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)

Staurosporine is an antibiotic that specifically inhibits protein kinase C. Fourteen staurosporine- and temperature-sensitive (stt) mutants of Saccharomyces cerevisiae were isolated and characterized. These mutants were divided into ten complementation groups, and characterized for their cross-sensitivity to K-252a, neomycin, or CaCl2. The STT1 gene was cloned and sequenced. The nucleotide sequence of the STT1 gene revealed that STT1 is the same gene as PKC1. The STT1 gene conferred resistance to staurosporine on wild-type cells, when present on a high copy number plasmid. STT1/stt1::HIS3 diploid cells were more sensitive to staurosporine than STT1/STT1 diploid cells. Analysis of temperature-sensitive stt1 mutants showed that the STT1 gene product functioned in S or G2/M phase. These results suggest that a protein kinase (the STT1 gene product) is one of the essential targets of staurosporine in yeast cells.
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PMID:Characterization of a staurosporine- and temperature-sensitive mutant, stt1, of Saccharomyces cerevisiae: STT1 is allelic to PKC1. 153 90

The present study specifically addresses the role of protein kinase C (PKC) activation in human endothelial cell Ca2+ mobilization, a response that is functionally coupled to the production of the potent arachidonate (AA) metabolite, prostacyclin (PGI2). Phorbol 12-myristate 13-acetate (PMA), alpha-thrombin, and sodium fluoride (NaF), a direct G-protein activator, produced a rapid and time-dependent translocation of PKC from the cytosol to the membrane. Activation of PKC by brief pretreatment of human umbilical vein endothelial cell (HUVEC) monolayers with PMA resulted in the inhibition of NaF-induced inositol phosphate increases and attenuation of both alpha-thrombin- and NaF-activated increases in intracellular Ca2+ (Ca2+i). Ca2+ mobilization induced by ionophore A23187 was not affected by PKC preactivation, suggesting PKC-dependent negative feedback inhibition of phosphatidylinositol (PI)-specific phospholipase C (PLC). Agonist-stimulated AA release and PGI2 synthesis in PMA-pretreated cultured human endothelial cells, however, was potentiated, and the enhanced PGI2 synthesis produced by A23187, NaF, and alpha-thrombin was dependent upon the dose of PMA. Treatment of HUVEC monolayers with an intracellular Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid-acetoxymethylester (BAPTA-AM), dramatically reduced alpha-thrombin-, NaF-, and A23187-induced PGI2 synthesis, demonstrating the importance of Ca2+i availability in PGI2 synthesis. BAPTA pretreatment did not inhibit PMA-induced PKC activation, and BAPTA-mediated inhibition of agonist-stimulated PGI2 synthesis was partially attenuated by prior PMA pretreatment. Staurosporine, a potent PKC inhibitor, at concentrations that inhibited PKC-induced phosphorylation of histone-1, augmented both alpha-thrombin- and NaF-induced production of inositol phosphates but markedly inhibited alpha-thrombin-, NaF-, and A23187-induced PGI2 synthesis. The downregulation of PKC activity by prolonged PMA treatment (18 h) produced similar inhibition of PGI2 synthesis by these agonists (approximately 50% inhibition). These studies indicate that the integrated phospholipase A2 and PLC activities are under complex regulation by factors that include both PKC activation and [Ca2+i]. PKC exerts dual effects on prostaglandin synthesis via negative regulation of Gp-coupled PI-specific PLC and positive feedback regulation of AA release and PGI2 synthesis. PKC is thus a critical determinant in the regulation of human endothelial cell prostaglandin synthesis by both receptor-mediated and G-protein-dependent cellular activation.
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PMID:Role of protein kinase C in the regulation of prostaglandin synthesis in human endothelium. 154 Mar 95

A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin caused an induction of epidermal ornithine decarboxylase (ODC) activity. When mice were topically pretreated with staurosporine, a most potent protein kinase C inhibitor, 6-84 h prior to TPA treatment, TPA-caused ODC induction was markedly enhanced. The enhancement of TPA-caused ODC induction by staurosporine was most pronounced when the time interval between staurosporine and TPA treatment was 36 h. Staurosporine elicited this enhancing effect in a dose-related manner. Staurosporine by itself also induced epidermal ODC activity. But the activity induced was very slight and would not directly contribute to the enhancing effect of this compound. Although staurosporine markedly augmented TPA-caused ODC induction, staurosporine-caused ODC induction was not augmented by this compound. Other protein kinase C inhibitors, such as 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, sphingosine and palmitoylcarnitine did not mimic the enhancing effect of staurosporine. These results indicate that the enhancement of ODC induction by staurosporine is specific for the induction caused by TPA and that this enhancing effect is not related to the protein kinase C inhibitory action of staurosporine. TPA-caused epidermal ODC induction was inhibited by indomethacin, and this inhibition was reversed by prostaglandin E2 (PGE2). Staurosporine-caused ODC induction was also inhibited by indomethacin but the inhibition was not reversed by PGE2, indicating that the mechanism of staurosporine-caused ODC induction is different from that of TPA.
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PMID:Staurosporine, a potent protein kinase C inhibitor, augments phorbol ester-caused ornithine decarboxylase induction in mouse epidermis. 154 24

The priming effect of LHRH in vitro (which results in increased responsiveness of gonadotropes to both LHRH receptor-mediated and receptor-independent stimuli) is brought about by an unknown mechanism. The present results indicate that induction of the LHRH priming effect is inhibited in a concentration-dependent manner by the protein kinase C (PKC) inhibitors staurosporine, K252a, H7 and by the novel highly-selective PKC inhibitor, Ro 31-8220. In contrast, a range of other compounds that are relatively selective inhibitors of other kinases such as tyrosine kinases and Ca2+/calmodulin-dependent kinases were unable to prevent priming. The PKC inhibitors prevented priming without affecting initial LHRH-induced gonadotropin secretion. Thus, the priming-elicited increment in secretion was selectively removed, restoring hormone release to the level measured during an initial response to LHRH. Similar results were obtained on different days of the estrous cycle where the magnitude of the priming effect varies. Experiments on the time course of PKC inhibitor action revealed that the critical period was in the induction of the priming effect, not its expression. The PKC inhibitors had neither acute nor delayed effects on gonadotropin secretion induced by ionomycin. Staurosporine, K252a and Ro 31-8220 inhibited LHRH priming with identical potencies to their inhibition of phorbol ester-induced gonadotropin secretion. The reduced potency of H7 seen on LHRH priming compared to phorbol ester-induced gonadotropin release parallels results seen with this inhibitor on phorbol ester-induced secretion of growth hormone (Johnson and Mitchell (1989) Biochem. Soc. Trans. 17, 751-752) and on the pharmacological characteristics of PKCs partially purified from anterior pituitary tissue. In all aspects of this study, effects on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion appeared to be entirely similar.
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PMID:The priming effect of luteinizing hormone-releasing hormone (LHRH) but not LHRH-induced gonadotropin release, can be prevented by certain protein kinase C inhibitors. 163 16

The protein kinase C (PKC) inhibitor staurosporine, a member of the K252a family of fungal alkaloids that are known as protein kinase inhibitors, induces neurite outgrowth in pheochromocytoma PC12 cells. The progressive staurosporine-induced neurotropic effect (EC50 = 50 nM) has the following characteristics: it is evident after 4 hr of incubation, requires the continuous presence of staurosporine, occurs at 37 degrees but not at 4 degrees, and is not blocked by K252a derivatives. Scanning electron micrographs showed long neurites, ruffling, and dense networks in nerve growth factor (NGF)-treated cells and short neurites, flattening, and smooth cell surface in staurosporine-treated cells. [3H]Staurosporine binding, which was time, temperature, and dose dependent, saturated at 5-10 nM. Other kinase inhibitors were poor competitors. The [3H]staurosporine bound over 20 hr at 37 degrees was poorly dissociated by acetic acid wash or unlabeled staurosporine. These results suggest an uptake process occurring at 37 degrees that is required for the neurotropic effect of staurosporine. NGF did not interfere with staurosporine binding, and staurosporine did not affect NGF receptor binding. At neurotropic concentrations of staurosporine, PKC in PC12 cells was completely inhibited. When PKC activity was down-regulated by prolonged exposure to phorbol myristate acetate, PC12 cells responded to staurosporine with neurite outgrowth similar to that of untreated cells. Although the target and mechanism of the neurotropic effects of staurosporine remain to be determined, the observed effects on PKC-deficient cells indicate that PKC may not be required for the neurotropic effect of this compound in PC12 cells. These results suggest that caution should be taken in the interpretation of staurosporine action in vivo, and they provide a pharmacological tool for the development of potential neurotropic drugs.
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PMID:Staurosporine-induced neurite outgrowth in PC12 cells is independent of protein kinase C inhibition. 163 52

The present study was undertaken to determine the effects of a protein kinase C inhibitor, staurosporine, on gonadotropin-releasing hormone agonist (GnRHa)-induced oocyte maturation and follicular prostaglandin (PG) production, and the response to direct activators of protein kinase C using rabbit mature follicle culture. Treatment of mature follicles with GnRHa (buserelin and leuprolide acetate) neither stimulated nor inhibited cAMP accumulation in both the follicle and oocyte. Exposure to staurosporine at 10(-6) M 60 or 15 min before GnRHa (buserelin) administration reduced significantly the meiotic maturation of follicle-enclosed oocytes induced by GnRHa at 10(-7) M. However, staurosporine addition coincident with the agonist or thereafter did not inhibit meiotic maturation. Staurosporine suppressed GnRHa-induced meiotic maturation in a dose-dependent manner, whereas hCG-stimulated oocyte maturation was not inhibited. Similarly, staurosporine administered 60 min before exposure to GnRHa suppressed GnRHa-stimulated PG production by mature follicles. The active phorbol esters, 10(-6) M 12-0-tetra-decanoyl phorbol 13-acetate (TPA) and 10(-6) M 4 beta-phorbol 12,13-didecanoate (4 beta-PDD) stimulated meiotic maturation whereas the biological inactive isomer, 4 alpha-PDD, did not. The kinetics of germinal versicle breakdown of follicle-enclosed oocytes in the presence of active phorbol esters paralleled that of GnRHa-treated oocytes. Furthermore, the concomitant addition of staurosporine at 10(-6) M to the culture medium inhibited significantly (p less than 0.05) TPA-induced meiotic maturation. These data demonstrate that GnRHa stimulated both the meiotic maturation of follicle-enclosed oocytes and follicular PG formation via a mechanism other than the cAMP-mediated process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C mediates gonadotropin-releasing hormone agonist-induced meiotic maturation of follicle-enclosed rabbit oocytes. 163 39

H7 has been described as a potent inhibitor of protein kinase C (PKC) and has been widely used to investigate the regulatory role of this enzyme in intact cell systems. In this comparative study between H7 and the microbial alkaloid, staurosporine, we found that the former inhibited rat brain PKC and cAMP dependent protein kinase with IC50 values of 18 and 16 microM respectively whereas the latter was a much more potent inhibitor of both kinases with IC50 values of 9.5 nM and 42 nM respectively. H7, at concentrations up to 100 microM, failed to block cellular events induced by phorbol esters, agents which specifically stimulate PKC, yet was a potent inhibitor of IL-2 induced T cell proliferation with an IC50 value of 19 microM. In contrast, staurosporine was a potent inhibitor of both phorbol ester induced p47 phosphorylation in platelet (I50 value = 540 nM) and also CD3 and CD4 down-regulation in T cells (I50 values 200 nM and 50 nM respectively). Staurosporine was also a potent inhibitor of IL-2 induced T cell proliferation I50 value = 9 nM). These results provide a strong argument against the use of H7 to probe for PKC involvement in cellular processes.
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PMID:Modulation of cellular processes by H7, a non-selective inhibitor of protein kinases. 165 May 19

Erythrophagocytosis induces in monocytes-macrophages the synthesis of stress proteins including the classical heat shock proteins (HSPs) and heme oxygenase (HO). To evaluate the role of oxygen radicals in this induction, we used the antioxidant flavonoids quercetin and kaempferol. These compounds inhibited HSP and HO synthesis, the latter being more sensitive. Quercetin and kaempferol also are inhibitors of protein kinase C (PKC). In order to determine whether inhibition of stress protein synthesis by flavonoids was mediated by their antioxidant properties or by PKC inhibition, we also tested more specific PKC antagonists, staurosporine and H-7. Staurosporine (SS) and H-7 decreased the synthesis of HSP70 and HSP83 but had no effect on HO. These data suggest that (1) erythrophagocytosis-related oxygen radicals are involved in the induction of the stress response in phagocytic cells, (2) the induction of HSPs and HO is differentially regulated, and (3) the effects of flavonoids on HO are linked to their scavenging activity rather than to PKC modulation.
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PMID:Flavonoids, but not protein kinase C inhibitors, prevent stress protein synthesis during erythrophagocytosis. 165 71

Phorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C, dramatically decreased topoisomerase II-reactive drug-induced DNA cleavage in HL-60 human leukemia cells. The effect of staurosporine, an inhibitor of protein kinase C, on drug-induced, topoisomerase II-mediated DNA cleavage was quantified in the same cells. Staurosporine decreased the magnitude of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)- and etoposide-induced DNA cleavage in a dose- and time-dependent fashion. Measurement of several parameters of cell proliferation revealed no clear and uniform correlation between staurosporine's inhibition of these parameters and its effects on drug-induced DNA cleavage. A direct comparison with PMA's effects on drug-induced DNA cleavage showed that whereas PMA's inhibition of etoposide-induced cleavage was much greater than its inhibition of m-AMSA-induced cleavage, the magnitude of staurosporine's effect on the cleavage produced by the two topoisomerase II-reactive drugs was similar. Thus, although PMA stimulates protein kinase C and staurosporine inhibits this enzyme, it is unlikely that the actions of either on topoisomerase II-reactive, drug-induced DNA cleavage are mediated directly via protein kinase C. Furthermore, it is likely that the mechanisms by which PMA and staurosporine inhibit topoisomerase II-reactive drug-induced cleavage are different.
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PMID:The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. 166 Mar 53

We have previously shown that HL-60 cells treated with 1 alpha, 25-(OH)2D3 in magnesium-deficient medium are committed to differentiate but do not express differentiation-related phenotypes. In the present study, we demonstrated that Mg2+ deprivation blocked the process of differentiation before the induction of lysozyme mRNA and that the process of HL-60 cell differentiation could be divided into two steps, i.e., a commitment step and a phenotypic expression step. We studied the effects of protein kinase A (PKA) and calcium/phospholipid-dependent protein kinase (PKC) modulators at each step. The results indicated that agonists of PKA enhanced both steps but that N-(2-[methylamino]ethyl-5-isoquinolinesulfonamide inhibited them. On the other hand, 1-oleyl-2-acetylglycerol and 12-O-tetradecanoylphorbol-13-acetate enhanced the commitment step but inhibited that of phenotypic expression. Staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine inhibited the commitment step and enhanced that of phenotypic expression. These results indicate that PKA acts as a positive regulatory signal and that PKC has a dual role in the process of HL-60 cell differentiation, i.e., as a positive regulatory signal in the commitment step and as a negative one in the phenotypic expression step. Recently, we have also shown that in K-562 cell differentiation into erythroid lineage, PKA may serve as a negative regulatory signal in both steps; however, PKC may act dually, namely as a negative regulatory signal in the commitment step and as a positive one in the phenotypic expression step.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of protein kinase A and calcium/phospholipid-dependent kinase modulators in the process of HL-60 cell differentiation: their opposite effects between HL-60 cell and K-562 cell differentiation. 166 Nov 33


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