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)

Prior studies demonstrated that ceramide was phosphorylated by a novel Ca(2+)-dependent kinase distinct from diacylglycerol (DG) kinase in human myelogenous leukemia (HL-60) cells (Kolesnick, R. N., and Hemer, M. R. (1990) J. Biol. Chem. 265, 10900-10904). The present studies were initiated to determine whether mammalian DG kinase purified to homogeneity possessed phosphotransferase activity toward ceramide. A high molecular weight rat brain DG kinase demonstrated Mg(2+)-(but not Ca(2+)-) dependent DG kinase activity and did not phosphorylate ceramide in the presence of either cation. In contrast, ceramide served as a competitive inhibitor with an inhibition constant (Ki) 2-6-fold greater than the Km for DG. Inhibition was noncompetitive with respect to ATP and Mg2+. A cell-permeable ceramide, N-octanoyl sphingosine (C8-cer), was used to study effects of ceramide on DG kinase in intact HL-60 cells. C8-cer induced dose- and time-dependent increases in cellular DG levels. As little as 1 microM C8-cer increased DG from a basal level of 103 to 177 pmol.10(6) cells-1, and a maximal 2.9-fold elevation to 292 pmol.10(6) cells-1 occurred with 10 microM C8-cer. DG elevation was detected after 1 min, maximal by 7.5 min, and sustained for 30 min. The DG elevation was accompanied by a reduction in 32P incorporation in phosphatidic acid in cells short term-labeled with [32P]orthophosphoric acid, consistent with inhibition of DG kinase. In contrast, a similar elevation in the DG level induced by exogenous phospholipase C increased 32P incorporation into phosphatidic acid. C8-cer was not metabolized to sphingomyelin, indicating that DG was not generated through the phosphatidylcholine:ceramide cholinephosphotransferase reaction. DG elevation after C8-cer or phospholipase C treatment was sufficient to redistribute protein kinase C from cytosol to membrane. These findings provide evidence that ceramide may serve as a competitive inhibitor of DG kinase.
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PMID:Ceramide is a competitive inhibitor of diacylglycerol kinase in vitro and in intact human leukemia (HL-60) cells. 130 77

CD34 is a transmembrane sialoglycoprotein expressed by early hematopoietic progenitor cells as well as endothelial cells. Previously we found that CD34 is rapidly and stoichiometrically phosphorylated by activated protein kinase C (PKC) (Fackler, M.J., Civin, C.I., Sutherland, D.R., Baker, M.A., and May, W.S. (1990) J. Biol. Chem. 265, 11056-11061). In the present study, we find dose-dependent up-regulation of CD34 surface expression following treatment of normal human CD34+ bone marrow progenitor cells, cord blood-derived KMT-2, or KG1 a myeloid leukemia cells with the PKC activator 12-O-tetradecanoylphorbol-13-acetate. Up-regulation begins within 1 min of treatment, is maximal by 30 min, is maintained for at least 3 h, and is associated with CD34 hyperphosphorylation. A specific inhibitor of PKC, 2,6-diamino-N-(1[1-(1-oxotridecyl)-2-piperadinyl]methyl)h exan-amide (NPC 15437), blocks both up-regulation and hyperphosphorylation of CD34. CD34 up-regulation is independent of transcription and/or translation and results from the recruitment of preformed intracellular CD34. The endocytosis rate of surface CD34 is unaltered by 12-O-tetradecanoylphorbol-13-acetate. Thus, activation of PKC mediates increased surface expression of the CD34 molecule possibly as a result of phosphorylation of CD34.
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PMID:Up-regulation of surface CD34 is associated with protein kinase C-mediated hyperphosphorylation of CD34. 138 51

We have previously reported (J. P. Durkin et al., Blood, 79: 1161-1171, 1992) the isolation of a human differentiation-inhibiting protein (DIP) which selectively inhibits and blocks the differentiation of erythroid burst-forming unit progenitor cells in bone marrow colony assay, and the dimethyl sulfoxide (DMSO)-induced differentiation of cultured murine erythroleukemia (MEL) cells. DIP blocks MEL cell differentiation directly, without affecting the ability of the cells to proliferate. In the present study, DIP (at < 1 ng/ml) inhibited MEL cell differentiation only when added to the culture medium within 1 h after DMSO induction, indicating that it blocked an early, critical step in erythroleukemia cell differentiation. The protein kinase C (PKC) inhibitor H-7 also maximally inhibited the differentiation of MEL cells during this same period following induction, suggesting that DIP may have blocked an early PKC-dependent process. Indeed, DIP was found to abolish a transient increase in membrane PKC activity which was triggered in MEL cells within 10-30 min after DMSO addition. This increase in membrane PKC activity resulted from the activation of an inactive pool of PKC residing on membranes, and not from the translocation of cytosolic PKC to membranes. DMSO also stimulated membrane PKC activity and differentiation in human erythroleukemia cells and HL-60 myeloid leukemia cells. As was the case with MEL cells, DIP prevented the early activation of PKC and the differentiation of human erythroleukemia cells. However, it did not inhibit the early increase in PKC activity in HL-60 cells or the subsequent differentiation of these cells. These results suggest that DIP blocks erythroleukemia cell differentiation by inhibiting an early and critical activation of inactive membrane PKC.
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PMID:Evidence that a novel human differentiation-inhibiting protein blocks the dimethyl sulfoxide-induced differentiation of erythroleukemia cells by inhibiting the activation of membrane protein kinase C. 142 78

Macrophage colony-stimulating factor (M-CSF) is required for the proliferation, differentiation, and activation of monocytes. High-affinity receptors for M-CSF are encoded by the c-fms proto-oncogene. In the present study, we show that c-fms transcripts are detectable in human THP-1 myeloid leukemia cells. Furthermore, radiolabeled 125I-M-CSF is rapidly internalized into THP-1 cells and then degraded intracellularly. The results also show that treatment of THP-1 cells with M-CSF is associated with the activation of protein kinase C (PKC) and the induction of tumor necrosis factor (TNF) gene expression. TNF transcript levels were low to undetectable in uninduced THP-1 cells, reached maximal levels by 1 hour of exposure to M-CSF, and returned to those of control cells by 24 hours. Transcriptional run-on analysis showed that a low level of TNF transcription is detectable in untreated THP-1 cells, and M-CSF treatment increased the rate of TNF transcription. Pretreatment of THP-1 cells with pertussis toxin inhibited the increase in PKC activity but not the induction of TNF transcripts by M-CSF. Moreover, exposure of THP-1 cells to inhibitors of protein kinase activity blocked the increase in TNF messenger RNA. These findings suggest that at least two M-CSF-mediated signaling pathways exist in THP-1 cells and that the induction of TNF may be regulated by a protein kinase-dependent mechanism distinct from PKC.
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PMID:Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells. 153 7

ETR103 cDNA was cloned as an immediate early gene in the course of macrophagic differentiation of HL-60 cells stimulated by TPA (12-O-tetradecanoylphorbol-13-acetate). The induction by TPA was immediate-early (within 30 min) and transient. This gene was not induced by vitamin D3 or by retinoic acid, which stimulates differentiation of HL-60 cells to the monocytic or granulocytic lineage, respectively. The ETR103 mRNA was induced by TPA in lymphoid or myeloid leukemia cell lines of several maturation stages. The induction by TPA seems to proceed by a protein kinase C-mediated mechanism, on the basis of the results obtained by using protein kinase C inhibitor (H-7), protein kinase C activator (diC8), and an activator of protein kinase A (dibutyryl cAMP). Okadaic acid, an inhibitor of protein phosphatases, also induced the ETR103 mRNA expression. The nucleotide sequence of the ETR103 cDNA reveals that ETR103 encodes a human zinc finger-containing transcription factor identical to Egr-1 and 225, which is homologous to mouse Egr-1, Zif/268, Krox-24, and TIS8, or to rat NGFI-A.
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PMID:A gene coding for a zinc finger protein is induced during 12-O-tetradecanoylphorbol-13-acetate-stimulated HL-60 cell differentiation. 156 51

Human myeloid leukemia cells (i.e., HL-60, U937, THP-1) which are induced to differentiate along the monocytic pathway by 12-O-tetradecanoylphorbol-13-acetate (TPA), revert back to the undifferentiated phenotype after 3 to 4 weeks. During this differentiation and retrodifferentiation process the cells obviously establish a distinct sequence of biological processes which is integrally regulated to simultaneously control differentiation and cell growth. Thus, induction of monocytic markers by TPA is associated with a down-regulation of cell cycle genes and cessation of proliferation. In particular, crosstalk between the TPA-induced translocation of protein kinase C (PKC) and the activation of transcription factors, especially AP-1, enhances the expression of genes associated with the monocytic phenotype. This is accompanied by induction of intermediate filament proteins, surface glycoproteins, changes in membrane properties and intracellular metabolism. In parallel, the cells cease to divide, and genes associated with cell cycle progression including cdc2, cyclins, cdc25, and histones are down-regulated. Although signals responsible for arrested cell growth remain unclear, there are several control mechanisms regarding cell cycle genes and differentiation parameters (for a review, see Nigg, E. A., Seminars in Cell Biol., 2, 262-270, 1991). For example, activated p34cdc2 kinase is involved in lamina disassembly by direct phosphorylation of lamin proteins which may contribute to nuclear envelope breakdown during mitosis (Enoch, T., M. Peter, P. Nurse, J. Cell Biol. 112, 797-807 (1991)). Moreover, endomembrane traffic is arrested by a cdc2-like kinase probably via phosphorylation of members of the rab protein family which contributes to vesiculation and membrane transport by hydrolyzing GTP (Tuomikoski, T., et al., Nature 342, 942-945 (1989)). Although there are several reports on a possible feedback control between differentiation and cell cycle, including phosphorylation of cyclins and activation of a ubiquitin-dependent proteolytic degradation, signaling pathways and possible mechanisms for retrodifferentiation and reentry into the cell cycle remain unclear. While some terminally differentiated cells are committed to die, the major part of the differentiated monocytic population undergoes retrodifferentiation. All cellular signals characterized so far are reverted during retrodifferentiation: Redistribution of PKC and down-regulation of c-fos and c-jun contribute to an interruption of the differentiation-associated transsignaling cascade. Thus, down-regulation of markers associated with monocytic differentiation in combination with metabolic changes restore the original cell phenotype. At the same time cell cycle genes are up-regulated, and the cells regain proliferative capacity. Finally, retrodifferentiated and untreated control cells demonstrate indistinguishable properties.
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PMID:Retrodifferentiation--an alternative biological pathway in human leukemia cells. 164 56

We have examined the role of retinoic acid (RA), the biologically active metabolite of vitamin A, in expression of the IL-1 beta gene in the human myeloid leukemia cell line THP-1 and in human monocytes. Both protein kinase C-activating phorbol esters, e.g., PMA, and LPS induce IL-1 beta expression in these cells. Physiologic RA concentrations alone were not able to induce any IL-1 beta production, but they strongly enhanced the PMA-induced IL-1 beta protein production and mRNA accumulation in both human monocytes and in THP-1 cells. Nuclear run-off analysis revealed that the enhancing effect was at the transcriptional level. RA also slightly potentiated LPS-induced IL-1 beta expression in THP-1 cells but not in human monocytes. These data suggest that RA can be a strong up-regulator of IL-1 production, but its strength varies depending on the nature of the activating signal.
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PMID:Retinoic acid enhances IL-1 beta expression in myeloid leukemia cells and in human monocytes. 164 41

cis-Diamminedichloroplatinum(II) (CDDP) is a chemotherapeutic agent known to inhibit DNA, RNA, and protein synthesis. The cytotoxicity of this drug is thought to result from the formation of DNA intrastrand cross-links. The present work demonstrates that treatment of human myeloid leukemia cells (HL-60, U-937, and KG-1) with CDDP is associated with increased expression of the c-jun gene and that this effect is related to activation by a transcriptional mechanism. The results also demonstrate that treatment with CDDP is associated with increases in protein kinase C (PKC) activity. Furthermore, the finding that pretreatment with H7, an inhibitor of PKC, abrogates the effect of CDDP on c-jun expression suggested the involvement of PKC in this process. Down-regulation of PKC by prolonged pretreatment with 12-O-tetradecanoylphorbol-13-acetate was also associated with inhibition of CDDP-induced c-jun expression. The results further demonstrate that there is a temporal relationship between the CDDP-induced increase in c-jun expression and the occurrence of internucleosomal DNA cleavage characteristic of programmed cell death. These findings suggest that c-jun may be involved in the cellular response to DNA-damaging agents, such as CDDP, and that this effect may be mediated by a PKC-dependent pathway.
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PMID:cis-Diamminedichloroplatinum(II) induces c-jun expression in human myeloid leukemia cells: potential involvement of a protein kinase C-dependent signaling pathway. 173 49

We have recently demonstrated that certain camptothecin derivatives are effective agents in the treatment of human tumor xenografts in nude mice. While camptothecin and its derivatives are recognized as inhibitors of topoisomerase I, little is known about the effects of these agents on specific gene expression, particularly genes involved in growth control. The c-jun early response gene codes for a leucine zipper transcription factor. The present studies demonstrate that 20(S)-camptothecin, 9-amino-20(S)-camptothecin, and 9-nitro-20(S)-camptothecin inhibit the growth of human U-937 myeloid leukemia cells and induce expression of the c-jun gene. c-jun transcripts were increased at 3 h and reached a maximum at 6 h of drug exposure. We also demonstrate that the induction of c-jun gene expression by these agents occurs at the transcriptional level. H7, a nonselective inhibitor of protein kinase C, completely blocked c-jun expression in 20(S)-camptothecin-treated cells, while another protein kinase inhibitor, HA1004, had no detectable effect. Similar findings were obtained for other leucine zipper encoding genes, including jun-B. These results suggest that 20(S)-camptothecin, 9-amino-20(S)-camptothecin, and 9-nitro-20(S)-camptothecin activate a cellular response involving the induction of early response genes. Finally, we demonstrate that induction of c-jun expression occurs in association with internucleosomal DNA fragmentation, a characteristic of programmed cell death.
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PMID:Camptothecin and its derivatives induce expression of the c-jun protooncogene in human myeloid leukemia cells. 174 37

Treatment of human myeloid leukemic cells with phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with activation and then partial down-regulation of protein kinase C activity. Previous work has suggested that the activation of protein kinase C by TPA contributes to the decrease in c-myc expression during differentiation of these cells. The present studies demonstrate that the decline in c-myc mRNA levels following exposure of HL-60 cells to TPA is preceded by an increase in expression of this gene. In contrast, exposure of HL-60 cells to inhibitors of protein kinase C activity is associated with down-modulation of c-myc expression. Similar findings have been obtained in U-937 myeloid leukemia cells. Taken together, these findings suggest that phorbol esters have a biphasic effect on c-myc expression. Whereas the activation of protein kinase C by phorbol esters may be associated with an increase in c-myc gene expression, the subsequent partial down-regulation of kinase activity may initiate a cascade of events resulting in the down-modulation of c-myc expression.
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PMID:Inhibition of protein kinase C is associated with a decrease in c-myc expression in human myeloid leukemia cells. 174 96


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