Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the intracellular processes of the shape change in the human megakaryoblastic leukemia cell, MEG-01, by platelet agonists. Thrombin induced the formation of many pseudopods. This shape change was also induced by TPA and A23187, but not by ADP, collagen, or epinephrine. Electron microscopy and FITC-labeled phalloidin staining revealed thick submembranous microfilament bundles in the pseudopods of the shape-changed cells induced by thrombin. Shape change was inhibited by cytochalasin B. Protein kinase C (RKC) inhibitor, H-7, markedly inhibited thrombin-induced shape change, while the myosin light chain kinase (MLCK) inhibitor, ML-9 did not. These results suggest that thrombin-induced reorganization of microfilaments and shape change of MEG-01 cells are mediated by PKC but not by MLCK.
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PMID:[Shape change in human megakaryoblastic leukemia cells, MEG-01]. 161 74

Abelson murine leukemia virus is an acutely transforming replication-defective virus which encodes a transforming protein with tyrosine-specific protein kinase activity. A variety of benzopyranone and benzothiopyranone derivatives have been identified which selectively inhibit the v-abl tyrosine protein kinase with 50% inhibitory concentrations ranging from 1 to 30 microM. The most active derivative inhibited v-abl with a Ki value of 0.9 microM. Active derivatives showed selectivity for the v-abl tyrosine protein kinase relative to the epidermal growth factor receptor tyrosine protein kinase (50% inhibitory concentration greater than 100 microM). Protein kinase C and protein kinase A, two members of the serine/threonine protein kinase family, were not inhibited by benzopyranones or benzothiopyranones (50% inhibitory concentration greater than 100 microM). Kinetically, a representative derivative (compound 2) showed competitivity with respect to ATP and noncompetitive behavior with respect to the exogenous peptide substrate. Autophosphorylation of p120v-abl and recombinant p70v-abl tyrosine protein kinases were also inhibited by benzopyranones and benzothiopyranones in vitro. When tested in Abelson murine leukemia virus-transformed BALB/c cell, active benzopyranone and benzothiopyranone derivatives inhibited tyrosine phosphorylation of cellular proteins by the v-abl tyrosine protein kinase.
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PMID:Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase. 164 41

The role of protein kinase C in phospholipase A2 (PLA2) activation in rat basophilic leukemia cells (RBL-2H3) and macrophages was investigated. 12-O-Tetradecanoyl phorbol 13-acetate (TPA) doubled ionomycin-induced PLA2 activity, assessed by [3H]arachidonate release. Protein kinase C inhibitors, staurosporine and K252a (100 nM) or H-7 (15 micrograms/ml) inhibited ionomycin-stimulation of PLA2 activity by 62, 75 and 80%, respectively. Down-regulation of protein kinase C by prolonged treatment with TPA inhibited Ca2(+)-ionophore A23187 or antigen-stimulation of [3H]arachidonate release by 80%. We examined whether the inhibitory effect of dexamethasone (DEX) on PLA2 activity is related to modulation of protein kinase C activity. The 50% inhibition by DEX of ionomycin elevation of [3H]arachidonate release was almost overcome by addition of TPA. The Ca2+ ionophore and antigen-induced increase in [3H]TPA binding to intact RBL cells was not impaired by DEX. However, DEX markedly reduced phosphorylation of several proteins. 1-Oleoyl-2-acetyl-glycerol (OAG) had a sustained stimulatory effect on PLA2 activity in isolated plasma membranes derived from treated bone-marrow intact mouse macrophages, while both DEX and staurosporine reduced elevated PLA2 activity by 68 and 84%, respectively. The results support an essential role for protein kinase C in regulation of PLA2 activity.
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PMID:Arachidonic acid release by basophilic leukemia cells and macrophages stimulated by Ca2+ ionophores, antigen and diacylglycerol: essential role for protein kinase C and prevention by glucocorticosteroids. 200 19

We studied the differentiation of acute promyelocytic leukemia (APL) cells in 14 patients with APL. After the induction by retinoic acid (RA) the mature cells rose to 60 +/- 11.8% compared to 0.7 +/- 1% of the control, while the promyelocytes declined to 8.7 +/- 6.4% (93.3 +/- 5.6% in the control group). Protein kinase C (PKC) activity was significantly increased to 149.3 +/- 156.2 pmol/mg per min compared to 47 +/- 40.9 of the control (p less than 0.01). In HL-60 cells, the activity of PKC increased also from 52.3 +/- 35 to 129.2 +/- 64.6 pmol/mg per min (n = 10, p less than 0.01) after the induction of differentiation with RA. If the leukemia cells were pretreated with a kind of PKC inhibitor such as trifluoperazine, the increase of PKC activity was inhibited, and the rate of nitroblue tetrazolium reduction decreased from 89.9 +/- 7.7% to 62 +/- 25% (n = 6, p less than 0.01) and the mature cells reduced from 63.1 +/- 11.7% to 19.7 +/- 12.2% (p less than 0.01). We presumed that the activity of PKC is closely related to the differentiation of human promyelocytic leukemia cells induced by all-trans-retinoic acid.
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PMID:Studies on the relationship between protein kinase C and differentiation of human promyelocytic leukemia cells induced by retinoic acid. 258 42

Protein kinase C (PKC) from human leukemia ML-1 cells was found to be susceptible to inhibition by the antineoplastic anthracycline adriamycin (ADR). Half-maximal inhibition (IC50 value) was observed at 200 microM. However, preincubation of ADR with phosphatidylserine (PS) or PKC enzyme, prior to the enzyme assay, reduced the IC50 value from 200 microM to 52 microM or 40 microM, respectively, indicating an affinity of ADR for PS, and also a possible action site for ADR on PKC molecules. Preincubation of ADR with diacylglycerol (DAG) before the PKC assay resulted in a more pronounced effect, i.e., a more rapid decline of PKC activity with an IC50 value of 7 microM. However, the IC50 for ADR inhibition was not altered when ATP, histone or Ca++ were preincubated with ADR. Studies of the kinetic nature of the inhibition revealed that ADR inhibition assumes competitive kinetics with respect to DAG. Therefore, the mechanism by which ADR inhibits PKC activity may involve a multi-site action: a primary interaction with DAG, and a secondary lower interaction with membrane PS and PKC apoenzyme.
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PMID:Adriamycin interacts with diacylglycerol to inhibit human leukemia protein kinase C. 270 49

Protein kinase C (PKC) was purified to near homogeneity from human leukemia ML-1 cells. The purified enzyme showed a single polypeptide band of 80 kDa on SDS-polyacrylamide gel after electrophoresis, and was totally dependent on Ca2+/phospholipid for activity. Diacylglycerol and the tumor-promoting on Ca2/phospholipid for activity. Diacylglycerol and the tumor-promoting phorbol esters stimulated the enzyme activity. Autophosphorylation of PKC purified from phenyl-Sepharose column showed both 80- and 37 kDa polypeptides. Further fractionation of PKC on a hydroxyapatite column revealed two peaks of enzyme activity, indicating that there may be two different forms of protein kinase C present in human leukemia cells. The purified PKC was used to phosphorylate RNA polymerase II of human leukemia cells in vitro and the autoradiogram showed that RNA polymerase II large subunits (240, 220 and 150 kDa) were phosphorylated in a time-dependent manner.
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PMID:Isolation and purification of protein kinase C from human leukemia ML-1 cells phosphorylation of human leukemia RNA polymerase II in vitro. 275 42

The growth of A65T cells, a mouse thymic leukemia cell line, was strictly dependent on the presence of tumor promoters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), teleocidin and mezerein. In the presence of the tumor promoters, A65T cells proliferated rapidly in a concentration-dependent manner. When the cells were cultured with a synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG) or 1,2-dicaprylin, cell proliferation was not stimulated. In addition, bihourly cumulative addition of OAG or 1,2-dicaprylin again failed to induce A65T cell proliferation. Phospholipase C (PLC) induced a concentration-dependent stimulation of A65T cell proliferation, though the effect was slight compared with that of the tumor promoters. Protein kinase C activity was detected both in cytosol and particulate fractions of A65T cells. When the cells were incubated in the TPA-free medium for 5 h, the protein kinase C activity in the cytosol fraction increased, whereas the activity in the particulate fraction decreased. Treatment of the cells with the tumor promoters mentioned above resulted in the increased phosphorylation of proteins with apparent mol. wts of 27,000 and 68,000. The effects were concentration-dependent and the half maximal phosphorylation was observed either with 3.6 nM TPA, 4.5 ng/ml teleocidin or 0.33 microM mezerein, respectively. On the other hand, a half maximal effect on cell proliferation was observed either with 0.14 nM TPA, 47 pg/ml teleocidin or 6.3 nM mezerein, respectively. At these concentrations, these tumor promoters never induced the detectable stimulations of the protein phosphorylation. A synthetic diacylglycerol 1,2-dicaprylin failed to stimulate the phosphorylation of 27- and 68-kd proteins, but stimulated the phosphorylation of proteins with apparent mol. wts of 100,000 and 54,000. The effect was concentration-dependent and a half maximal stimulation was observed with 35 micrograms/ml 1,2-dicaprylin. Neither TPA, teleocidin nor mezerein stimulated the phosphorylation of these 100- and 54-kd proteins. OAG and PLC failed to induce any detectable alterations in the protein phosphorylation in A65T cells. Both OAG and 1,2-dicaprylin, which we used, actually activated partially purified mouse brain protein kinase C in a concentration-dependent manner. These results clearly demonstrate that in A65T cells TPA and diacylglycerol mutually stimulate the phosphorylation of the completely different set of endogenous proteins, and also suggest that the cell-proliferating effects of the tumor promoters do not appear to be mediated through the phosphorylation of 27- and 68-kd proteins.
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PMID:Differential effects of diacylglycerols and 12-O-tetradecanoylphorbol-13-acetate on protein phosphorylation and cell proliferation of tumor promoter-dependent leukemia cell line A65T. 313 19

Purified RNA polymerase II from chicken leukemia cells was found to be an effective substrate for protein kinase C but not cAMP-dependent protein kinase. Protein kinase C catalyzed the incorporation of 1-2 mol of phosphate per mol of polymerase II and the reaction was totally calcium and lipid dependent. Electrophoresis studies revealed a time-dependent increase of phosphate incorporation into RNA polymerase II subunits of 220 KDa, 180 KDa and 150 KDa, with a preferential phosphorylation of the 180 KDa polypeptide. The phosphorylated enzyme has a preference for using single-stranded DNA as the template for transcription, including transcription of the single-stranded myb oncogene sequence. Phosphoamino acid analysis indicated that both serine and threonine residues were phosphorylated at equal amounts. Phosphorylation by protein kinase C increased the affinity of substrate-polymerase binding and the initial rate of RNA synthesis, suggesting a mechanism by which gene expression can be activated by protein kinase C.
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PMID:Protein kinase C phosphorylates leukemia RNA polymerase II. 347 67

Protein kinase C plays a crucial role in the transmission and control of secretory cell membranal signals. This Ca2+ and phospholipid dependent kinase have been isolated and partially purified from histamine secreting rat basophilic leukemia cells (RBL-2H3 line). The tumor promoter 12-O-tetradecanoyl phorbol-13-acetate ester (TPA) directly activated this isolated enzyme. In the intact RBL-2H3 cells, TPA did not significantly affect free intracellular Ca2+ ions concentration or induce secretion. However, at low concentrations it synergistically enhanced secretion induced either by antigen or ionophore. Significantly, at TPA concentrations exceeding 25 ng/ml both the increase in cytosolic free Ca2+ and the ensuing degranulation were inhibited. The synergism between TPA and the ionophore reaches saturation. These findings suggest that free cytosolic Ca2+ and kinase C-mediated protein phosphorylation are synergistically involved in the mediation of the cellular response. Moreover, kinase C appears to play a dual role both in the activation and termination of secretion. The latter is most probably achieved by closure of the Ca2+ channels in the cells.
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PMID:Protein kinase C, a coupling element between stimulus and secretion of basophils. 624 Apr 39

A human leukemia K562 cell mutant (K562/OA200) selected for resistance to okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A (PP1/PP2A), has been established. In wild type cells, the cytotoxicity of OA was associated with mitotic arrest and concentration- and time-dependent DNA fragmentation, a hallmark of apoptosis. The mutant was 100-fold more resistant to OA in terms of effects on these parameters. Although the synthesis of several proteins was altered, enzyme assay and immunoblot analysis indicated that the levels of PP1 and PP2A were unchanged in the mutant. Protein kinase C (PKC) assays and immunoblot analysis of calcium-dependent (cPKC) and calcium-independent (nPKC) isoforms revealed that nPKC-epsilon was strikingly absent in the mutant, which otherwise expressed in comparable amounts all other isotypes (cPKC-alpha, cPKC-beta, and nPKC-zeta) also present in the wild type. Northern blot analysis confirmed an absence of PKC-epsilon mRNA in the mutant cells. The OA200 cells were cross-resistant not only to another PP1/PP2A inhibitor, calyculin A, but also to structurally unrelated anticancer drugs (such as vinblastine and taxol) and furthermore, overexpressed the verapamil-sensitive drug pump P-glycoprotein at both the protein and mRNA levels. The mutant, however, was not cross-resistant to several PKC inhibitors tested including cardiotoxin, mastoparan, staurosporine, and an alkylphospholipid. Cardiotoxin, at a subtoxic concentration, enhanced by 6-fold vinblastine cytotoxicity in OA200 cells. These findings indicate that the multidrug resistance phenotype can be induced by cytotoxic agents other than conventional anticancer drugs, show that the development of multidrug resistance is not necessarily associated with increased cPKC activity, and identify certain PKC inhibitors that have potential as resistance modulators.
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PMID:Human leukemia K562 cell mutant (K562/OA200) selected for resistance to okadaic acid (protein phosphatase inhibitor) lacks protein kinase C-epsilon, exhibits multidrug resistance phenotype, and expresses drug pump P-glycoprotein. 751 66


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