process. PMA-treatment did not affect the levels of CD3 and CD8 molecules expressed on the CTL, nor was the level of a CTL-specific serine esterase, BLT esterase, affected by this treatment. However, the target cell-induced release of BLT esterase from the CTL was suppressed if the cells were pretreated with PMA. PMA-treatment of the CTL led to the down-regulation of protein kinase C (PKC) activity by about 50%. On the other hand, staurosporin, an inhibitor of PKC, completely blocked the target cell lysis when added at 10(-6) M. These results suggest that the down-regulation of at least some isoform(s) of PKC is responsible for the PMA-induced loss of the cytotolytic activity of CTL.
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PMID:Phorbol ester-induced reversible inactivation of cytotoxic T cell function: correlation with down-regulation of protein kinase C activity. 772 18

We have tested the effect of several bile acids on the proliferation and differentiation of the HL60 human promyelocytic leukemia cell line in vitro. Deoxycholate, chenodeoxycholate and lithocholic acid caused dose-dependent inhibition of cell proliferation and induction of differentiation along the monocyte/macrophage pathway as determined by morphology, NBT test, non-specific esterase, and staining by monoclonal antibodies against specific cell-surface antigens. Optimal effects were obtained at 100, 75, and 60 microM of the 3 bile acids respectively. Cell-cycle flow-cytometric analysis showed that a substantial fraction of HL60 cells accumulated at the G0/G1 transition. Protein-kinase-C inhibitors such as sphinganine and H-7 inhibited the differentiation-inducing effect of bile acids, suggesting a possible role for PKC in this regulation. When bile acids were combined with non-effective concentrations of all-trans retinoic acid, enhancement of the monocytic differentiation of THP-1 human leukemia cells was observed. Our findings demonstrate induction of tumor-cell differentiation by bile acids, compounds that present minimal undesirable effects in humans.
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PMID:Inhibition of proliferation and induction of monocytic differentiation on HL60 human promyelocytic leukemia cells treated with bile acids in vitro. 792 7

Chronic exposure of humans to benzene (BZ) affects hematopoietic progenitor cells in intermediate stages of differentiation which can lead to aplastic anemia and/or acute myelogenous leukemia and some of its variant forms. We studied the effects of BZ and hydroquinone (HQ), a toxic bone marrow metabolite, on the human HL-60 promyelocytic leukemic cell line. Because the HL-60 cell is bipotential and can be induced to differentiate to monocytes or granulocytes it has been used in many studies as a surrogate for the granulocyte/macrophage committed cell, GM-CFU. Treatment of HL-60 cells with BZ specifically induced differentiation along the granulocytic lineage as measured by morphology, induction of superoxide production and chloroacetate esterase activity and the appearance of the L12-2 surface antigen. Differentiation was induced via the activation of protein kinase C and the phosphorylation of several proteins known to be involved in HL-60 cell differentiation. Subsequent to kinase C activation, arachidonic acid was released from membrane phospholipids and the 5-lipoxygenase pathway was activated for the production of leukotriene D4 (LTD4) required for granulocytic differentiation. BZ induction of granulopoiesis was prevented by preincubation of HL-60 cells with inhibitors of protein kinase C, 5-lipoxygenase, gamma-glutamyl transpeptidase required for the conversion of LTC4 to LTD4, or LTD4 receptor antagonists. Treatment of HL-60 cells with tetraphorbol myristate acetate (TPA), 1 alpha, 25-dihydroxyvitamin D3 (1,25-(OH2)D3) or interleukin-1 (IL-1) induced HL-60 cells to differentiate to monocytes/macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of benzene and hydroquinone on myeloid differentiation of HL-60 promyelocytic leukemia cells. 812 4

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