Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) induced significant superoxide production in human neutrophils within 30 minutes after addition of stimulus and the response was complete within 2 hr. Other agents known to prime neutrophils, including LPS and tumor necrosis factor-alpha, lacked activity under the experimental conditions employed. Using a panel of pharmacologic inhibitors, we sought to compare GM-CSF-induced neutrophil superoxide to that produced by cells exposed to N-formyl methionyl-leucyl-phenylalanine (fMet-Leu-Phe) and phorbol 12-myristate 13-acetate (PMA). Each stimulant displayed a different profile. Rolipram, a peak IV phosphodiesterase inhibitor, specifically inhibited neutrophil activation by GM-CSF and fMet-Leu-Phe, while superoxide production stimulated by PMA was unaffected. Staurosporine, a protein kinase C (PK-C) inhibitor, suppressed superoxide production induced by all three neutrophil stimulants. Cytochalasin B totally inhibited superoxide induced by GM-CSF under conditions that promote the fMet-Leu-Phe-induced response. Cytochalasin B did not markedly affect PMA-induced superoxide. The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophil activators. Superoxide secretion from GM-CSF-treated neutrophils appears to be a direct, delayed response that requires assembly of microfilaments during exposure to the cytokine.
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PMID:Effect of recombinant human granulocyte/macrophage colony-stimulating factor on neutrophil superoxide production. 166 43

Leucocyte Na+/H+ antiport activity is elevated in patients with essential hypertension and Type 1 diabetes with nephropathy. To examine the effects of hyperglycemia on the Na+/H+ antiport, normal leucocytes were incubated with 25 mmol l-1 D-glucose, L-glucose or glucose-6-phosphate for two days. Leucocyte Na+/H+ antiport activity was measured by a novel double ionophore fluorimetric method for controlling intracellular pH. Only incubation with D-glucose led to an increase in Na+/H+ antiport activity of about 31%. This effect was not due to non-enzymic glycation since glucose-6-phosphate, which glycates proteins faster than D-glucose, caused no significant difference in antiport activity. Also, osmotic effects could be excluded. Staurosporine (10 nmol l-1), a specific inhibitor of protein kinase C, prevented the rise in antiport activity due to incubation with D-glucose. As hyperglycaemia is known to increase protein kinase C activity, elevation of this kinase may be one mechanism for activation of the Na+/H+ antiport in Type 1 diabetes.
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PMID:Stimulation of the human leucocyte Na+/H+ antiport by D-glucose is mediated by protein kinase C. 166 30

Staurosporine is a potent but nonselective inhibitor of protein kinase C (PKC) and blocks responses to 12-O-tetradecanoylphorbol-13-acetate (TPA) in several cell types in vitro. In cultured primary mouse keratinocytes, however, staurosporine fails to inhibit TPA-mediated keratinocyte maturation and itself elicits responses that are similar to TPA (T. Sako et al., Cancer Res., 48: 4646-4650, 1988). After exposure to 10 nM staurosporine for 24 h, essentially all keratinocytes undergo morphological differentiation, whereas 160 nM TPA induces this response in about 50% of epidermal cells. These concentrations of staurosporine and TPA cause a 4-5-fold induction of epidermal transglutaminase activity and cornified envelopes, both markers of the terminal stage of keratinocyte differentiation. Staurosporine, but not TPA, also induces morphological and biochemical maturation in 2 neoplastic mouse keratinocyte cell lines, 308 and SP-1. The ability of staurosporine to elicit the same responses as TPA suggested that it may be functioning paradoxically as a PKC agonist in intact keratinocytes. In support of this hypothesis, staurosporine induces ornithine decarboxylase activity, inhibits 125I-labeled epidermal growth factor binding, and induces expression of c-fos mRNA. Down-regulation of PKC by pretreatment of primary keratinocytes with 60 nM bryostatin partially blocks staurosporine-mediated induction of cornified envelopes and inhibition of 125I-labeled epidermal growth factor binding, implicating PKC in these responses. The ability of staurosporine to mimic and/or enhance certain responses to TPA suggests that this agent is acting as a functional PKC agonist in cultured keratinocytes.
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PMID:Staurosporine induces protein kinase C agonist effects and maturation of normal and neoplastic mouse keratinocytes in vitro. 167 84

The effects of the calcium channel antagonist nifedipine and the protein kinase C (PKC) inhibitor, staurosporine were examined on the pressor actions of a full, cirazoline, and a partial, St587, alpha 1-adrenoceptor agonist as well as the alpha 2-adrenoceptor agonist B-HT 920 in the pithed rat preparation. Administration of nifedipine or staurosporine significantly reduced the diastolic blood pressure of pithed rats. Staurosporine displaced the dose-diastolic pressure response curves for B-HT 920 and St587 to the right in a dose-dependent manner. The ED50 value for the dose-response curves to B-HT 920 and St587 were found to be significantly increased after the administration of staurosporine. Staurosporine also caused a depression of the maximum response to B-HT 920 and St587. The presence of nifedipine resulted in an increase in the ED50 value of the dose-response curve to B-HT 920 and St587, and this was accompanied by significant reductions of the maximum response, whereas the administration of either staurosporine or nifedipine did not significantly affect the calculated ED50 value of the dose-response curve to cirazoline. In the presence of the calcium channel antagonist but not the PKC inhibitor the maximum response to cirazoline was significantly depressed. As judged from the slope function of the dose-response curves the nature of the inhibition produced by nifedipine compared to staurosporine also appeared to differ. Thus, with nifedipine as the antagonist, the slope function of the dose-response curve for alpha-agonists was significantly reduced. Moreover, in contrast to the actions of staurosporine, nifedipine reduced the maximum response to cirazoline in a dose-independent manner. This study supports the hypothesis that activation of alpha-adrenoceptors that have a substantial dependence on extracellular calcium for vasoconstriction are susceptible not only to the action of calcium channel antagonists but also to the actions of the PKC inhibitor staurosporine, thus suggesting that PKC may modulate directly/indirectly calcium channel activity in vascular smooth muscle.
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PMID:Effects of staurosporine on the pressor responses to alpha-adrenoceptor agonists in pithed rats: a comparison with nifedipine. 168 70

Staurosporine is a potent microbial inhibitor of a number of protein kinases, including protein kinase C, cyclic AMP-dependent kinase, and the tyrosine kinase pp60src. We have used staurosporine to investigate the role of phosphorylation in the regulation of the epidermal growth factor (EGF) receptor in both human epidermal carcinoma A431 cells and mouse Swiss 3T3 fibroblasts. We report here that staurosporine treatment causes enhancement in high affinity EGF binding and a decrease in the phosphorylation state of the unstimulated receptor at a number of residues, including threonine 669. Staurosporine also antagonizes the inhibition of high affinity EGF binding and the increase in phosphorylation state of the unstimulated EGF receptor by phorbol esters and the calcium ionophore A23187. Staurosporine is an effective inhibitor of the EGF-stimulated receptor tyrosine kinase in vitro and thus does not enhance EGF stimulation of EGF receptor autophosphorylation in vivo. These results suggest that phosphorylation plays a major role in the regulation of the high affinity binding state of the EGF receptor in both unstimulated and mitogenically activated cells.
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PMID:Regulation of the epidermal growth factor receptor by growth-modulating agents: effects of staurosporine, a protein kinase inhibitor. 168 32

The effects of two putative inhibitors of protein kinase C activity, staurosporine and H-7, on partially purified protein kinase C and amylase secretion from isolated rabbit pancreatic acini were investigated. Staurosporine dose-dependently inhibited amylase release stimulated by an optimal concentration of cholecystokinin C-terminal octapeptide. At a concentration of 100 nM, the drug inhibited the secretory response to the secretagogue by approximately 50%. At the same concentration, staurosporine inhibited 12-O-tetradecanoylphorbol 13-acetate-stimulated enzyme secretion by 90%. Moreover, the potentiating effect of this phorbol ester on cholecystokinin-induced amylase release was completely abolished in the presence of staurosporine. Interestingly, amylase release was decreased to the level observed with the combination of cholecystokinin and staurosporine. In contrast, H-7, potentiated rather than inhibited cholecystokinin-stimulated enzyme secretion, whereas the secretory response to 12-O-tetradecanoylphorbol 13-acetate was not affected by the drug. Both staurosporine and H-7, however, inhibited protein kinase C purified from exocrine pancreatic tissue. Kinetic analysis revealed that both compounds inhibited protein kinase C competitively with respect to ATP. The Ki value for staurosporine was 0.55 nM and for H-7 13.5 microM. Our results obtained with staurosporine are in line with a stimulatory role of protein kinase C in cholecystokinin-induced enzyme secretion from the exocrine pancreas. The results obtained with H-7 emphasize that care has to be taken in interpreting the biological effects of this drug.
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PMID:Dissimilar effects of the protein kinase C inhibitors, staurosporine and H-7, on cholecystokinin-induced enzyme secretion from rabbit pancreatic acini. 169 56

Nerve growth factor (NGF) cooperates with glucocorticoids, activators of adenylate cyclase, and lithium to induce the expression of teh gene encoding the neuropeptides neurotensin and neuromedin N (NT/N gene) in PC 12 pheochromocytoma cells. High level expression requires simultaneous treatment with three or all four inducers. To examine the mechanism underlying this complex synergism, we have examined the effects of protein kinase inhibitors and other agents which influence intracellular signal transduction on NT/N gene expression. Two structurally similar bacterial alkaloids, staurosporine and K-252a, inhibit several protein kinases in vitro, including protein kinase C and cyclic nucleotide-dependent kinases. K-252a has been reported to specifically inhibit the effects of NGF on PC12 pheochromocytoma cells. Surprisingly, staurosporine in combination with other inducers markedly potentiated NT/N gene expression. In contrast, K-252a had no effect on NT/N gene expression when added simultaneously with other inducers. Expression of the NT/N gene was also potentiated by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, which directly activates protein kinase C, and by bradykinin, which stimulates phosphatidylinositol turnover in PC12 cells, and these effects were not blocked by staurosporine. Staurosporine was generally more effective in stimulating NT/N gene expression when used in inducer combinations that did not include NGF. These results, taken together with recent evidence that staurosporine is also able to induce neurite outgrowth from PC12 cells, suggest that the effects of staurosporine and NGF may converge, in part, on a common intracellular target.
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PMID:A protein kinase inhibitor, staurosporine, mimics nerve growth factor induction of neurotensin/neuromedin N gene expression. 170 31

Tumor necrosis factor (TNF) inhibits granulocyte-colony-stimulating factor (G-CSF)-induced human acute myeloid leukemia (AML) growth in vitro. Incubation of blasts from three patients with AML in serum-free medium with TNF (10(3) U/ml), and subsequent binding studies using 125I-G-CSF reveal that TNF downregulates the numbers of G-CSF receptors by approximately 70%. G-CSF receptor numbers on purified blood granulocytes are also downmodulated by TNF. Downregulation of G-CSF receptor expression becomes evident within 10 min after incubation of the cells with TNF at 37 degrees C and is not associated with an apparent change of the dissociation constant (Kd). The TNF effect does not occur at 0 degrees C and cannot be induced by IL-2, IL-6, or GM-CSF. TNF probably exerts its effect through activation of protein kinase C (PKC) as the TNF effect on G-CSF receptor levels can be mimicked by 12-O-tetradecanoylphorbol-13- acetate. The PKC inhibitor Staurosporine (Sigma Chemical Co., St. Louis, MO) as well as protease inhibitors can completely prevent G-CSF receptor downmodulation. Thus, it appears TNF may act as a regulator of G-CSF receptor expression in myeloid cells and shut off G-CSF dependent hematopoiesis. The regulatory ability of TNF may explain the antagonism between TNF and G-CSF stimulation.
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PMID:Tumor necrosis factor downregulates granulocyte-colony-stimulating factor receptor expression on human acute myeloid leukemia cells and granulocytes. 170 66

The implication of protein kinase C in the phenomenon of pancreatic acinar cell desensitization to carbamylcholine, caerulein and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated using a potent PKC inhibitor, staurosporine. At a concentration of 1 microM, staurosporine caused a maximum 64% inhibition of amylase release from rat pancreatic acini stimulated by 100 nM TPA. At 100 nM, staurosporine reduced by 50 to 55% amylase secretion elicited by maximal concentrations of carbamylcholine or caerulein without affecting their potency. Staurosporine was also able to prevent completely desensitization by TPA of the subsequent secretory response to carbamylcholine and caerulein. Furthermore, staurosporine also totally prevented desensitization by caerulein of the subsequent secretory response to caerulein. In contrast, staurosporine only partially prevented desensitization by carbamylcholine of the subsequent secretory response to carbamylcholine. These results indicate that staurosporine is a potent inhibitor of protein kinase C as it inhibited the secretory response to carbamylcholine, caerulein and TPA. They also suggest that desensitization of the secretory response induced by TPA and caerulein used a common pathway involving protein kinase C activation. Finally, desensitization by carbamylcholine is more complex as it is only partially prevented at staurosporine; therefore, protein kinase C activation seems to be one of the factors involved.
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PMID:The ability of staurosporine to modulate pancreatic acinar cell desensitization by TPA, carbamylcholine and caerulein. 171 80

Glial fibrillary acidic protein (GFAP) mRNA levels in the human astrocytoma line U-373MG were examined to explore further the effects of agents that regulate protein kinase C. U-373MG cells exhibit a biphasic change in steady-state GFAP mRNA in the presence of the phorbol ester phorbol-12-myristate-13-acetate (PMA). Short-term treatment with PMA results in increased GFAP mRNA, and long-term treatment results in decreased GFAP mRNA. Nuclear run-off experiments demonstrate that the PMA-induced decrease in GFAP mRNA levels is not at the level of GFAP gene transcription. PMA exerts its effect in the presence of protein synthesis inhibitors, demonstrating that de novo protein synthesis is not required for the PMA-induced changes in GFAP mRNA. Staurosporine, a protein kinase C inhibitor, reduces GFAP mRNA expression in a dose-dependent manner; in the presence of PMA the effect is additive. By contrast HA1004, an inhibitor of cAMP-dependent protein kinase, is not inhibitory to GFAP steady-state mRNA. Total protein kinase C activity was determined to be 2,398.8 +/- 94.3 pmol/min/mg protein, with most of the activity in the cytosol. Short-term PMA treatment results in the translocation of the cytosolic protein kinase C activity to the membrane. Long-term PMA treatment results in a decrease in total protein kinase C activity indicating that downregulation occurs. These studies demonstrate that in the U-373MG cells, protein kinase C inhibitors and long treatment with PMA result in a decrease in steady-state GFAP mRNA.
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PMID:Phorbol-12-myristate-13-acetate (PMA) and inhibitors of protein kinase C alter glial fibrillary acidic protein (GFAP) mRNA levels. 172 Jul 62


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