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)

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

The effects of protein kinase C inhibitor H-7 (1-(5-isoquinolinylsulfonyl)-2-methylpiperazine) on tumor-promoting phorbol ester induced inhibition of vincristine uptake in P388 murine leukemic cells were investigated with the objective of assessing the possible role of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) in vincristine uptake. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a potent inhibitor at concentrations above 1 nM. Other phorbol esters also inhibited vincristine uptake in approximate proportion to their activity in competing for [20-3H]phorbol 12,13-dibutrate binding. TPA enhanced the Ca2+-activated, phospholipid-dependent phosphorylation of histone III-S by a soluble protein fraction of cells. Phosphorylation of various cell lysate proteins (p18, p21, p29, p34 and p45) were also stimulated by TPA. These TPA-induced stimulations were also inhibited dose-dependently by H-7. It is tentatively concluded that the phosphorylation of cell lysate protein substrates by protein kinase C may be an important mechanism linked to the regulation of vincristine uptake in leukemic cell.
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PMID:An inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine(H-7) inhibits TPA-induced reduction of vincristine uptake from P388 murine leukemic cell. 376 16

Naphthalenesulfonamides such as N-(6-amino-hexyl)-5-chloro-1-naphthalenesulfonamide (W-7) are potent calmodulin (CaM) antagonists and act upon several protein kinases at higher concentration. When the naphthalene ring was replaced by isoquinoline, the derivatives were no longer CaM antagonists but retained the ability to inhibit protein kinases, and some of the derivatives exhibited selective inhibition toward a certain protein kinase. cAMP-dependent, cGMP-dependent, and Ca2+-phospholipid-dependent (protein kinase C) protein kinases were inhibited significantly by addition of 10(-6) M N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H-8) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). H-8 was the most active of the inhibitors in this series and inhibited more markedly cyclic nucleotide dependent protein kinases, than other kinases, while the derivative with the sulfonylpiperazine residue (H-7) was the most potent in inhibiting protein kinase C. Apparent Ki values of H-8 were 0.48 and 1.2 microM for cGMP-dependent and cAMP-dependent protein kinases, respectively, and the Ki value of H-7 for protein kinase C was 6 microM. Both the holoenzyme and the catalytic subunit (or fragment), which is active without an enzyme activator, are susceptible to these compounds with a similar concentration dependency, thereby indicating that the inhibitory effect is attributed to the direct interaction of the compound with the active center of the enzyme but not with the enzyme activator. The inhibitions were freely reversible and of the competitive type with respect to ATP and of the noncompetitive type with respect to the phosphate acceptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. 623 27

Previous studies have shown that protein kinase stimulators can induce the release of the metaphase II arrest in mouse ova. The present report is about the role of protein kinase in parthenogenic activation of pig oocytes, which was studied using a broad-spectrum protein kinase inhibitor. Metaphase II oocytes were obtained via in vitro maturation. Two sources of H7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine, HCl] were tested--Sigma (H7s) and Calbiochem (H7c). Both were found to be equally effective in promoting release of the metaphase II block. Activation, release of the metaphase II arrest, and progression to the first interphase could be induced at the highest percentage with an exposure to 2.0 mM H7s for 80 min (68.1%). In another experiment, H7c resulted in 69.5% activation, while iso-H7 [1-(5-isoquinolinesulfonyl)-3-methylpiperazine, HCl] at a similar concentration and exposure duration resulted in 25.7% activation. H7s and H7c were more effective than iso-H7 in inducing the appearance of a 22-kDa protein that is associated with normal fertilization in the pig. In contrast, although pronuclei could form and the protein profiles were indicative of activation, cortical granule exocytosis did not occur, and oocytes failed to develop to the blastocyst stage after H7 treatment. In contrast to the H7-treated oocytes, electrostimulation resulted in pronuclear formation, the appearance of the 22-kDa protein, release of cortical granules, and development to the blastocyst stage. These data demonstrate that broad-spectrum inhibitors of protein kinase are unable to induce all the events associated with normal fertilization.
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PMID:Parthenogenic activation of pig oocytes by protein kinase inhibition. 749 78

One component of the nocturnal changes in cellular immediate-early gene expression in the rat pineal gland is a decrease in c-jun expression, mediated through beta-adrenoceptors. An in vitro study of the intracellular mechanisms which control c-jun expression has now shown that a norepinephrine-induced increase in c-jun mRNA levels in organ-cultured pineals is differentially modulated by protein kinase inhibitors; N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004) potentiated the response; however, in the presence of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a significant decrease in c-jun mRNA was found. Treatment with HA-1004 alone elevated the level of c-jun mRNA, H-7 alone was without effect. Forskolin together with 3-isobutyl-1-methylxanthine suppressed c-jun, whereas phorbol 12,13-dibutyrate raised c-jun mRNA levels. The results demonstrate opposing pathways for c-jun regulation in the pineal gland, and indicate that the nocturnal attenuation of c-jun expression involves selective activation of a negative pathway which may be linked to cAMP.
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PMID:Noradrenergic regulation of c-jun expression in the rat pineal gland in culture: positive and negative components. 750 96

Human recombinant interleukin-1 alpha (IL-1) stimulated the mouse osteoblast-like cell line, MC3T3-E1, to produce prostaglandin E2 (PGE2). This was inhibited by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) in a dose-dependent manner. The protein kinase A (PKA)-specific inhibitor, KT5720, also inhibited the IL-1-induced PGE2 production in MC3T3-E1 cells, as did staurosporine, a potent inhibitor of protein kinase C (PKC). The PKA activator, 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), weakly stimulated MC3T3-E1 cells to produce PGE2, as did the PKC activator, 12-O-tetradecanoylphorbol 13-acetate (TPA). However, 8-Br-cAMP and TPA acted synergistically to induce PGE2 production equal to that of IL-1. These observations suggest that activation of both PKA and PKC are involved in IL-1-induced PGE2 production in MC3T3-E1 cells.
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PMID:Involvement of protein kinase A and C in the production of interleukin-1 alpha-induced prostaglandin E2 from mouse osteoblast-like cell line, MC3T3-E1. 751 May 23

In this study, the interaction between 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in [3H]adenine- or [3H]-guanine-prelabelled adult guinea-pig cerebellar slices was investigated. Basal levels of [3H]cGMP were enhanced by forskolin, although no plateau was reached over the concentration range tested (0.1-100 microM). However, forskolin elicited a concentration-dependent, saturable potentiation of sodium nitroprusside (SNP)-stimulated [3H]cGMP accumulation (forskolin EC50 value of 0.98 +/- 0.23 microM; 10 microM forskolin produced a 1.8 +/- 0.3-fold potentiation of the SNP response at 2.5 min). The forskolin potentiation was observed at all concentrations of SNP tested (0.001-10 mM). Forskolin also elicited a large stimulation of [3H]-cAMP in [3H]adenine-prelabelled guinea-pig cerebellar slices; however, 1,9-dideoxyforskolin failed to elicit either a [3H]cAMP response or a potentiation of the SNP-induced [3H]cGMP response at concentrations up to 100 microM. Pretreatment with oxyhaemoglobin (50 microM) inhibited the response to SNP (1 mM) and forskolin (10 microM), as well as the response evoked by the combination of SNP and forskolin. NG-Nitro-L-arginine (100 microM) inhibited the response to forskolin alone, but did not change the response to SNP or the potentiation induced by forskolin on SNP-induced [3H]cGMP levels. The protein kinase inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7; 100 microM), staurosporine (10 microM), polymyxin B (100 microM), and Ro 31-8220 (10 microM) had no effect on the [3H]cGMP response to either SNP or the combination of SNP plus forskolin. N6,2'-Dibutyryl cAMP, at concentrations up to 10 mM, was also without effect on [3H]cGMP levels induced by SNP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Forskolin and 3-isobutyl-1-methylxanthine increase basal and sodium nitroprusside-elevated cyclic GMP levels in adult guinea-pig cerebellar slices. 751 48

Pretreatment of NG108-15 cells for 1 h with 1 microM phorbol 12-myristate,13-acetate produced no significant effect on the subsequent stimulation of adenylate cyclase activity by the IP receptor agonist, iloprost, the adenosine A2 receptor agonist, N-ethylcarboxamidoadenosine (NECA), or sodium fluoride, suggesting that protein kinase C activation does not produce desensitization in this system. Pretreatment of cells with 10 microM iloprost or forskolin for 17 h produced a decrease in the specific binding of [3H]iloprost, consistent with a decrease in IP receptor number. Iloprost pretreatment produced a decrease in responses to iloprost, NECA and sodium fluoride, whereas forskolin pretreatment produced a decrease in subsequent responsiveness to iloprost and NECA, but the response to sodium fluoride remained unaffected. The desensitization produced by forskolin could be completely inhibited by the inhibitor of protein kinase A and protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), but H7 had no effect on the desensitization produced by iloprost.
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PMID:The role of protein kinase A and protein kinase C in prostanoid IP receptor desensitization in NG108-15 cells. 751 85

The B-cell antigen CD40 transduces signals, which synergize with interleukin (IL)-4 to induce IgE synthesis in human B cells. IL-4 induces epsilon germline transcription but not mature epsilon transcripts or IgE protein synthesis in B cells. Addition of anti-CD40 monoclonal antibody to IL-4-treated B cells results in deletional S mu--> S epsilon switch recombination, expression of mature epsilon transcripts, and IgE synthesis and secretion. Because both IL-4 and anti-CD40 induce protein tyrosine phosphorylation in B cells, we investigated the role of protein tyrosine kinase in IL-4/CD40-mediated IgE synthesis. The protein tyrosine kinase inhibitors genistein and herbimycin A, but not the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) or the protein kinase A inhibitor N-2-guanidinoethyl-5-isoquinolinesulfonamide, inhibited IgE synthesis in B cells stimulated with IL-4 and CD40. Genestein and herbimycin, but not H7, inhibited IL-4-driven epsilon germline transcription in B cells. Both genestein and herbimycin, but not H7, inhibited CD40-mediated IgE synthesis in B cells pretreated for 4 days with IL-4 to allow optimal expression of epsilon germline transcripts. Inhibition of IgE synthesis in these cultures was accompanied by inhibition of S mu--> S epsilon deletional switch recombination as assayed by nested polymerase chain reactions. These results suggest that activation of protein tyrosine kinase plays an important role in both the IL-4 and the CD40 signalling pathways that lead to IgE isotype switching in B cells.
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PMID:Role of protein tyrosine kinases in CD40/interleukin-4-mediated isotype switching to IgE. 752 75

In this study, the effect of cGMP on the dihydropyridine-sensitive (L-type) Ca2+ current was investigated using the whole cell version of the patch-clamp technique in rat pinealocytes. Dibutyryl-cGMP (1 x 10(-4) M) induced a pronounced inhibition of the L-type Ca2+ channel current. The dibutyryl-cGMP effect was concentration dependent. Elevation of cGMP by nitroprusside had a similar inhibitory action on the L-type Ca2+ channel current. Norepinephrine, which increased cGMP in rat pinealocytes, also inhibited this current. The action of cGMP was independent of cAMP elevation since the cAMP antagonist, Rp-cAMPs, had no effect on the inhibitory action of dibutyryl-cGMP. The involvement of cyclic GMP-dependent protein kinase was suggested by the blocking action of two protein kinase inhibitors, (1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), on the dibutyryl-cGMP effect on the L-type Ca2+ channel current. Taken together, these results suggest that (1) cGMP modulates L-type Ca2+ channel currents in rat pinealocytes, causing inhibition of this current; (2) the action of cGMP appears to be independent of cAMP elevation; and (3) phosphorylation by cGMP-dependent protein kinase may be involved.
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PMID:cGMP inhibits L-type Ca2+ channel currents through protein phosphorylation in rat pinealocytes. 753 27


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