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)

In the rat medullary thick ascending limb (MTAL), hyperosmolality inhibits transepithelial HCO3- absorption (JHCO3-) by inhibiting apical membrane Na+/H+ exchange. To examine signaling mechanisms involved in this regulatory response, MTALs were isolated and perfused in vitro with 25 mM HCO3- solutions (290 mosmol/kg H2O). Osmolality was increased in lumen and bath solutions by addition of 300 mM mannitol or 75 mM NaCl. Addition of mannitol reduced JHCO3- by 60% and addition of NaCl reduced JHCO3- by 50%. With the protein tyrosine kinase (PTK) inhibitor genistein (7 microM) or herbimycin A (1 microM) in the bath, addition of mannitol reduced JHCO3- only by 11% and addition of NaCl reduced JHCO3- only by 15%. Staurosporine (10(-7) M) or forskolin (10(-6) M) in the bath had no effect on inhibition of JHCO3- by hypertonic NaCl. Genistein had no effect on inhibition of JHCO3- by vasopressin (a cyclic AMP-dependent process) or stimulation of JHCO3- by prostaglandin E2 (a protein kinase C-dependent process). Under isosmotic conditions, addition of genistein or herbimycin A to the bath increased JHCO3- by 30% through stimulation of apical membrane Na+/H+ exchange. Addition of the tyrosine phosphatase inhibitor molybdate (50 microM) to the bath reproduced the inhibition of JHCO3- observed with hyperosmolality. These data indicate that 1) the effect of hyperosmolality to inhibit MTAL HCO3- absorption through inhibition of apical membrane Na+/H+ exchange is mediated via a PTK-dependent pathway that functions independent of regulation by cyclic AMP and protein kinase C, and 2) a constitutive PTK activity inhibits apical membrane Na+/H+ exchange and HCO3- absorption under isosmotic conditions. Our results suggest that tyrosine phosphorylation is a critical step in inhibition of the apical Na+/H+ exchanger isoform NHE-3 by hyperosmolality.
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PMID:Hyperosmolality inhibits bicarbonate absorption in rat medullary thick ascending limb via a protein-tyrosine kinase-dependent pathway. 773 Mar 71

It has recently been shown that the activation of protein kinase C (PKC) induces protein tyrosine phosphorylation in osteoblast-like MC3T3-E1 cells. We previously reported that the activation of PKC stimulates phosphatidylcholine-hydrolyzing phospholipase D in these cells. In this study, we examined whether protein tyrosine kinase is involved in the PKC-induced activation of phospholipase D in MC3T3-E1 cells. Genistein, an inhibitor of protein tyrosine kinases, which by itself had little effect on choline formation, significantly suppressed the formation of choline induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of PKC, in a dose-dependent manner. Tyrphostin, an inhibitor of protein tyrosine kinases chemically distinct from genistein, also dose-dependently suppressed the TPA-induced formation of choline. Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, significantly enhanced the TPA-induced formation of choline in a dose-dependent manner. These results strongly suggest that protein tyrosine kinase regulates phospholipase D activity at a point downstream from PKC in osteoblast-like cells.
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PMID:Tyrosine kinase regulates phospholipase D activation at a point downstream from protein kinase C in osteoblast-like cells. 775 61

Long-term administration of lithium is one of the well-known causes of goiter. It can stimulate DNA synthesis in rat thyroid cells (FRTL-5) treated with thyroid-stimulating hormone (TSH). To investigate the mitogenic signal transduction system activated by lithium, lithium-induced DNA synthesis and Ca2+ influx were studied using two protein kinase inhibitors, genistein as a specific tyrosine kinase inhibitor and staurosporine as a potent inhibitor of protein kinase C. Genistein but not staurosporine blocked the DNA synthesis induced by lithium in TSH-primed cells but neither compound had any effect on the Ca2+ entry stimulated by lithium. Genistein clearly attenuated the phosphotyrosine content of the 175 kDa substrate in the presence of lithium but staurosporine failed to do so. Moreover, lithium could also stimulate DNA synthesis in protein kinase C down-regulated cells. These data demonstrate that lithium may require the activation of a particular genistein-sensitive kinase, possibly a tyrosine kinase, to induce cell proliferation. It is suggested that the phorbol ester-sensitive protein kinase C family might not participate in the mitogenic signal transduction pathway activated by lithium.
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PMID:Genistein but not staurosporine can inhibit the mitogenic signal evoked by lithium in rat thyroid cells (FRTL-5). 782 87

Fertilization results in the activation of protein tyrosine kinases within minutes of sperm-egg binding, although the role of the kinase(s) involved is not clear. In the present study, we have treated sea urchin eggs with genistein, as well as other protein tyrosine kinase inhibitors, and have characterized the subsequent effect on fertilization and egg activation. Genistein treatment of sea urchin eggs inhibits the overall fertilization-dependent tyrosine kinase activity as well as the specific phosphorylation of a 350-kDa protein, but it did not inhibit cAMP-dependent kinase and had little effect on protein kinase C at concentrations less than 100 microM. Genistein, erbstatin, and tyrphostin B42 did not inhibit the early events of fertilization such as elevation of the fertilization envelope; however, later events such as pronuclear migration, DNA synthesis, and cell division were inhibited. These results suggest that protein tyrosine kinases activated following fertilization play a role in the later events of egg activation such as the initiation of pronuclear movement and entry into the S phase of the cell cycle.
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PMID:Effects of protein tyrosine kinase inhibitors on egg activation and fertilization-dependent protein tyrosine kinase activity. 788 65

We have previously demonstrated that oxysterols and calcitriol potentiate arachidonic acid (AA) release and prostaglandin (PG) synthesis when NRK cells (fibroblastic clone 49F) are activated by foetal calf serum. As serum is essential for a full oxysterol effect, we hypothesized that these compounds could act on one or more of the events triggered by serum growth factor binding to their specific receptors and leading to PLA2 activation; we showed that the oxysterol effect on AA release is synergistic with, but not fully dependent on, protein kinase C (PKC) activity and Ca2+ ion fluxes, suggesting that oxysterols could effect early events in the cell signalling pathway. In the present paper, we investigated the effect of some oxysterols and calcitriol on epidermal growth factor (EGF)-induced AA release and PGE2 synthesis in NRK cells. The clear potentiation of EGF effect by most of the oxygenated sterols--chiefly when polyoxidized--cannot be explained by a modification of EGF high affinity binding site number which was only moderately increased after a 4 h incubation of cells with these compounds, and moreover was not related to the ability of a given oxysterol to increase PLA2 activity; whatever the compound, the dissociation constant (Kd) of either a high or low affinity binding site was unchanged (respectively, 3.5 x 10(-11) M and 4.4 x 10(-10) M). Genistein, a known inhibitor of EGF receptor tyrosine kinase, changed neither the EGF effect on AA release nor its potentiation by oxysterol, whereas it inhibited PGE2 synthesis in both situations. PKC activation by phorbol ester TPA increased the effect of EGF alone as well as the oxysterol potentiating effect, whereas PKC down-regulation strongly decreased both of these effects, showing that both are dependent on PKC activity. Nevertheless staurosporine, a PKC inhibitor, did not reproduce the effects of PKC down-regulation on EGF activation: stimulatory when AA release was induced by EGF alone, inhibitory when AA release is induced by TPA alone, this compound did not modify the oxysterol potentiating effect. In conclusion, the potentiating effect of oxysterols on AA release seems to be exerted downstream to the growth factor receptor (as demonstrated here with EGF) and probably at the PKC level, but not exclusively.
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PMID:Potentiation by cholesterol and vitamin D3 oxygenated derivatives of arachidonic acid release and prostaglandin E2 synthesis induced by the epidermal growth factor in NRK 49F cells: the role of protein kinase C. 788 3

The existence and activation of mitogen-activated protein (MAP) kinase in isolated pancreatic acini have been demonstrated. Immunoblotting and immunoprecipitation revealed two forms of MAP kinase in pancreatic acini, with relative molecular masses of approximately 42 and 44 kDa. Both forms of MAP kinase were activated by cholecystokinin (CCK). The threshold concentration of CCK was approximately 3 pM, and the maximal effect occurred at 1 nM, which enhanced MAP kinase activity by 2.5-fold, as determined in polyacrylamide gel copolymerized with substrate myelin basic protein. Activation of MAP kinase by CCK was rapid, reaching a maximum within 5-10 min that subsequently declined. Bombesin and carbachol but not secretin or vasoactive intestinal peptide also activated MAP kinase. CCK-induced activation of MAP kinase may be mediated by protein kinase C, since 12-O-tetradecanoylphorbol 13-acetate (TPA) mimicked the effect of CCK and staurosporine concentration dependently inhibited the action of CCK. Treatment of acini with thapsigargin, ionomycin, or ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid did not influence MAP kinase, indicating that mobilization of intracellular calcium by CCK is not important in activation of acinar MAP kinase. CCK and TPA increased tyrosine phosphorylation of both 42- and 44-kDa forms. Genistein and tyrphostin 23, the inhibitors of tyrosine kinase, suppressed the activation of MAP kinase by CCK. In conclusion, MAP kinase in pancreatic acini is activated by agonists related to hydrolysis of phosphoinositide, via a mechanism involving protein kinase C and tyrosine kinase.
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PMID:Cholecystokinin rapidly activates mitogen-activated protein kinase in rat pancreatic acini. 794 37

We investigated the signal transduction pathways leading to the 12-O-tetradecanoylphorbol-13-acetate (TPA)- and interleukin-1 alpha (IL-1)-induced IL-1 alpha mRNA in mouse keratinocytes. Induction of IL-1 alpha mRNA by TPA or IL-1 alpha was followed by increases in cell-associated IL-1 alpha protein measured by enzyme-linked immunosorbent assay. Although protein kinase C (PKC) was involved in TPA-induced IL-1 alpha mRNA, down-regulation of PKC did not block the induction of this gene by TPA. The autocrine induction of IL-1 alpha was not mediated through PKC or cAMP. IL-1 alpha did activate mitogen-activated protein kinase. Genistein, a tyrosine kinase inhibitor, blocked both IL-1 alpha-induced mitogen-activated protein kinase activation as well as IL-1 alpha mRNA expression. Genistein, at an unsaturating dose, plus a serine/threonine kinase inhibitor, H7, completely blocked the autocrine induction of IL-1 alpha suggesting that expression of this gene is regulated by tyrosine kinase(s) in combination or independently with serine/threonine kinase(s). In addition, both TPA and IL-1 alpha caused increases not only in the phosphorylation of c-Jun and c-Fos protein but also in the transactivating activity of AP-1 nuclear transcription factor. Neither TPA nor IL-1 alpha induced NF-kappa B binding activity, as assessed by electrophoretic mobility shift analysis. This study suggests that the activation of AP-1 may be a common event through which TPA and IL-1 alpha induce IL-1 alpha mRNA.
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PMID:Signal transduction pathway(s) involved in phorbol ester and autocrine induction of interleukin-1 alpha mRNA in murine keratinocytes. 802 56

The immunosuppressive synthetic methylated polycyclic aromatic hydrocarbon (PAH), 7,12-dimethylbenz[a]anthracene (DMBA), has been shown to cause both an immediate and a sustained elevation of free intracellular calcium (Ca2+) in human T cells. In the present studies, a series of anthracene- and pyrene-based PAHs were tested for rapid (3 min) and sustained (4 hr) Ca2+ mobilization in the HPB-ALL human T cell line measured by flow cytometry using Fluo-3 as a Ca2+ indicator. Immunosuppressive PAHs produced a sustained Ca2+ elevation for at least 4 hr, while weakly immunosuppressive PAHs caused only a transient increase in Ca2+. The immunosuppressive PAHs, DMBA, benzo[a]pyrene, dibenz[a,h]anthracene, and 9,10-dimethylanthracene, produced a sustained increase in intracellular Ca2+ in HPB-ALL cells. Those PAHs with moderate to minimal immunosuppressive properties (i.e., dibenz[a,c]anthracene, benz[a]anthracene, benzo[e]pyrene, and anthracene) produced small and transient Ca2+ mobilization responses in HPB-ALL cells. It appeared that methylation of anthracene at the 9,10-positions increased the duration of Ca2+ mobilization, whereas the addition of a benzene group in the "a" position was associated with a transient increase in Ca2+ levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, partially inhibited the rapid and sustained PAH-induced Ca2+ mobilization responses, while the protein kinase C (PKC) inhibitors, staurosporine and calphostin C, had essentially no effect on PAH-induced Ca2+ elevation. It appears that the action of PAHs on PTKs is important in the rapid Ca2+ response of human T cells. However, additional biochemical mechanisms appear to be responsible for the sustained elevation of Ca2+ produced by PAHs in T cells. The results of these studies demonstrate that persistent elevation of intracellular Ca2+ by PAHs correlates with their known immunosuppressive properties.
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PMID:Persistence of calcium elevation in the HPB-ALL human T cell line correlates with immunosuppressive properties of polycyclic aromatic hydrocarbons. 804 70

Intracellular calcium may be a mediator of insulin action in vascular smooth muscle cells. This study investigates effects of physiological concentrations of insulin on intracellular free calcium concentrations in primary unpassaged vascular smooth muscle cells derived from 3- and 17-week-old normotensive rats (Wistar and Wistar-Kyoto) and spontaneously, hypertensive rats (SHR). Underlying mechanisms responsible for insulin-evoked calcium responses were also studied. Basal calcium was significantly higher in 17-week SHR cells (134 +/- 8 nmol/L) compared with cells from Wistar-Kyoto (98 +/- 12 nmol/L) and Wistar (99 +/- 10 nmol/L) rats. Insulin (70 microU/mL) significantly increased calcium in all cells. Responses from 3-week rat cells were similar. The increase was amplified in 17-week SHR cells (177 +/- 7 nmol/L) compared with Wistar-Kyoto (130 +/- 14 nmol/L) and Wistar (132 +/- 16 nmol/L) cells. Genistein (0.1 mumol/L) and tyrphostin 23 (0.1 mumol/L) (tyrosine kinase inhibitors) completely abolished insulin-induced calcium effects. Stimulatory effects of insulin were significantly inhibited by 0.1 mumol/L diltiazem, staurosporine, calphostin C, and thapsigargin. The inhibitory effects of diltiazem (calcium channel antagonist) and the protein kinase C inhibitors staurosporine and calphostin C were significantly lower in cells from hypertensive compared with those from normotensive rats. Calcium recovery after insulin administration was delayed in SHR cells. In conclusion, insulin increases vascular smooth muscle cell calcium concentrations, possibly via calcium channel activation, protein kinase C-mediated mechanisms, and intracellular calcium mobilization. Alterations of these pathways as well as impaired calcium recovery to baseline may be associated with increased insulin-sensitive calcium responses in cells from SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-induced Ca2+ transport is altered in vascular smooth muscle cells of spontaneously hypertensive rats. 820 30

Growth factors stimulate cellular protein synthesis, but the intracellular signaling mechanisms that regulate initiation of mRNA translation in neurons have not been clarified. A rate-limiting step in the initiation of protein synthesis is the formation of the ternary complex among GTP, eukaryotic initiation factor 2 (eIF-2), and the initiator tRNA. Here we report that genistein, a specific tyrosine kinase inhibitor, decreases tyrosine kinase activity and the content of phosphotyrosine proteins in cultured primary cortical neurons. Genistein inhibits protein synthesis by > 80% in a dose-dependent manner (10-80 micrograms/ml) and concurrently decreases ternary complex formation by 60%. At the doses investigated, genistein depresses tyrosine kinase activity and concomitantly stimulates PKC activity. We propose that a protein tyrosine kinase participates in the initiation of protein synthesis in neurons, by affecting the activity of eIF-2 directly or through a protein kinase cascade.
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PMID:Depression of neuronal protein synthesis initiation by protein tyrosine kinase inhibitors. 822 95


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