Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human erythroleukemia (K562) cell line is induced to differentiate into megakaryocytic cells by treatment with the tumor promoter phorbol myristate acetate (PMA). PMA-induced differentiation is characterized by (1) almost complete cessation of cellular proliferation, (2) expression of the megakaryocytic cell surface marker glycoprotein IIb/IIIa (gpIIIa), (3) increased secretion of granulocyte/macrophage-colony stimulating factor (GM-CSF) and (4) increased secretion of interleukin-6 (IL-6). PMA-induced differentiation is dose-dependent with maximal activity seen at 10 nM PMA. In contrast, bryostatin (bryo), a structurally distinct protein kinase C (PKC) activator, fails to induce megakaryocytic differentiation or growth arrest at the concentrations tested (0.01-100 nM). Rather, bryo inhibits PMA-induced growth arrest and megakaryocytic differentiation in a dose-dependent fashion (full inhibition at 100 nM). The divergent biological effects of PMA and bryo correspond to the differential activation and translocation of PKC isotypes in K562 cells. PKC isotype analysis demonstrates that undifferentiated cells express both alpha and beta II PKC but no detectable beta I, gamma or epsilon PKC. Treatment of cells with either PMA or bryo leads to rapid translocation of both alpha and beta II PKC from the cytosol to the non-nuclear particulate fraction. However, bryo also induces selective translocation of beta II PKC to the nuclear membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C isotypes in human erythroleukemia cell proliferation and differentiation. 152 49

We have investigated the effect of 8-Br-cyclic adenosine 3':5' monophosphate (cAMP), a pharmacological activator of cAMP-dependent protein kinase, on the proliferation and the nuclear proto-oncogene induction in a murine granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent myeloid cell line. Cells were growth arrested by granulocyte macrophage colony-stimulating factor and serum deprivation and were allowed to proceed in the cell cycle by addition of the lymphokine in the presence or absence of 8-Br-cAMP. 3H-thymidine incorporation assays showed that addition of 8-Br-cAMP inhibited the entry of cells into S phase and the subsequent proliferation. Northern analysis showed that 8-Br-cAMP had opposite effects on c-fos and c-myc mRNA induction. 8-Br-cAMP induced c-fos in the absence of any GM-CSF. In the presence of GM-CSF, c-fos mRNA was superinduced (30-fold induction compared to four- to fivefold by each signal alone). On the contrary, 8-Br-cAMP was not able to induce c-myc in the absence of growth factor and hardly interfered with the induction of c-myc by GM-CSF. Phorbol myristate acetate (PMA), a pharmacological activator of the lipid and CA++-dependent protein kinase C, was shown to induce nuclear proto-oncogene mRNA in the GM-CSF-dependent cell line. We investigated the effect of 8-Br-cAMP on PMA-induced c-fos and c-myc mRNA levels. When both cAMP dependent and lipid-dependent kinase systems were co-stimulated in the absence of GM-CSF, c-fos message was again superinduced (60-fold induction). On the contrary, c-myc message induction by PMA was inhibited by 80% by coactivation of cAMP-dependent protein kinase with 8-Br-cAMP. Our data indicate that an antiproliferative signal induces or even superinduces c-fos message and hardly interferes with c-myc induction, suggesting that the intracellular pathways resulting in c-fos and c-myc induction may be distinct and that two different pathways can lead to c-fos induction, with synergistic effects when both are activated.
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PMID:Regulation of proliferation in a murine colony-stimulating factor-dependent myeloid cell line: superinduction of c-fos by the growth inhibitor 8-Br-cyclic adenosine 3':5' monophosphate. 306 31

The gene for human granulocyte/macrophage colony-stimulating factor (GM-CSF) is expressed in a tissue-specific as well as an activation-dependent manner. The interaction of nuclear proteins with the promoter region of the GM-CSF gene that is likely to be responsible for this pattern of GM-CSF expression was investigated. We show that nuclear proteins interact with DNA fragments from the GM-CSF promoter in a cell-specific manner. A region spanning two cytokine-specific sequences, cytokine 1 (CK-1, 5' GAGATTCCAC 3') and cytokine 2 (CK-2, 5' TCAGGTA 3') bound two nuclear proteins [nuclear factor (NF)-GMa and NF-GMb] from GM-CSF-expressing cells in gel retardation assays. NF-GMb was inducible with phorbol 12-myristate 13-acetate and accompanied induction of GM-CSF message. NF-GMb was absent in cell lines not producing GM-CSF, some of which had other distinct binding proteins. NF-GMa and NF-GMb eluted from a heparin-Sepharose column at 0.3 and 0.6 M KCl, respectively. We hypothesize that the sequences CK-1 and CK-2 bind specific proteins and regulate GM-CSF transcription.
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PMID:Nuclear proteins interacting with the promoter region of the human granulocyte/macrophage colony-stimulating factor gene. 325 71

To identify the possible role of calcium ions in cell differentiation, we studied the extracellular Ca2+ requirement and the effect of Ca2+/phospholipid-dependent protein kinase (protein kinase C) inhibitor on proliferation and differentiation of human promyelocytic leukemic HL-60 cells. HL-60 cells grew equally well in 0.1 and 1.0 mM Ca2+ media. The addition of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), 1,25-dihydroxyvitamin D3, and all-trans-beta-retinoic acid inhibited the cell growth and induced mature macrophage and granulocyte phenotypes in 1.0 mM Ca2+ medium. 1,25-Dihydroxyvitamin D3 and all-trans-beta-retinoic acid induced HL-60 differentiation to the same degree in 0.1 mM Ca2+ and 1.0 mM Ca2+ media. However, TPA failed to induce HL-60 differentiation or to inhibit proliferation in a 0.1 mM Ca2+ medium. The decrease of extracellular Ca2+ from 1.0 to 0.1 mM caused a significant drop in the intracellular Ca2+ level in undifferentiated and TPA-treated HL-60 cells, although no rapid change in cytosolic Ca2+ was detected in response to TPA addition. 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase C inhibitor, inhibited proliferation of HL-60 cells in a dose-dependent manner. In contrast, H-7 selectively restored the proliferation of TPA-treated HL-60 cells and inhibited TPA-induced phenotypic differentiation. However, the same concentrations of 1-(5-isoquinolinylsulfonyl)-2,3-dimethylpiperazin and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, analogues of H-7 that inhibit protein kinase C more weakly, had no effect on the proliferation or differentiation induction. H-7 also suppressed 1,25-dihydroxyvitamin D3- and all-trans-beta-retinoic acid-induced phenotypic changes of HL-60 cells but did not eliminate the growth inhibition by these inducers. These results demonstrate the Ca2+ requirement and the protein kinase C involvement in phorbol ester-induced phenotypic differentiation of HL-60 cells.
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PMID:Inhibition of phorbol ester-induced phenotypic differentiation of HL-60 cells by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, a protein kinase inhibitor. 360 50

Long-term marrow cultures prepared from mice have been infected with a molecular recombinant of Rous sarcoma virus and murine amphitropic leukemia virus. This resulted in introduction of the src gene into the cultured cells and expression of its protein kinase function. The infected cultures displayed an altered balance in the accumulation of cells in different compartments of granulocyte differentiation. There was a dramatic increase in the stem cell (CFU-S) compartment and the committed progenitor cell (GM-CFC) compartment and a decrease in mature granulocytes. The altered balance appears to be caused by intrinsic alterations in the CFU-S and GM-CFC themselves, which increase their "self-renewal" capacity at the expense of cell differentiation. Remarkably, unlike its effects in other systems, src did not produce a neoplastic transformation of the hemopoietic cells.
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PMID:Effect of src infection on long-term marrow cultures: increased self-renewal of hemopoietic progenitor cells without leukemia. 632 Oct 38

Leukocyte alkaline phosphatase (LAP) is synergistically induced by the combination of all-trans retinoic acid (ATRA) and granulocyte-colony-stimulating factor (G-CSF) in acute promyelocytic leukemia (APL) cells (Gianni' M. et al., Blood 83: 1909-1921, 1994). The role of cAMP and tyrosine kinases in the induction of LAP was investigated. In the APL cell line NB4, adenosine-3': 5'-monophosphothioate, cyclic, Rp isomer, a reversible inhibitor of cAMP-dependent protein kinase (PKA), has no effect on the induction of LAP enzymatic activity and mRNA triggered by ATRA+G-CSF, in conditions where this compound completely blocks the upregulation of LAP transcript caused by the combination of the PKA agonist, dibutyryl-cAMP (db-cAMP), and ATRA. Challenge of NB4 cells with G-CSF, dbcAMP and ATRA causes a much higher induction of LAP relative to that observed in the presence of ATRA+G-CSF or ATRA+dbcAMP. Treatment of NB4 with ATRA and G-CSF results in increases in the tyrosine phosphorylation of several proteins. In the presence of the cytokine and the retinoid, tyrosine kinase inhibitors decrease LAP enzymatic activity and mRNA.
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PMID:Tyrosine kinases but not cAMP-dependent protein kinase mediate the induction of leukocyte alkaline phosphatase by granulocyte-colony-stimulating factor and retinoic acid in acute promyelocytic leukemia cells. 753 55

Raf-1 is a 74-kD serine/threonine kinase located in the cell cytoplasm that is activated by phosphorylation in cells stimulated with a variety of mitogens and growth factors, including hematopoietic growth factors. Using c-raf antisense oligonucleotides to block Raf-1 expression, we have established that Raf-1 is required for hematopoietic growth factor-induced proliferation of murine cell lines stimulated by growth factors whose receptors are members of several different structural classes: (a) the hematopoietin receptor family, including interleukin (IL)-2, IL-3, IL-4, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor (GM-CSF), and erythropoietin; (b) the tyrosine kinase receptor class, including Steel factor and CSF-1; and (c) IL-6, leukemia inhibitory factor, and oncostatin M, whose receptors include the gp130 receptor subunit. Although results of previous experiments had suggested that IL-4 does not phosphorylate or activate the Raf-1 kinase, c-raf antisense oligonucleotides inhibited IL-4-induced proliferation of both myeloid and T cell lines, and IL-4 activated Raf-1 kinase activity in an IL-4-dependent myeloid cell line. In colony assays, c-raf antisense oligonucleotides completely inhibited colony formation of unseparated normal murine bone marrow cells stimulated with either IL-3 or CSF-1 and partially inhibited cells stimulated with GM-CSF. In addition, c-raf antisense oligonucleotides completely inhibited both IL-3- and GM-CSF-induced colony formation of CD34+ purified human progenitors stimulated with these same growth factors. Thus, Raf-1 is required for growth factor-induced proliferation of leukemic murine progenitor cell lines and normal murine and human bone marrow-derived progenitor cells regardless of the growth factor used to stimulate cell growth.
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PMID:Raf-1 protein is required for growth factor-induced proliferation of hematopoietic cells. 753 43

The granulocyte activation Ags, CD66a, CD66b, CD66c, and CD66d, are expressed at low levels on resting blood granulocytes, but their surface expression is up-regulated following stimulation. CD66a, in contrast to CD66b and CD66c which are anchored to the membrane via a glycosyl-phosphatidylinositol linkage, is a transmembrane protein with a cytoplasmic domain. We have previously reported that CD66a is phosphorylated in human neutrophils, largely on tyrosine, with a lower level of phosphoserine. We have now found that CD66a undergoes a rapid increase in phosphorylation following stimulation with FMLP, platelet-activating factor, and 12-O-tetradecanoyl-phorbol-13-acetate. This increase in phosphorylation was transient, with maximal phosphorylation observed by 1 min and a return to base line by 5 min following stimulation. Protein kinase activity was detected in neutrophils associated with CD66a, CD66b, and CD66c. Most of the protein kinase activity associated with these Ags was tyrosine kinase activity, with a lesser amount of threonine and serine kinase activities. Lyn and Hck accounted for much of the associated tyrosine kinase activity. The data suggest that phosphorylation of CD66a on tyrosine by an associated tyrosine kinase may play a role in the function of CD66a. In addition, associated tyrosine kinase activity may play a role in signal transduction from CD66a, CD66b, and CD66c to regulate other cell functions.
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PMID:CD66 family members are associated with tyrosine kinase activity in human neutrophils. 759 54

We report that engagement of a particular epitope near the C-terminal region of complement receptor type 3 (CR3, CD11b/CD18) alpha-chain with CD11b mAb VIM12 induces granulocyte activation with a rise in cytosolic-free Ca2+, actin polymerization, an up-regulation of CR3 cell surface expression and enhanced adhesiveness. Induction of enhanced adhesiveness and homotypic aggregation of human granulocytes represents an active process. It is temperature and energy dependent, requires divalent cations, and an intact cytoskeleton. The mAb VIM12-induced enhanced adhesiveness seems to be mediated, at least in part, by activated CR3 molecules. It can be significantly inhibited, although not completely abolished, with blocking mAbs against adhesiotopes of CR3. VIM12-induced adhesion could be blocked with the serine/threonine inhibitors okadaic acid and calyculin A and with dibuturyl-cAMP but not with the protein kinase inhibitors herbimycin A and staurosporine. We further present evidence that the particular molecular region of CR3 recognized by mAb VIM12 might be involved in the reported intramembrane sugar-lectin type interaction and complex formation between transmembrane CR3 and glycosylphosphatidylinositol (GPI)-anchored Fc gamma RIIIB (CD16) molecules on human granulocytes. Binding of mAb VIM12 to CR3 on granulocytes enhances the release of GPI-anchored Fc gamma RIIIB molecules from granulocytes upon phosphoinositol-phospholipase C treatment. The sugar preparation N-acetyl-D-glucosamine, previously shown to dissociate CR3-Fc gamma RIIIB complex formation, inhibits mAb VIM12 binding. Engagement of CR3 with mAb VIM12 may thus mimic a biologically relevant intramembrane cooperation between two distinct receptor molecules on human granulocytes.
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PMID:Granulocyte activation via a binding site near the C-terminal region of complement receptor type 3 alpha-chain (CD11b) potentially involved in intramembrane complex formation with glycosylphosphatidylinositol-anchored Fc gamma RIIIB (CD16) molecules. 773 Jun 47

Treatment of acute promyelocytic leukemia (APL) blasts with cyclic adenosine monophosphate (cAMP) analogs, in combination with all-trans retinoic acid (ATRA), results in the upregulation of the expression of leukocyte alkaline phosphatase (LAP), a marker for the differentiation of the granulocyte. The synergistic interaction between the cyclic nucleotide analogs and the retinoid is not unique to APL cells, as it is observed also in the peripheral granulocytes of chronic myelogenous leukemia (CML) patients. The molecular mechanisms underlying LAP induction were studied in NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is dependent on the time of exposure and on the concentrations of dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors that influence the kinetics of appearance of detectable levels of the enzyme. Augmentation of LAP levels by ATRA and cAMP is the result of both transcriptional and early posttranscriptional events and requires de novo protein synthesis. LAP induction correlates with augmentation in the levels of the type I catalytic subunit of cAMP-dependent protein kinase transcript and with granulocytic differentiation. The transcriptional component of the process leading to increased LAP gene expression was reproduced in its main features by transient transfection experiments performed in COS-7 cells using the normal retinoic acid receptor type alpha (RAR-alpha) or the APL-specific aberrant form (PML-RAR) and the upstream promoter of the liver/bone/kidney (L/B/K)-type alkaline phosphatase gene. The promoter is upregulated by treatment with ATRA, and this upregulation is further increased by cAMP analogs.
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PMID:All-trans retinoic acid and cyclic adenosine monophosphate cooperate in the expression of leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. 778 Jan 46


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