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)

Lipopolysaccharide (LPS)-induced murine B cell proliferation was blocked by 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine dihydrochloride (H7), an inhibitor of protein kinase C (PKC), in a dose- and time-dependent manner. The maximum inhibition of B cell proliferation was observed when H7 was added at the initiation of cultures. H7-induced inhibition was prolonged and irreversible. Furthermore, pretreatment of B cells with phorbol myristate acetate ester, a process that degrades membrane-associated PKC, rendered them unresponsive to LPS. These data strongly suggest that the activation of PKC is one of the mechanisms of LPS-induced murine B cell proliferation.
 ...
PMID:Lipopolysaccharide-induced murine B cell proliferation: a role of protein kinase C. 326 17

Stimulation of the neutrophils with fMet-Leu-Phe inhibits the rise in intracellular concentration of free calcium produced by the subsequent addition of platelet-activating factor. This deactivation is not observed in pertussis toxin treated cells. In addition, preincubation of the cells with the protein kinase C activator phorbol 12-myristate 13-acetate for three minutes abolishes completely the rise in calcium produced by platelet-activating factor. This inhibition is prevented by the addition of the protein kinase C inhibitor 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine prior to the addition of the phorbol ester. Phorbol 12-myristate 13-acetate, at a concentration that does not produce significant inhibition, accelerates the rate of calcium removal from the cytoplasm, and this is abolished by the protein kinase C inhibitor. In contrast, the deactivation by fMet-Leu-Phe is not prevented by the protein kinase C inhibitor. The results presented here suggest that the protein kinase C system may regulate the opening by platelet-activating factor of possible plasma membrane associated pertussis toxin independent calcium channels and/or the binding of platelet-activating factor to the receptors. In addition, protein kinase C activation increases the rates of the calcium efflux pump and/or calcium sequestering by intracellular organelles. The most simple and straightforward explanation of the observed deactivation by fMet-Leu-Phe is that the addition of fMet-Leu-Phe to neutrophils stimulates the production of platelet-activating factor which then binds to and deactivates the receptors.
 ...
PMID:Intracellular calcium rise produced by platelet-activating factor is deactivated by fMet-Leu-Phe and this requires uninterrupted activation sequence: role of protein kinase C. 334 14

Naphthalenesulfonamides such as N-(6-amino-hexyl)-5-chloro-1-naphthalenesulfonamide (W-7) are potent calmodulin (CaM) antagonists and act upon several protein kinases at higher concentration. When the naphthalene ring was replaced by isoquinoline, the derivatives were no longer CaM antagonists but retained the ability to inhibit protein kinases, and some of the derivatives exhibited selective inhibition toward a certain protein kinase. cAMP-dependent, cGMP-dependent, and Ca2+-phospholipid-dependent (protein kinase C) protein kinases were inhibited significantly by addition of 10(-6) M N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H-8) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). H-8 was the most active of the inhibitors in this series and inhibited more markedly cyclic nucleotide dependent protein kinases, than other kinases, while the derivative with the sulfonylpiperazine residue (H-7) was the most potent in inhibiting protein kinase C. Apparent Ki values of H-8 were 0.48 and 1.2 microM for cGMP-dependent and cAMP-dependent protein kinases, respectively, and the Ki value of H-7 for protein kinase C was 6 microM. Both the holoenzyme and the catalytic subunit (or fragment), which is active without an enzyme activator, are susceptible to these compounds with a similar concentration dependency, thereby indicating that the inhibitory effect is attributed to the direct interaction of the compound with the active center of the enzyme but not with the enzyme activator. The inhibitions were freely reversible and of the competitive type with respect to ATP and of the noncompetitive type with respect to the phosphate acceptor.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. 623 27

Fas antigen is a cell membrane protein that has been suggested to mediate apoptosis. Using SV40-transformed human keratinocytes, we investigated the Fas-antigen-dependent apoptotic process. The expression of Fas antigen mRNA was markedly induced by interferon-gamma (IFN-gamma) treatment (500 U/ml). After IFN-gamma treatment in the presence of anti-Fas monoclonal antibody, apoptosis was induced, as detected by the formation of nucleosome-sized fragments of DNA and morphologically by apoptotic cells with round homogeneous nuclear beads detected by acridine orange staining. The apoptotic SV40-transformed keratinocytes were analyzed quantitatively by enzyme-linked immunosorbent assay using antihistone and peroxidase-conjugated anti-DNA antibodies to detect cell death. The IFN-gamma- and anti-Fas antibody-dependent apoptotis was observed by 3 h, and the maximal response was observed by 12 h. The induction of apoptosis was significantly augmented by treatment with 10 ng/ml 12-o-tetradecanoyl-phorbol-13-acetate (TPA). TPA alone had no effect on either Fas antigen expression or on the apoptotic process. Other protein kinase C activators (1-oleoyl-2-acetylglycerol and mezerein) also stimulated IFN-gamma-dependent apoptosis, whereas 4-o-methyl phorbol myristate acetate, a very weak protein kinase C activator, had only a slight effect. The TPA-induced augmentation of apoptosis was inhibited by the protein kinase C inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine dihydrochloride (H-7). However, H-7 inhibited only the TPA-induced augmentation of apoptosis; the basal IFN-gamma- and anti-Fas-dependent apoptosis remained in the presence of H-7. Northern blot analysis revealed that c-jun mRNA was induced by IFN-gamma plus anti-Fas antibody treatment as well as by TPA treatment; the addition of IFN-gamma alone to the incubation medium had no effect on the expression of c-jun mRNA. These results indicate that IFN-gamma induces a Fas-antigen-dependent apoptotic process in SV40-transformed keratinocytes and that TPA augments the process through the activation of protein kinase C.
 ...
PMID:Interferon-gamma-dependent stimulation of Fas antigen in SV40-transformed human keratinocytes: modulation of the apoptotic process by protein kinase C. 749 Apr 76

Cytoplasmic extracts from proliferating Neuro-2a cells contain a protein factor, ADR (activator of DNA replication) that induces DNA synthesis in isolated quiescent nuclei. Cytoplasmic extracts derived from quiescent-made Neuro-2a cells contain none or very little ADR activity, but this activity can be generated after a brief exposure of cytosolic extracts to a membrane-enriched fraction derived from exponentially growing Neuro-2a cells. ADR activity appears at the beginning of the S phase of the cell cycle. Moreover it appears to be a protease, because aprotinin inhibits ADR activity. ADR activity can be also inhibited by the protein kinase C inhibitors, 1-(5-isoquinoline-sulfonyl)-2- methylpiperazine (H7) and calphostin C.
 ...
PMID:Protein kinase C inhibitors, H7 and calphostin C, inhibit induction of DNA synthesis by cytosolic extracts of exponentially growing neuroblastoma cells in isolated nuclei. 753 73

In addition to a role for de novo protein synthesis in apoptosis we have previously shown that activation of a protein phosphatase or loss of activity of a kinase is also important in radiation-induced apoptosis in human cells [Baxter, and Lavin (1992): J Immunol 148:149-1954]. We show here that some inhibitors of protein kinases exacerbate radiation-induced apoptosis in the human cell line BM13674. The specific protein kinase A inhibitor isoquinoline sulfonamide (20 microM) gave rise to significantly increased levels of apoptosis at 2-6 h postirradiation compared to values after radiation exposure only. The same concentration of isoquinolinesulfonamide, which was effective in increasing apoptosis, reduced activity markedly. A 66% inhibition of cyclic AMP-dependent protein kinase A activity occurred in unirradiated cells at this concentration of H89 and activity was reduced to 58% in irradiated cells. Calphostin C, a specific inhibitor of protein kinase C, at a concentration of 0.1 microM, which caused 68% inhibition of enzyme activity in irradiated cells, failed to enhance the level of radiation-induced apoptosis. Other kinase inhibitors did not lead to an additional increase in apoptosis over and above that observed after irradiation. The results obtained here provide further support for an important role for modification of existing proteins during radiation-induced apoptosis.
 ...
PMID:Protein kinase A inhibitors enhance radiation-induced apoptosis. 753 51

NIM 1 cells, a human thyroid cell line established from a patient with thyroid papillary adenocarcinoma, produce cytokines such as interleukin-1 alpha (IL-1 alpha) and granulocyte-colony stimulating factor. In the present study, we investigated the signal transduction pathway in the proliferation of NIM 1 cells evoked by IL-1 alpha. Incubation of NIM 1 cells with IL-1 alpha for 48 h increased the incorporation of 3H-thymidine (3H-TdR). The stimulatory effect of IL-1 alpha was evident at 0.01 ng/ml and the maximal effect was seen at 10 ng/ml. IL-1 alpha evoked an influx of 45Ca into NIM 1 cells within 3 min in a concentration-dependent manner (0.01-1 ng/ml). These stimulatory effects of IL-1 alpha on both 3H-TdR incorporation and 45Ca influx were similarly inhibited by nicardipine, an inhibitor of voltage-dependent Ca2+ channels, in a concentration-dependent manner (10-1000 nM). The stimulatory effect of IL-1 alpha on 3H-TdR incorporation was inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), an antagonist of calmodulin, but not by 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinase C. While the culture medium initially contained 0.75 mM Ca2+, inhibition of 3H-TdR incorporation by nicardipine and W-7 under these baseline conditions was also recognized. These results suggest that IL-1 alpha stimulates cell proliferation through a Ca2+/calmodulin-dependent pathway in NIM 1 cells.
 ...
PMID:Stimulatory effect of interleukin-1 alpha on proliferation through a Ca2+/calmodulin-dependent pathway of a human thyroid carcinoma cell line, NIM 1. 755 85

We have examined the effect of pretreatment with a potent protein kinase C (PKC) inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7), against metabolic alterations induced by sodium cyanide (NaCN), 4.2 mg/kg, in brain of anesthetized male micropigs (6-10 kg). Brain high energy phosphates were analyzed using a 31P nuclear magnetic resonance (NMR) spectroscopic surface coil in a 4.7 Telsa horizontal bore magnet. H-7, 1 mg/kg, was given intravenously (i.v.) 30 min before NaCN challenge (H-7 + CN-). Prior to NaCN, H-7, or H-7 + CN- administration, baseline 31P resonance spectra of 1-min duration were acquired for 5-10 min, and continued for an additional 60 min following i.v. NaCN injection, each animal serving as its own control. Peaks were identified as phosphomonoester (PME), inorganic phosphate (Pi), phosphodiester (PDE), phosphocreatine (PCr) and adenosine triphosphate (ATP), based on their respective chemical shifts. Without H-7 pretreatment, NaCN effects were marked by a rising Pi and a declining PCr peak 2 min after injection, with only 2/5 of the animals surviving the 60 min experiment. Through a pretreatment period of 30 min, H-7 did not affect baseline cell energy profile as reflected by the 31P-NMR spectra, but in its presence, those changes (i.e. diminishing PCr and rising Pi peaks) elicited by NaCN were markedly blunted; 4/5 of the animals in this group survived the NaCN challenge. It is proposed that H-7, a pharmacologic inhibitor of PKC, may be useful in CN- antagonism, underscoring the role of PKC in cyanide intoxication.
 ...
PMID:A protein kinase C inhibitor attenuates cyanide toxicity in vivo. 762 70

Using the chick chorioallantoic membrane as a model system for the study of angiogenesis, we have shown that promoters of protein kinase C (PKC) such as 4-beta-phorbol-12-myristate-13-acetate (4-beta-PMA) and 1,2-dioctanoyl-sn-glycerol (DiC8) stimulated angiogenesis. This effect was specific since 4-alpha-PMA and 1,2-dioleoyl-sn-glycerol, which either do not activate or cannot reach PKC, were devoid of angiogenic activity. Furthermore, Ro 31-8220, a specific inhibitor of PKC, suppressed both basal and 4-beta-PMA- or DiC8-induced angiogenesis. Similar results were obtained with the commonly used inhibitor of PKC, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine and with tricyclodecan-9-yl-xanthogenate, an antitumor agent which has been suggested to be an inhibitor of PKC. Activation of PKC may be, therefore, an important signalling pathway in the initiation and control of the angiogenic response.
 ...
PMID:Protein kinase C involvement in the regulation of angiogenesis. 768 46

Staurosporine, an inhibitor of protein kinases, induced outgrowth of cultured embryonic Xenopus myocytes. The outgrowing membrane elicited by staurosporine was stained uniformly with fluorescein isothiocyanate-phalloidin. Pretreatment with microfilament-disrupting agents but not microtubule inhibitors inhibited staurosporine-induced membrane outgrowth. Microfilament assembly is thus required for the action of staurosporine. Protein kinase C activators did not antagonize the membrane outgrowing effect of staurosporine. Furthermore, none of H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride), H-8 (N[2-(methylamino)ethyl]-5-isoquinoline sulfonamide), sphingosine, phloretin, genistein or calmidazolium induced any significant morphological changes of embryonic myocytes, indicating that tyrosine kinases, protein kinase C, protein kinase A or calmodulin-dependent protein kinases may not be involved in the membrane outgrowing action of staurosporine. Total protein content of myocytes was not altered by staurosporine and protein or RNA synthesis inhibitors did not inhibit the membrane outgrowth induced by staurosporine. Furthermore, membrane outgrowth induced by staurosporine was less pronounced in older cultured myocytes or myocytes acutely isolated at later stages of tadpoles, indicating that there is different developmental susceptibility to the action of staurosporine.
 ...
PMID:Pharmacological evidence for a lack of role for protein kinase C in staurosporine-induced morphological changes in embryonic Xenopus myocytes. 780 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>