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)

Glucocorticoid hormones (GCH) and IL-2 induce apoptotic cell death by a PKC-dependent mechanism. IL-4 counteracts apoptosis by inhibiting PKC activity. GCH and IL-2 show antagonistic effects on apoptosis when administered together. These data indicate that PKC activation in response to different stimuli can both enhance or reduce thymocyte survival.
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PMID:Glucocorticoid-induced DNA fragmentation: role of protein-kinase-C activity. 140 24

The mechanism by which hypolipidemic drugs and industrial plasticizers cause hepatic tumors in rodents remains unknown. Protein kinase C is elevated during hepatic cell turnover, and sustained cellular replication has been shown to correlate with an increase in hepatic tumors. Therefore, the effect of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) on protein kinase C activity was examined. Female Sprague-Dawley rats were given 100 mg/kg Wy-14,643 in olive oil (i.g.), while control rats received equal volumes of oil vehicle. After 24 h, the activity of protein kinase C was estimated in isolated hepatic fractions by measuring the binding of 3H-phorbol-12,13-dibutyrate, a specific ligand for protein kinase C. Administration of Wy-14,643 significantly increased protein kinase C activity nearly 2-fold in microsomal fractions. Thus, it is possible that Wy-14,643 increases cell proliferation and causes tumors by mechanisms involving protein kinase C.
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PMID:Wy-14,643 stimulates hepatic protein kinase C activity. 141 17

Protein kinase C plays a vital role in the activation of C3H/HeJ B lymphocytes by endotoxin associated protein; however, it is unlikely that G proteins are involved in the early signals stimulated by EP. On the other hand, LPS suppresses C3H/HeJ B cell DNA synthesis induced by EP which may be the result of PKC down regulation. LPS inhibits C3H/HeJ B cells from progressing through the G1 phase of the cell cycle blocking RNA synthesis within the first 12 hr after the cells are stimulated. Finally, this inhibition extends to activation of the arachidonic acid metabolism in C3H/HeJ macrophages and T cell proliferation to a limited extent.
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PMID:Immunomodulation of C3H/HeJ cells by endotoxin associated protein and lipopolysaccharide endotoxin. 141 4

Platelets are released into the peripheral circulation from the bone marrow where they arise as fragments of megakaryocyte cytoplasm. To characterize the effects of platelet agonists on megakaryocytes, we examined calcium signaling and desensitization to thrombin, the thromboxane A2 (TxA2) mimetic (15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619), and platelet-activating factor (PAF) in cultured CHRF-288-11 megakaryocytic cells. Initially, we compared agonist-stimulated calcium transients in fura-2-loaded CHRF-288-11 cells and human platelets. The 50% effective concentration values for the agonists to increase free cytosolic calcium were as follows: thrombin (0.11 +/- 0.02 U/ml in CHRF, 0.19 +/- 0.03 U/ml in platelets), U46619 (147 +/- 33 nM in CHRF, 157 +/- 5 nM in platelets), and PAF [15 +/- 2 nM in CHRF, 16 +/- 2 nM in platelets (n = 4 each)]. CHRF-288-11 thrombin, TxA2, and PAF receptors were demonstrated to be coupled to phospholipase C because each of the agonists stimulated phosphatidylinositol hydrolysis in myo-[3H]inositol-loaded CHRF-288-11 cells and pharmacological inhibition of phospholipase C-blunted agonist-stimulated calcium signaling. CHRF-288-11 cells exposed to the three agonists for 1 h showed different patterns and extent of homologous and heterologous desensitization. Protein kinase C activation appeared to be necessary but not sufficient for desensitization because 1) activation of protein kinase C with phorbol 12-myristate 13-acetate inhibited the calcium responses to all three agonists, 2) inhibition of protein kinase C with staurosporine attenuated subsequent desensitization to each agonist, and 3) each agonist increased protein kinase C activity in CHRF-288-11 cell homogenates.
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PMID:Differential megakaryocytic desensitization to platelet agonists. 141 71

The 39-43 residue polypeptide (amyloid beta protein, beta A4) deposited as amyloid in Alzheimer's disease (AD) is derived from a set of 695-770 residue precursors referred to as the amyloid beta A4 protein precursor (beta APP). In each of the 695, 751, and 770 residue precursors, the 43 residue beta A4 is an internal peptide that begins 99 residues from the COOH-terminus of the beta APP. Each holoform is normally cleaved within the beta A4 to produce a large secreted derivative as well as a small membrane associated fragment. Neither of these derivatives can produce amyloid because neither contains the entire beta A4 peptide. In this study, we employ cells stably transfected with full length beta APP695, beta APP751, or beta APP770 expression constructs to show that phorbol ester activation of protein kinase C substantially increases the production of secreted forms from each isoform. By increasing processing of beta APP in the secretory pathway, PKC phosphorylation may help to prevent amyloid deposition.
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PMID:Secretory processing of the Alzheimer amyloid beta/A4 protein precursor is increased by protein phosphorylation. 141 5

Modification of basic residues of protein kinase C by phenylglyoxal results in a reversible, dose-dependent inhibition of autophosphorylation and substrate phosphorylation. The inhibition is not due to specific modification of the Ca2+ or ATP binding sites. Modified PKC bound more [3H] phorbol ester than unmodified providing further evidence that the binding of lipids and the catalytic phosphotransferase activity have different regulatory sequences. Additionally, the effects of these modifying reagents were different on enzyme stimulated by phorbol esters or by the endogenous activator, 1,2-diacylglycerol. These studies suggest that there is at least 1 arginine residue that is unique in the binding site of these different activators.
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PMID:Chemical modification of arginine residues of protein kinase C. 141 81

The aim was to examine systematically the potencies of protein kinase C inhibitors as a function of the kinase activator. Protein kinase C is activated by at least four stimulators: calcium plus phosphatidylserine (Ca/PS), phorbol 12-myristate 13-acetate plus PS (PS/PMA), arachidonic acid plus calcium (Ca/AA) and the synthetic peptide activator PCK530-558. With histone or GS1-12 as substrates, protein kinase C was maximally activated by Ca/PS, or to maxima of 62%, 89% or 82% with PS/PMA, Ca/AA or PKC530-558, respectively. One group of inhibitors, including H-7 and staurosporine, were equipotent, regardless of the activator. All other inhibitors showed variable selectivity, dependent upon the activator. A second group of inhibitors, including sphingosine and lipophosphoglycan, were eight or 200 times more potent for inhibition of PS/PMA-stimulated activity (relative to Ca/PS) and a third group, including retinal and palmitoylcarnitine, were 14 or 262 times more potent towards Ca/PS-stimulated activity. A final group (rhodamine 6G) was nine times more potent when Ca/AA was the activator. Similar results were obtained using the endogenous substrates dephosphin or MARCKS in synaptosol. Phosphorylation of MARCKS was stimulated by PS/PMA or Ca/PS, while phosphorylation of dephosphin was stimulated only by Ca/PS. The phosphorylation of either by Ca/PS-activated kinase was nine times more potently inhibited by palmitoylcarnitine, while phosphorylation of MARCKS by PS/PMA-activated kinase was 10 times more potently inhibited by sphingosine. H-7 inhibited both at similar concentrations. A model encompasses these differences in potency if the inhibitors are divided into four groups (A-D) according to their competitive inhibition with the appropriate activator or at the active site. The non-selective inhibitors interact at the active sites of protein kinase C (group A). The compounds which preferentially inhibit PS/PMA-activated kinase (sphingosine and lipophosphoglycan) are competitive inhibitors of PMA and 1,2-diacylglycerol (group B), those selective for Ca/PS-activated kinase (palmitoylcarnitine and retinal) are competitive with PS (group C) and those selective for Ca-AA activation (rhodamine 6G) are likely to be competitive with fatty acid (group D). Therefore, the effectiveness of protein kinase C inhibitors is dependent upon the activator employed.
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PMID:Potencies of protein kinase C inhibitors are dependent on the activators used to stimulate the enzyme. 141 56

In human breast carcinoma MCF-7 cells, phorbol diesters inhibit proliferation and induce cell maturation. We investigated the involvement of TGF-beta 1 in the PCK-mediated inhibition of breast cancer cell proliferation. Using an RNase protection assay, we showed that TPA induced a dose-dependent increase in levels of TGF-beta 1 mRNA that paralleled the inhibitory effect on MCF-7 proliferation. Similar results were obtained with another TPA-sensitive breast cancer cell line (BT-20). TPA did not increase TGF-beta 1 mRNA levels in the MCF-7:RPh-4 and T47D cell lines, which are both insensitive to the growth inhibitory effects of phorbol esters. In addition, the increase in TGF-beta 1 mRNA level was not observed after treatment of the MCF-7 cell with other inducers of cell differentiation such as forskolin, DMF, HMBA and sodium butyrate. The induction of TGF-beta 1 mRNA by TPA along with its inhibitory effect on cell proliferation suggests that TGF-beta 1 mediates, at least in part, the inhibitory effect of PKC activation.
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PMID:[Regulation by protein kinase C of TGF-beta 1 expression in cultured cells of breast adenocarcinoma]. 142 93

1. Glomerular epithelial cells (GEC) were cultured from human kidneys and immunologically characterized. 2. The effect of extracellular nucleotides on the cytosolic free calcium activity [Ca2+]i was investigated with the fura-2 microfluorescence method. Extracellular UTP, UDP, UMP, ATP, adenosine 5'-O-(3-thio)-trisphosphate (ATP-gamma-S), inosine-triphosphate (ITP), guanyltriphosphate (GTP), 2-methylthio-ATP, AMP, alpha,beta-methylene-ATP and adenosine led to a rapid, transient, concentration-dependent increase of [Ca2+]i, followed by a plateau above the baseline level. 3. In a calcium-free extracellular solution, the rapid increase of [Ca2+]i was still present, whereas the plateau level was abolished. 4. ATP and UTP (ED50 both: 10(-5) M) stimulated inositol trisphosphate (InsP3) formation in GEC. 5. The order of potency for the purine nucleotides in stimulating InsP3 formation was ATP = ATP-gamma-S greater than ADP greater than 2-methylthio-ATP greater than AMP = a,beta methylene-ATP = adenosine. 6. The increase of InsP3 induced by ATP (10(-5) M) could be inhibited by the P2 receptor blocker suramin (greater than 10(-4) M). Reactive blue 2 exhibited a weak stimulating effect on the InsP3 formation and only a weak inhibitory effect at a concentration of 10(-3) M was observed. 7. Protein kinase C activation by preincubation of GEC with phorbol 12-myristate 13-acetate (PMA, 100 ng ml-1, 15 min) abolished the effect of ATP (10(-5) M) on InsP3 formation. Downregulation of protein kinase C by long term incubation (18 h) with PMA had no significant effect on the phosphoinositol turnover induced by ATP.8. The results indicate that an increase of [Ca2+]i and inositol phosphate breakdown can be mediated via activation of a P2 receptor in human GEC.
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PMID:Effect of nucleotides on the cytosolic free calcium activity and inositol phosphate formation in human glomerular epithelial cells. 142 72

The effects of dizocilipine maleate (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor/channel antagonist, were tested on the dysfunction of neurotransmitter and signal transduction systems and morphological damage 7 days after transient forebrain ischemia in gerbils. Neurotransmitter system (adenosine A1, muscarinic cholinergic receptor) and signal transduction system (inositol 1,4,5-trisphosphate receptor: IP3, protein kinase C: PKC, L-type calcium channels) binding sites were mapped by in vitro quantitative receptor autoradiography. All ligands used in the present study decreased significantly in the CA1 subfield 7 days after ischemia. In normothermic animals, pretreatment with MK-801 failed to protect against decreased receptor binding in the hippocampus 7 days after ischemia. Moreover, in a morphological study, pre- and posttreatment of MK-801 failed to show protective effects against ischemic neuronal damage. On the other hand, pretreatment of MK-801, without maintaining body temperature, prevented the neuronal death of CA1 subfield 7 days after ischemia. These results weaken the hypothesis that NMDA receptor/channel may play a pivotal role in the pathogenesis of neuronal damage after transient forebrain ischemia.
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PMID:Effects of hyperthermia on the effectiveness of MK-801 treatment in the gerbil hippocampus following transient forebrain ischemia. 142 62


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