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)

Using the human hepatoma cell line Hep G2, we have studied a possible role of protein kinase C (PKC) activity for regulation of erythropoietin (EPO) production. During a 72-h incubation, EPO production by the cells was stimulated sevenfold by exposure to low oxygen tension (1%) and threefold by exposure to cobaltous chloride (100 microM). The phorbol ester phorbol 12-myristate-13 acetate (PMA) led to a concentration-dependent inhibition of basal and stimulated EPO formation (ED50 10 nM). This decrease of EPO production, which was apparent already after 1 h of incubation with PMA, reached its maximal effect after 24 h and held on for 72 h. It was paralleled by an inhibition of the increase of EPO mRNA levels in response to stimulation. A 24-h preincubation of the cells with PMA (100 nM) virtually blunted the effect of hypoxia on EPO formation. Recovery of EPO synthesis after removal of PMA took 48-72 h. The effect of PMA on EPO production was mimicked by phorbol 12,13-dibutyrate (ED50 1 microM) but not by 4 alpha-phorbol 12,13-didecanoate. The synthetic diacylglycerol analogues oleolyl-acetylglycerol and dioctanoylglycerol (2-200 microM) also had no effect on either basal or stimulated EPO production. Treatment with PMA caused a translocation of the alpha-isoenzyme of PKC from the cytosol to the membrane after 1 h and a disappearance of the membrane-bound form after 24 h of incubation. Staurosporine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, two structurally different inhibitors of PKC activity, inhibited basal and stimulated EPO production with ED50 values of 9 nM and 50 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phorbol ester inhibits erythropoietin production in human hepatoma cells (Hep G2). 131 1

Unlike resident peritoneal macrophages (RPM) or tumor necrosis factor alpha (TNF alpha)-primed bone marrow-derived macrophages (BMM), unprimed BMM do not generate superoxide in response to the protein kinase C (PKC) activator, phorbol myristate acetate (PMA). However, these cells do contain significant levels of PKC activity. In contrast to PMA, zymosan induces the generation of superoxide in unprimed BMM, as well as in TNF alpha-primed BMM and RPM. Staurosporine, a potent PKC inhibitor, failed to affect the zymosan-induced production of superoxide by unprimed and TNF alpha-primed BMM and RPM, in spite of substantial inhibition of PMA-induced superoxide production by the primed BMM and RPM. However, when PKC was depleted from unprimed BMM by prolonged (24 h) treatment with phorbol dibutyrate (PdBt) (10(-7) M) the ability of zymosan to induce the production of superoxide was greatly diminished. Such a result could be interpreted as suggesting a role for PKC in the zymosan-induced response, a conclusion which contrasts with the inhibitor data. However, PKC depletion, in this case, is achieved via the PdBt-induced activation of PKC. It is thus possible that it is the initial activation of PKC, rather than its depletion, that suppresses superoxide production. Consistent with this interpretation, the co-stimulation of unprimed BMM with both zymosan and PMA resulted in a reduced superoxide release compared to zymosan alone. The activation of PKC therefore appears to have a suppressive effect on the generation of superoxide by unprimed cells. We thus conclude that PKC is not required for zymosan-induced superoxide production by either primed or unprimed macrophages and suggest that PKC may be involved in regulatory mechanisms restricting superoxide production by macrophages. However, since PMA alone can initiate the release of superoxide from primed BMM and RPM, it would appear that PKC can mediate both stimulatory and suppressive signals for macrophage superoxide production.
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PMID:Protein kinase C has both stimulatory and suppressive effects on macrophage superoxide production. 132 39

Staurosporine, a microbial alkaloid, enhances inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DG) production rapidly and dose-dependently in fMet-Leu-Phe (FMLP)-stimulated human neutrophils showing maximal effects at 1 microM concentration. The IP3 increase was specific for staurosporine as three other putative protein kinase C (PKC) inhibitors, H7, sphingosine and palmitoylcarnitine were unable to enhance the IP3 generation in FMLP-stimulated human neutrophils. Staurosporine, at concentrations 0.3-1.0 microM, did not affect the initial mobilization of FMLP-induced intracellular Ca2+ (Ca2+i), although a sustained elevation of cytosolic Ca2+ level was observed within 5 min. This effect could not be suppressed, even by 1 microM phorbol-myristate 12,13-acetate (PMA). Whereas lower concentrations of staurosporine (less than or equal to 100 nM) were unable to affect FMLP-induced IP3 production, DG accumulation and Ca2+i, the PMA-inhibited initial Ca2+i signal and IP3 formation triggered by FMLP were almost completely restored. At higher concentrations (greater than or equal to 300 nM) staurosporine reversed the inhibitory effect of other protein kinases, distinct from the PMA-inducible one, which may be responsible for the phosphatidyl inositol 4,5-bisphosphate (PIP2) breakdown, thus causing accumulation of IP3 and DG and an elevation of C2+i level. Whereas IP3 declined to basal level within 5 min, the DG level remained elevated during the same period. This phenomenon is attributed to phospholipase D (PLD) stimulation by staurosporine, which augments the DG synthesis, in part through PA degradation via phosphatidic acid (PA) phosphohydrolase.
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PMID:Effect of staurosporine on fMet-Leu-Phe-stimulated human neutrophils: dissociated release of inositol 1,4,5-trisphosphate, diacylglycerol and intracellular calcium. 132 Apr 9

Previous data suggest that atrial natriuretic factor (ANF) and bradykinin (BK) interact to increase Na+ and water excretion. We propose that this interaction is due to a synergistic action that inhibits Na+ absorption in the distal nephron. We examined the effects of BK and ANF on transport by monolayers of a cortical collecting duct cell line, M-1. BK (10(-8) M) had no effect on short-circuit current (Isc). Similarly, ANF (10(-8) M) did not inhibit Isc. In contrast, Isc decreased by 18% (from 57 +/- 8 to 46 +/- 6 microA/cm2) when BK and ANF were added simultaneously at this concentration (P less than 0.05). Because guanosine 3',5'-cyclic monophosphate (cGMP) and protein kinase C are implicated in the second messenger cascades of ANF and BK, we investigated their potential roles in mediating this interaction. Dibutyryl-cGMP (10(-4) M) inhibited Isc from 33 +/- 4 to 22 +/- 3 microA/cm2 (P less than 0.05) in the presence of BK but not in its absence. Staurosporine and calphostin C, inhibitors of protein kinase C, completely blocked the decrease in Isc caused by simultaneous addition of ANF and BK. cAMP levels in M-1 cells were not affected by either ANF alone or BK alone; however, when cultures were treated with both hormones, cAMP decreased from 856 +/- 56 to 332 +/- 26 fmol/10(6) cells (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ANF and bradykinin synergistically inhibit transport in M-1 cortical collecting duct cell line. 132 53

6-Phosphofructo-2-kinase (PFK-2) catalyses the synthesis of fructose 2,6-bisphosphate (Fru-2,6-P2), a potent stimulator of glycolysis. In chick-embryo fibroblasts, PFK-2 activity and Fru-2,6-P2 concentration increase upon transformation by Rous sarcoma virus. We show here that the increase in PFK-2 activity required more than 2 h after shifting fibroblasts infected with a thermosensitive mutant of Rous sarcoma virus from the restrictive to the permissive temperature. Pretreatment of the cells with actinomycin D prevented this increase in PFK-2 activity, suggesting a requirement for RNA synthesis. However, the increase in PFK-2 activity did not correspond to an increase in immunoprecipitable PFK-2. Moreover, the thermostability of PFK-2 and the affinity of this enzyme for its substrate fructose 6-phosphate were increased upon transformation by Rous sarcoma virus. Staurosporine, an inhibitor of protein kinase C, prevented the increase in PFK-2 activity brought about by the shift to the permissive temperature. This, together with a comparison of the effects of phorbol esters on PFK-2 activity, suggests that pp60v-src stimulates, via protein kinase C, the transcription of a gene whose products is a distinct PFK-2 isoenzyme or a protein that activates PFK-2.
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PMID:Activation of 6-phosphofructo-2-kinase by pp60v-src is an indirect effect. 132 31

The modulatory influence of the protein kinase C (PKC) activator phorbol dibutyrate (pDBu) and the PKC inhibitor staurosporine on the binding of the antagonist rauwolscine and the agonist (-)-epinephrine to alpha-2 adrenergic receptors was studied in plasma membranes from bovine aorta. In control membranes [3H]rauwolscine binding exhibited high (KDH = 110 pM) and low (KDL = 2.4 nM) affinity components. The addition of 0.1 mM 5'-guanylylimidodiphosphate [Gpp(NH)p] reduced binding to a single component (KD = 1.3 nM) and the addition of 140 mM NaCl increased the proportion of high affinity sites from 7 to 15%, whereas the combination of both Gpp(NH)p and NaCl did not differ from values for NaCl alone. PDBu pretreatment had little effect on [3H]rauwolscine binding with the exception of a small increase in KD in the presence of Gpp(NH)p. Staurosporine pretreatment, however, eliminated the high-affinity component in the absence of Gpp(NH)p or NaCl and rendered Gpp(NH)p ineffective. NaCl was able to restore two components of [3H]rauwolscine binding to the same extent as in untreated membranes. Epinephrine displaced [3H]rauwolscine in a biphasic manner (KDH = 93 nM, KDL = 3.5 microM; %RH = 42). In untreated membranes Gpp(NH)p reduced epinephrine affinity, but did not alter the %RH. NaCl alone increased KDL and caused a partial decrease in %RH, whereas the combination of Gpp(NH)p and NaCl was required to produce a single, low-affinity state (KD = 11.9 microM). PDBu pretreatment reduced epinephrine affinity and blocked the effectiveness of Gpp(NH)p, but the action of NaCl was more pronounced than in untreated membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phorbol ester and staurosporine modulation of antagonist and agonist binding to alpha-2 adrenergic receptors: differential influence on Na+ versus guanylylnucleotide regulation. 132 62

12-0-Tetradecanoyl phorbol-13-acetate (TPA) has been widely known as an activator of Epstein-Barr Virus (EBV) replication and is a direct activator of protein kinase C (PKC). These facts suggest that EBV DNA synthesis might at least partly be dependent upon PKC activity. In this report, the effects of two different types of PKC inhibitors on EBV DNA synthesis were investigated by slot blot hybridization using a biotin-labeled probe. Staurosporine and H-7, inhibitors acting on the catalytic domain of PKC, prevented the growth reduction of P3HR-1 cells harboring EBV genomes and the induction of viral DNA synthesis by TPA. Calphostin C and sphingosine, which have been reported to suppress the enzyme activity by acting on the regulatory domain of PKC, did not exert efficiently effects on cellular growth and viral replication at increasing concentrations of TPA. From these results it is suggested that PKC is involved in the control of viral DNA synthesis in P3HR-1 cells and that for the inhibition of virus growth, it is more effective to suppress the activity of the catalytic domain of this enzyme than acting on the regulatory domain and competing with PKC activators such as TPA for binding.
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PMID:Effect of protein kinase C inhibitors with different action mechanisms on Epstein-Barr virus replication. 132 99

Staurosporine, a putative protein kinase C (PKC) inhibitor, increased the release of [14C]arachidonic acid dose dependently between 100 nM and 1000 nM in human neutrophils challenged with 100 nM N-formyl-methionine-leucine-phenylalanine (FMLP). Staurosporine also increased the formation of leukotriene B4 (LTB4) and platelet-activating factor (PAF) in a dose-dependent manner. In addition, exogenously added lyso-PAF further augmented [3H]PAF formation in staurosporine-pretreated human neutrophils stimulated by FMLP, thus suggesting an activation of acetyl-CoA: lyso-PAF acetyltransferase by staurosporine. The potentiation of [14C]arachidonic acid release and [3H]PAF formation by staurosporine was further enhanced in the presence of 100 nM phorbol 12-myristate 13-acetate (PMA), which pinpoints a mechanism other than the modulation of PKC in this process, inasmuch as staurosporine antagonizes PMA-induced O2- production and [3H]PAF formation. Additional studies with other putative PKC inhibitors also revealed the potentiating effects of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine (H-7, 20 microM) and sphingosine (2.5 microM) on FMLP-induced [14C]arachidonic acid release and [3H]PAF formation. We therefore conjecture that staurosporine-sensitive protein kinases including PKC are not involved in the activation of phospholipase A2 and acetyl-CoA:lyso-PAF acetyltransferase.
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PMID:Arachidonic acid release and platelet-activating factor formation by staurosporine in human neutrophils challenged with n-formyl peptide. 133 May 96

To investigate the mechanism of inositol trisphosphate (IP3)-induced Ca2+ release from the internal Ca2+ store, we examined the effects of heparin, phorbol ester and cyclic nucleotides on Ca2+ release induced by carbachol or inositol 1,4,5-trisphosphate (1,4,5-IP3). For monitoring changes of Ca2+ we used the fluorescent indicator, fura-2, in electropermeabilized rat pancreatic acini. An amount of 100 micrograms/ml heparin inhibited the Ca2+ release induced by 1 microM 1,4,5-IP3 in permeabilized acini. Pretreatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) for 10 min reduced the release of Ca2+ induced by 10 microM carbachol and 1 microM 1,4,5-IP3 in permeabilized acini. Staurosporine, a protein kinase C inhibitor, blocked the inhibitory effect of TPA. Cytosolic calcium concentration was restored by staurosporine in TPA-treated acini. Although cyclic AMP exaggerated the amylase release induced by carbachol, cyclic AMP and cyclic GMP had no effect on the carbachol-induced release of Ca2+ in permeabilized acini. These findings suggest that protein kinase C may act at the level of the IP3 receptors or the IP3-operated Ca2+ channels of the internal Ca2+ store and indicate that cyclic nucleotides do not affect the IP3-induced release of Ca2+ in rat pancreatic acini.
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PMID:Phorbol ester attenuates inositol 1,4,5-trisphosphate-induced Ca2+ release in electropermeabilized rat pancreatic acini. 133 51

Because of the importance of pH homeostasis in bone and the current uncertainty about the mechanisms by which intracellular pH (pHi) is regulated in this tissue, we have investigated the roles of cytosolic free Ca2+ concentrations ([Ca2+]i) and protein kinase C on the activation of Na+/H+ exchange in human osteoblast-like SaOS-2 cells. [Ca2+]i and pHi were measured using Fura-2 and 2'7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) respectively. The basal pHi in HCO3(-)-free buffer was 7.36 +/- 0.04 units (mean +/- S.D.). Addition of ionomycin in Ca(2+)-containing buffer did not cause a rise in basal pHi; however, addition of the phorbol ester phorbol 12-myristate 13-acetate (PMA) did cause a slowly developing rise in resting pHi of 0.14 +/- 0.02 unit over 4-5 min. Nigericin, a K+/H+ ionophore, caused an abrupt fall in pHi to 6.70 +/- 0.07 units. In nigericin-pretreated cells, PMA caused a rapid rise in pHi without changing the [Ca2+]i. In acidified cells, ionomycin increased [Ca2+]i and pHi in a parallel concentration-dependent (30-500 nM) manner. This action of ionomycin occurred in both the presence and the nominal absence of extracellular Ca2+. Ionomycin-induced alkalinization depended on extracellular Na+ and was inhibited in cells incubated with hexamethylene amiloride. When the incremental increase in [Ca2+]i induced by ionomycin was blocked by preincubation with bis-(o-aminophenoxy)ethane-NNN'N'-tetra-acetic acid (BAPTA)/AM, the effect on pHi was inhibited. Staurosporine, a protein kinase C inhibitor, blocked the action of PMA on pHi, but it had no effect on the ionomycin-induced increase in pHi. The action of ionomycin was not due to osmotic shock. We conclude that SaOS-2 cells have a protein kinase C-activatable Na+/H+ antiporter that is also stimulated, in acidified cells, in a concentration-dependent fashion by transients in [Ca2+]i which act via a non-protein kinase C pathway.
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PMID:Mechanisms of activation of Na+/H+ exchange in human osteoblast-like SaOS-2 cells. 133 93


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