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 signal transduction of TSH in invasion and growth of FTC 133, a human follicular thyroid cancer cell line, was investigated. TSH (0.01-1 mIU/ml) stimulated invasion of FTC 133 by 21% and growth by 20% of basal. Cyclic AMP-stimulators and inhibitors had no effect at any concentration. The PKC-agonist TPA enhanced invasion and growth by 15%, whereas staurosporine, a PKC-antagonist, inhibited them by 32% and 60%, respectively. The latter also reversed TSH stimulation. EGF enhanced invasion (42%) and growth of FTC 133 (25%). Staurosporine did not reverse EGF stimulation. The tyrosine kinase antagonist genistein reversed EGF, but not TSH stimulation. Pertussis toxin inhibited invasion (18%) and growth (22%). Cholera toxin was less inhibitive. We demonstrated for the first time, that TSH stimulates invasion and growth of human thyroid cancer cells in vitro by PKC- rather than PKA-stimulation.
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PMID:Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC- rather than PKA-activation. 821 54

The effects of the protein kinase C inhibitors staurosporine and H-7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] on glucose-induced regulation of glycogen synthase and phosphorylase activities were investigated in the primary culture of hepatocytes. Glycogen synthesis as measured by the incorporation of [14C]glucose into glycogen was enhanced up to 78% (P < .001) by 100 nmol/L staurosporine. In contrast, H-7 inhibited glycogen synthesis in a dose-dependent manner, with an IC50 value of 70 mumol/L. Activation of glycogen synthase by 30 mmol/L glucose was enhanced significantly (P < .02 and less) by staurosporine at 20 nmol/L and higher concentrations whereas the activity of this enzyme was inhibited by H-7 (IC50 = 50 mumol/L). The inactivation of phosphorylase by glucose was significantly greater when staurosporine was included in the medium. However, H-7 increased the phosphorylase activity ratio by 1.5- to 2.5-fold at concentrations of 20 to 100 mumol/L. The time course of synthase activation and phosphorylase inactivation showed that the effect of glucose was enhanced by staurosporine and inhibited by H-7. These novel reciprocal effects of protein kinase C inhibitors were also observed at different concentrations of glucose. The effects of H-8, a compound with structural resemblance to H-7 and an inhibitor of protein kinase A, were similar to those of staurosporine but not to those of H-7. Staurosporine blocked the effects of vasopressin and 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), whereas H-7 in combination with these protein kinase C activators acted in the same direction. The effects of staurosporine, a relatively more specific inhibitor of protein kinase C, indicated that this enzyme plays a role in the regulation of glycogen metabolism in liver. However, H-7, which is known to have protein kinase C-independent effects in intact cells, seems to alter the activities of glycogen synthase and phosphorylase by a different mechanism.
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PMID:Reciprocal effects of the protein kinase C inhibitors staurosporine and H-7 on the regulation of glycogen synthase and phosphorylase in the primary culture of hepatocytes. 823 44

Xenopus egg extracts prepared before and after egg activation retain M- and S-phase specific activity, respectively. Staurosporine, a potent inhibitor of protein kinase, converted M-phase extracts into interphase-like extracts that were capable of forming nuclei upon the addition of sperm DNA. The nuclei formed in the staurosporine treated M-phase extract were incapable of replicating DNA, and they were unable to initiate replication upon the addition of S-phase extracts. Furthermore, replication was inhibited when the staurosporine-treated M-phase extract was added in excess to the staurosporine-treated S-phase extract before the addition of DNA. The membrane-depleted S-phase extract supported neither nuclear formation nor replication; however, preincubation of sperm DNA with these extracts allowed them to form replication-competent nuclei upon the addition of excess staurosporine-treated M-phase extract. These results demonstrate that positive factors in the S-phase extracts determined the initiation of DNA replication before nuclear formation, although these factors were unable to initiate replication after nuclear formation.
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PMID:Determination of initiation of DNA replication before and after nuclear formation in Xenopus egg cell free extracts. 825 33

Intracellular recordings were made from S neurons of the submucosal plexus isolated from the guinea pig ileum. Adenosine or its analog 2-chloroadenosine (CADO) depolarized about 80% of neurons; previous work has shown that this results from activation of an A2 receptor. The depolarization was associated with an increase in membrane input resistance, became smaller with membrane hyperpolarization, reversed polarity at the potassium equilibrium potential and was mimicked and occluded by calcium-free solutions or by cadmium, suggesting that it is due to a reduction in a calcium-dependent potassium conductance. Both forskolin (though not 1,9-dideoxyforskolin) and phorbol 12,13-dibutyrate (PDBu) mimicked and occluded the action of CADO. Staurosporine (a nonspecific inhibitor of protein kinases) blocked the depolarization induced by the phorbol ester within 5 min, and blocked the effects of forskolin and CADO in 15-35 min. The depolarization caused by CADO was inhibited by the specific inhibitor of protein kinase A KT5720 [(8R*,9S*,11S*)-(-)-9-hydroxy-9-n-hexylester-8-methyl-2,3,9,10-tet rahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]c ycloocta[cd e]-trin-den-1-one], whereas this inhibitor did not affect the depolarization induced by PDBu. The results are consistent with the control of this potassium conductance by protein kinase C, protein kinase A and intracellular calcium, and they indicate that adenosine reduces the conductance by activating protein kinase A.
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PMID:Adenosine reduces the potassium conductance of guinea pig submucosal plexus neurons by activating protein kinase A. 825 24

We have investigated the effects of phosphatase and protein kinase inhibitors on calcium channel currents of bullfrog sympathetic neurons using the whole cell configuration of the patch clamp technique. Intracellular dialysis with the phosphatase inhibitors okadaic acid and calyculin A markedly enhanced the decline of inward current during a depolarizing voltage step. Tail current analysis demonstrated that this was genuine inactivation of calcium channel current, not activation of an outward current. The rapidly inactivating current is N-type calcium current (blocked by omega-conotoxin and resistant to nifedipine). Staurosporine, a nonselective protein kinase inhibitor, prevented the action of okadaic acid, suggesting that protein phosphorylation is involved. Under control conditions, the time course of inactivation could be described by the sum of two exponentials (tau = 150 ms and 1200 ms), plus a constant (apparently noninactivating) component, during depolarizations lasting 2 s. Okadaic acid induced a rapid inactivation process (tau = 15 ms) that was absent or negligible under control conditions, without obvious effect on the two slower time constants. As in control cells, inactivation in okadaic-acid-treated cells was strongest near -20 mV, with less inactivation at more positive voltages. However, inactivation did not depend on calcium influx. Modulation of calcium channel activity by phosphorylation may underly the spontaneous shift between inactivating and noninactivating modes recently observed for N-type calcium channels. Differences in basal phosphorylation levels could also explain why N-type calcium channels, originally described as rapidly and completely inactivating, inactivate slowly and incompletely in many neurons.
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PMID:Phosphorylation enhances inactivation of N-type calcium channel current in bullfrog sympathetic neurons. 825 38

During the assembly of the nucleocapsid of the hepatitis B virus a protein kinase, probably of cellular origin, is encapsidated. This enzyme phosphorylates serine residue(s) localized within the lumen of the particle. By using purified, liver-derived core particles, we characterized the protein kinase activity in the presence of different ions and inhibitors. Controls were performed with cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) and recombinant core particles. We showed that the endogenous protein kinase of the core particles was not inhibited by H89, a specific inhibitor of PKA. Staurosporine, a selective inhibitor of PKC inhibited the endogenous kinase activity only within the first minutes of the reaction. In contrast, quercetine, a selective inhibitor of the protein kinase M (PKM) did not inhibit during the first minutes but inhibited efficiently during later phases of incubation. PKM represents an enzymatically active proteolytic fragment of PKC. These results suggest that PKC is encapsidated into human core particles and is converted to PKM during the in vitro reaction. This conclusion implies the association of a protease activity localized with the HBV nucleocapsid inside liver-derived core particles.
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PMID:Characterization of the endogenous protein kinase activity of the hepatitis B virus. 826 Aug 77

Several protein kinase inhibitors (PKIs) were investigated for their effects on IL-1 beta, TNF alpha and PMA-induced IL-8 production from human umbilical vein endothelial cells (HUVEC). IL-1 beta (ED50 0.07 ng/ml), TNF alpha (ED50 100 ng/ml) and PMA (ED50 20 ng/ml) induced IL-8 production that could be detected as early as 2 h following stimulation. Staurosporine, a potent but non-specific inhibitor of protein kinases, inhibited PMA-induced (IC50 2 nM) but not IL-1 beta or TNF alpha (IC50 > 200 nM) induced IL-8 production. Neither the cAMP-dependent PKI, KT5720, nor the tyrosine PKIs, genistein, tyrphostin (1-100 microM) or lavendustin A (0.0001-1 microM), inhibited IL-8 production elicited by IL-1 beta. However, the macrolide protein kinase inhibitor geldanamycin (IC50 = 30 nM), but not the closely related analog herbimycin A (5-500 nM), inhibited IL-8 production by 60%. Northern blot analysis of IL-8 mRNA revealed that staurosporine suppressed mRNA increase following stimulation by PMA but not by IL-1. It is proposed that a novel protein kinase susceptible to geldanamycin inhibition may be involved in IL-1-mediated signal transduction.
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PMID:Effect of protein kinase inhibitors on IL-8/NAP-1 release from human umbilical vein endothelial cells. 827 91

A staurosporine-sensitive mutation (stt1) in yeast has been found in the PKC1 gene that encodes a protein kinase C homologue (Yoshida, S., Ikeda, E., Uno, I., and Mitsuzawa, H. (1992) Mol. Gen. Genet. 231, 337-344). We report here another staurosporine-sensitive mutant, stt4, which shows very similar phenotypes to that of the stt1 mutant. The stt4 temperature-sensitive mutant arrests mostly in G2/M phase at 37 degrees C, and the stt4 deletion mutant shows an osmoremedial phenotype. Staurosporine sensitivity of the stt4 mutant was suppressed by overexpression of PKC1/STT1, indicating genetic interaction between stt4 and pkc1/stt1. The nucleotide sequence of STT4 predicts a hydrophilic protein composed of 1,900 amino acid residues, with 26% sequence identity to the yeast VPS34 gene product and 27% to the catalytic subunit of mammalian phosphatidylinositol (PI) 3-kinase, respectively. Cell homogenates of the stt4 deletion mutant show normal PI3-kinase activity but lack most of the PI4-kinase activity that is detected in the wild-type. We conclude that STT4 encodes a yeast PI4-kinase that functions in the PKC1 protein kinase pathway.
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PMID:A novel gene, STT4, encodes a phosphatidylinositol 4-kinase in the PKC1 protein kinase pathway of Saccharomyces cerevisiae. 828 77

The effects of K2CrO4, H2O2, benzoyl peroxide, menadione, KBrO3 and UV365nm on gap junctional intercellular communication (GJIC) have been studied in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-sensitive Syrian hamster embryo (SHE) cell line BPNi. All agents were found to increase the level of GJIC by 50-100%. Also, in early passage SHE cells, a tendency for increased GJIC was found for the oxidative agents studied. Hydrogen peroxide was used as a model compound in the subsequent studies. The increase in GJIC was reversible, and it was not due to an increased non-junctional permeability. Hydrogen peroxide counteracted the TPA-induced decrease in GJIC, regardless of whether the cells were exposed to the compounds simultaneously or the cells were pre-exposed to TPA before addition of H2O2. The GJIC enhancement by H2O2 was slightly reduced by the addition of the hydroxyl radical scavenger dimethylsulphoxide or by the inhibition of catalase by amitrole. The cAMP/protein kinase A system is the only characterized signal transduction system that is known to increase GJIC in most cell types. Hydrogen peroxide did not increase the amount of cAMP (or cGMP) in BPNi cells, while forskolin and a phosphodiesterase inhibitor had to increase the cAMP level several-fold to affect GJIC to the same degree as the oxidative agents. Some inhibitors of protein kinase A were assayed for their ability to inhibit the increases in GJIC caused by H2O2 and forskolin. Staurosporine inhibited the forskolin-induced increase in GJIC, with much less effect on the H2O2-induced increase. H8, H88 and H89 had less effect than staurosporine on the forskolin-induced increase in GJIC. The results suggest that the cAMP/protein kinase A system may not be involved in the increase in GJIC caused by H2O2, although this cannot be completely ruled out.
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PMID:Increased gap junctional intercellular communication in Syrian hamster embryo cells treated with oxidative agents. 831 32

Three intracellular signal transduction pathways have been found to be utilized by gamma-interferon (IFN-gamma) in the induction of HLA-DR in several cell types, mainly monocytes/macrophages and B-cells: the protein kinase A (PKA); Ca(2+)-calmodulin; and protein kinase C (PKC) pathways. In this study, we investigated the role of these pathways in IFN-gamma-induced HLA-DR expression in normal and neoplastic human thyroid cells. The PKA pathway seemed to inhibit both neoplastic and normal IFN-gamma-induced HLA-DR expression; addition of thyroid-stimulating hormone to normal thyroid cells, as well as 8-bromo cyclic AMP and forskolin to normal and neoplastic cells, reduced the amount of IFN-gamma-induced HLA-DR. Moreover, H-8, a PKA inhibitor, enhanced such IFN-gamma-induced HLA-DR expression. The calcium-calmodulin pathway does not seem to play a role in IFN-gamma-induced HLA-DR expression in normal and neoplastic thyrocytes, since the Ca-ionophore A23187, EGTA, and the calmodulin antagonist, W-7, neither induced HLA-DR nor showed any effect on HLA-DR expression induced by IFN-gamma. Alone, phorbol 12-myristate 13-acetate, a PKC activator, did not induce HLA-DR on thyroid cells. However, its addition to neoplastic cells together with IFN-gamma caused a synergistic elevation of the expressed HLA-DR, whereas it significantly inhibited IFN-gamma-induced HLA-DR in normal thyrocytes. TPA had to be added before or together with IFN-gamma for optimal function. If added more than 6 h after IFN-gamma, TPA was not effective. An inactive TPA analogue did not affect HLA-DR induction, while an active analogue mimicked TPA. Staurosporine, a PKC inhibitor, reduced the TPA enhancing effect in neoplastic thyrocytes and cancelled TPA inhibition in normal cells. Moreover, when added to IFN-gamma without TPA in normal thyroid cells, staurosporine increased 3- to 4-fold the amount of HLA-DR. Thus, in normal thyroid cells the PKC pathway is activated by IFN-gamma and inhibits HLA-DR expression. In neoplastic thyrocytes, although IFN-gamma does not induce HLA-DR via PKC, this pathway augments HLA-DR expression.
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PMID:Control of HLA-DR antigen expression by gamma-interferon: separate signal transduction mechanisms in malignant and nonmalignant human thyroid cells. 835 21


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