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)

Two calcium binding proteins, MRP-8 and MRP-14, are specifically synthesized in human myeloid cells. This paper shows that Me2SO, all-trans-retinoic acid (RA) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3), but not 12-O-tetradecanoyl phorbol-13-acetate (PMA) are potent inducers of MRP-8/14 protein complex in human leukemic cells. Transforming growth factor-beta 1 (TGF-beta 1) is shown to enhance the inductive effect of RA and 1 alpha,25(OH)2D3. We have examined the possibility that MRP expression is regulated through the protein kinase pathway. Both cytosolic and membrane-bound protein kinase C (PKC) activities increased during differentiation by RA and 1 alpha,25(OH)2D3. PMA-treatment led to a decrease of cytosolic PKC activity and an increase of membrane-bound PKC activity in the presence of these differentiation inducers, while PMA alone resulted in low cytosolic and high membrane-bound PKC activities. PKC inhibitor H7 inhibited MRP synthesis in HL-60 cells treated with RA and 1 alpha,25(OH)2D3. These results suggest that cytosolic PKC activity may be involved in a stimulatory pathway of MRP synthesis and that protein phosphorylation reactions may play important roles in MRP expression during myelocytic differentiation.
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PMID:Regulation of myeloid-specific calcium binding protein synthesis by cytosolic protein kinase C. 147 21

We have previously shown that cyclic AMP-dependent protein kinase (protein kinase A) phosphorylates smg p21A and -B, ras p21-like small GTP-binding proteins. In the present study, we investigated the function(s) of this phosphorylation by use of the smg p21B purified from human platelets. smg p21B bound to plasma membranes and the protein kinase A-catalyzed phosphorylation of smg p21B reduced this binding. Moreover, the phosphorylation of smg p21B enhanced the two actions of its specific GDP/GTP exchange protein, named GDP dissociation stimulator, when tested in a cell-free system: one is the action to stimulate the GDP/GTP exchange reaction of smg p21B, and the other is the action to inhibit the binding of smg p21B to membranes. Consistently, smg p21B was translocated from the membranes to the cytoplasm when it was phosphorylated by protein kinase A in intact platelets in response to prostaglandin E1 or dibutyryl cyclic AMP. The protein kinase A-catalyzed phosphorylation of smg p21B affected neither its basal GDP/GTP exchange reaction, basal GTPase activity, nor the GTPase activity stimulated by its specific GTPase activating protein. On the other hand, we have recently clarified that the structure of the C-terminal region of the post-translationally processed human platelet smg p21B is Lys-Lys-Ser-Ser-all-trans-geranylgeranyl Cys181 methyl ester, and that this modification of the C-terminal region is essential for smg p21B to bind to membranes. We furthermore determined here that protein kinase A phosphorylated Ser179 in this C-terminal region of smg p21B. These results indicate that protein kinase A-catalyzed phosphorylation of smg p21B makes smg p21B sensitive to the actions of smg p21 GDP dissociation stimulator.
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PMID:Enhancement of the actions of smg p21 GDP/GTP exchange protein by the protein kinase A-catalyzed phosphorylation of smg p21. 190 Oct 63

The plasminogen activator activity of human synovial fibroblasts is raised by a monocyte-derived polypeptide, synovial activator and also by all-trans retinoic acid. The elevation of the synovial cell plasminogen activator activity by the two stimuli is potentiated both by agents which can raise cellular cyclic AMP levels, namely prostaglandin E2, cholera toxin and 3-isobutyl-1-methylxanthine, and also by exogenous 8-bromocyclic AMP. These findings suggest that there might be a substrate, which is phosphorylated by a cyclic AMP-dependent protein kinase and which is important in the modulation of the synovial cell plasminogen activator activity by the two stimuli. Prostanoids can be important in the stimulation of the synovial fibroblast plasminogen activator activity by mononuclear cell supernatants, since indomethacin can inhibit the increase in proteinase activity.
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PMID:The stimulation of human synovial fibroblast plasminogen activator activity. Involvement of cyclic AMP and cyclooxygenase products. 242 80

The effect of staurosporine, a novel calcium/phospholipid-dependent protein kinase (protein kinase C) inhibitor, on differentiation of human promyelocytic leukemic HL-60 cells, was investigated. Staurosporine inhibited HL-60-cell proliferation in a concentration-dependent manner, but did not induce HL-60-cell differentiation by itself. When staurosporine was added to HL-60 cells treated with a suboptimal concentration (1 nM) of 1 alpha,25 dihydroxyvitamin D3 (1,25(OH)2D3), cell differentiation was enhanced in a concentration-dependent manner and the percentages of nitro blue tetrazolium reducing ability and nonspecific esterase activity-positive cells increased from 6% to 51% and from 8% to 54%, respectively, on day 4 at a concentration of 5 nM. Staurosporine (5 nM) achieved almost the same enhancement effect in cultures treated with suboptimal concentrations of 1 nM all-trans-beta-retinoic acid (RA), 3 ng/ml actinomycin D (Act D), 100 microM dibutyryl cyclic adenosine 3':5'-monophosphate (dbc AMP), and 50 microM prostaglandin E1 (PG E1). These results suggest that the inhibition of protein kinase C activity by staurosporine exerts an important role in HL-60-cell differentiation induced by various compounds. Moreover, staurosporine (5 nM) completely inhibited optimal concentrations (50 nM) of [12-o-tetradecanoyl phorbol-13-acetate (TPA)]-induced cell differentiation, but enhanced optimal concentrations of dbc AMP (1 mM)-induced cell differentiation. On the other hand, 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine, which has been reported to inhibit cyclic adenosine 3':5'-monophosphate-dependent protein kinase (protein kinase A) as much as protein kinase C, completely inhibited both cell differentiations induced by optimal concentrations of TPA (50 nM) and induced by optimal concentrations of dbc AMP (1 mM), and did not significantly enhance HL-60-cell differentiation induced by suboptimal concentrations of 1,25(OH)2D3, RA, and dbc AMP. Therefore, these results suggest that the inhibition of protein kinase C, which is not accompanied by that of protein kinase A, is concerned with the induction of HL-60-cell differentiation.
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PMID:Staurosporine, a novel protein kinase inhibitor, enhances HL-60-cell differentiation induced by various compounds. 282

Human pluripotential embryonic teratocarcinoma cells differentially expressed gene activity controlled by the human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) long terminal repeats (LTRs) when differentiation was induced by the morphogen all-trans retinoic acid. The alterations occurred after commitment and before the appearance of the multiple cell types characteristic of these pluripotential cells. After commitment, gene activity controlled by the HIV-1 LTR markedly increased, whereas that controlled by the HTLV-I LTR decreased. Steady-state mRNA levels and nuclear run-on transcription indicated that the increased HIV-1-directed activity during differentiation occurred posttranscriptionally, whereas the decreased HTLV-I activity was at the transcriptional level. Phorbol esters did not cause commitment but strongly enhanced expression by both viral LTRs at the transcriptional level. A specific inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, indicated that the enhanced activity involved the activation of protein kinase(s) C; altered cyclic nucleotide metabolism was apparently not involved. Differentiating cells gradually lost the ability to respond to phorbol ester stimulation. Experiments with a deletion mutant of the HIV-1 LTR suggested that this was due to imposition of negative regulation during differentiation that was not reversed by phorbol ester induction. Cycloheximide, with or without phorbol ester, slightly stimulated HIV-1-directed activity at the transcriptional level and massively increased the amounts of steady-state mRNA by posttranscriptional superinduction. It appeared, however, that new nuclear protein synthesis was required for maximal transcriptional stimulation by phorbol esters. Thus, changing cellular regulatory mechanisms influenced human retrovirus expression during human embryonic cell differentiation.
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PMID:Regulation of expression driven by human immunodeficiency virus type 1 and human T-cell leukemia virus type I long terminal repeats in pluripotential human embryonic cells. 283 1

The intracisternal injection of either all-trans-retinoic acid or [alpha]-difluoromethylornithine (DFMO) into the brain of 9-day-old mice blocked (greater than 90%) phorbol ester-induced ornithine decarboxylase (ODC, EC 4.1.1.17) activity in a concentration-dependent fashion; this inhibition was not evident with the use of the biologically impotent furyl analog of retinoic acid. In a similar manner, retinoic acid reduced the soluble protein kinase-C (PK-C) activity by 60% as well as total EGTA-sensitive kinase activity (66%) associated with the plasma membrane. Sixty-six percent of the retinoic acid-induced loss of PK-C activity in the soluble fraction could be accounted for by the translocation of PK-C to the plasma membrane as measured by the specific binding of 12-O-[3H]tetradecanylphorbol-13-acetate (TPA). DFMO and furyl-retinoic acid were not effective in altering PK-C activity or TPA binding to PK-C. In the presence of retinoic acid, however, there was a 2.3-fold increase in specific [3H]TPA binding in the plasma membrane fraction, which was 3.4-fold greater than that lost from the cytosol. Because retinoids do not directly affect TPA binding to PK-C, the data suggest that (i) the presence of retinoic acid results in the exposure of heretofore cryptic TPA-binding sites in the membrane, where this binding is most likely related to the alteration of membrane structure and (ii) de novo ODC induction is not required for retinoid-dependent inhibition of PK-C, although the TPA induction of PK-C appears to be necessary with regard to ODC induction.
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PMID:The in vivo inhibition of mouse brain protein kinase-C by retinoic acid. 300 83

Dibutyryl cyclic adenosine 3':5'-monophosphate (Bt2cAMP) and beta-all-trans retinoic acid (RA) have been shown separately, and in some cases in combination, to modulate the growth, differentiation, and cAMP-dependent protein kinase (PK-A) activity of various tumor cells. The effects of Bt2cAMP and RA on a cholinergic clone (S20) of C1300 mouse neuroblastoma cells were explored in the present study. Treatment of these cells with 1 mM Bt2cAMP for 3 or more days resulted in 93% inhibition of cell proliferation in monolayer cultures and in 98% inhibition of colony formation in semisolid medium (0.5% agarose). In contrast, treatment of the cells with 1 or 10 microM RA had no inhibitory effects on cell proliferation in monolayer cultures but enhanced colony formation in agarose by up to 130%. The growth of cells treated with a combination of Bt2cAMP and RA was inhibited, although less so than with Bt2cAMP alone. Cells treated with Bt2cAMP alone or Bt2cAMP and RA extended long, neurite-like, cellular processes indicative of differentiation, whereas only a few untreated or RA-treated cells produced such extensions. The amount of [3H]cAMP-binding protein increased gradually up to 2-fold during a 3-day treatment with Bt2cAMP; in contrast it decreased by nearly 2-fold during RA treatment. These changes occurred in the level of the type I regulatory subunit (RI) of PK-A as determined by photoaffinity labeling with 8-azidoadenosine cyclic 3':5'-[32P]monophosphate. The increase in RI following Bt2cAMP treatment was corroborated by DEAE-cellulose chromatography. This analysis also demonstrated that type I PK-A is the predominant kinase in the untreated S20 cells and that RI exists as a free subunit in Bt2cAMP-treated cells. The activity of PK-A decreased by about 20% following treatment with either Bt2cAMP or RA and by 45% following treatment with a combination of both agents. These results suggest that the distinct effects of Bt2cAMP and RA on the anchorage-independent growth of S20 cells may be related to their opposite effects on the level of RI.
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PMID:Differential effects of dibutyryl cyclic adenosine monophosphate and retinoic acid on the growth, differentiation, and cyclic adenosine monophosphate-binding protein of murine neuroblastoma cells. 303 22

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

We have addressed the question of the possible presence of calcium-activated phospholipid-dependent protein kinase (Ca2+-PL protein kinase) activity in undifferentiated embryonal carcinoma cells, and if this activity might be altered during differentiation to a parietal endoderm cell type. Undifferentiated nullipotent F9 embryonal carcinoma cells, as well as differentiated parietal endoderm cells (PYS-2), were utilized. Using an in vitro assay with histone H1 as phosphate acceptor, Ca2+-PL protein kinase activity could not be found in the 100,000 X g supernatant prepared from either cell type. However, passage of 100,000 X g supernatant from PYS cells over a DEAE-cellulose column revealed Ca2+-PL protein kinase activity which eluted with 0.045 M NaCl. The partially purified PYS enzyme has an approximate Mr = 70,000 as determined by Sephadex G-150 gel filtration, and exhibits an apparent Ka for Ca2+ of 32 microM. The PYS Ca2+-PL protein kinase also exhibits a requirement for Mg2+, with maximal activity noted at 10 mM Mg2+. This enzyme is stimulated by acidic phospholipids, while neutral phospholipids such as phosphatidylcholine have little effect. Diacylglycerol markedly increased histone H1 phosphorylation in the presence of Ca2+ and phospholipid. Unlike that of PYS cells, when the 100,000 X g supernatant prepared from F9 cells was passed over a DEAE-cellulose column no Ca2+-PL protein kinase activity could be found in the eluted fractions. Previously it has been reported that exposure of F9 cells to all-trans-retinoic acid induces differentiation to a parietal endoderm cell type. Treatment of F9 cells with 0.1 microM retinoic acid provoked a time-dependent increase in cytosolic Ca2+-PL protein kinase activity as measured after DEAE-cellulose chromatography of the 100,000 X g supernatant. This increase in Ca2+-PL protein kinase activity correlates with differentiation to the parietal endoderm cell type. These findings indicate that cytosolic Ca2+-PL protein kinase activity is very low, or nonexistent, in undifferentiated embryonal carcinoma stem cells. With differentiation to a parietal endoderm cell type there is a marked increase in soluble Ca2+-PL protein kinase activity which exhibits properties similar to those described for this enzyme in other differentiated tissues.
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PMID:Characterization of cytosolic calcium-activated phospholipid-dependent protein kinase activity in embryonal carcinoma cells. Effect of retinoc acid-induced differentiation of F9 cells to parietal endoderm. 687 83

The human acute promyelocytic leukemia (APL) cell line HL-60 differentiates to functionally mature granulocytes by incubation with all-trans-retinoic acid (RA). Since T3 and RA are important in cell differentiation and development, and since their receptors are highly homological, we investigated the T3 effects on RA-induced HL-60 cell differentiation. Although T3 alone did not induce cell differentiation, RA-mediated differentiation was significantly enhanced in the presence of 10(-7) M T3. This effect of T3 was considered to be mediated, at least in part, by increased intracellular cAMP, since the phosphodiesterase inhibitor enhanced, and the protein kinase A antagonist partially blocked, T3 potentiation. When HL-60 cells were pretreated with RA for 20 h, T3 alone stimulated the cell differentiation. The time-course study showed that incubation with RA for 12 h was necessary for HL-60 cells to be primed to respond to T3 for differentiation. The present finding that T3 potentiates RA-induced HL-60 cell differentiation may raise the possibility that T3 supplement increases clinical remission in APL patients who are treated with RA.
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PMID:3,5,3'-Triiodothyronine stimulates retinoic acid-induced differentiation in HL-60 cells. 752 82


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