Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcium- and phospholipid-dependent kinase activity (protein kinase C) was isolated from bovine brains by a combination of DEAE-cellulose chromatography, gel filtration and hydrophobic chromatography on octyl-Sepharose and phenyl-Sepharose. The phorbol ester receptor co-purifies with the protein kinase C throughout the procedure yielding a homogeneous protein of 79 500 daltons on SDS-polyacrylamide gels. The purified kinase incorporated approximately 5000 nmol phosphate into substrate/min/mg protein at saturating concentrations of Ca2+ and phosphatidyl serine. Reciprocal plots of protein kinase activity at varying phosphatidyl serine concentrations were biphasic and yielded two apparent Ka values for phosphatidyl serine of 0.6-2 and 35-80 micrograms/ml). These apparent Ka values were reduced 2- to 3-fold by either diolein (20 micrograms/ml) or phorbol-12,13-dibutyrate (10 micrograms/ml). The protein binds [3H]phorbol-12,13-dibutyrate ( [3H]PDB) with high affinity (Ka = 15 nM) in a phosphatidyl serine-dependent manner. At saturating phosphatidyl serine concentrations 0.89 mol [3H]PDB are bound per mol protein. The identification of protein kinase C as the phorbol ester receptor is discussed with respect to the function and regulation of this protein.
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PMID:Purification to homogeneity of protein kinase C from bovine brain--identity with the phorbol ester receptor. 632 48

The pectic polysaccharide, bupleuran 2IIb, up-regulates Fc-receptor (FcR) expression on peritoneal macrophages in a dose-dependent manner. The intracellular signal transduction by bupleuran 2IIb leading to the expression of FcR was studied. Neither the protein kinase C (PKC) inhibitor, 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride, nor the structurally distinct PKC antagonist, calphostin C, inhibited bupleuran 2IIb-induced up-regulation of FcR, whereas two direct activators of PKC, L-alpha-1-oleoyl-2-acetyl-sn-3-glycerol and N-(6-phenylhexyl)-5-chloro-1-naphthalenesulphonamide were unable to up-regulate the expression of FcR. The protein kinase A (PKA) inhibitor, N-[2-(methylamino)ethyl]-5-isoquinolinesulphonamide dihydrochloride also did not inhibit bupleuran 2IIb-induced up-regulation of FcR. Fluorescence image analysis using the calcium-sensitive dye, Fura-2, demonstrated that bupleuran 2IIb induced a rapid increase in intracellular levels of calcium (Ca2+). When macrophages were treated with calcium antagonist, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride, bupleuran 2IIb-induced up-regulation of FcR was inhibited in a dose-dependent manner. The bupleuran 2IIb-induced up-regulation of FcR was also blocked by two structurally distinct calmodulin antagonists, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide hydrochloride. Furthermore, elevation of intracellular Ca2+ using the calcium ionophore, A23187, led to up-regulation of the FcR expression in a dose-dependent manner. These results suggest that bupleuran 2IIb induces the up-regulation of FcR on macrophages by a mechanism dependent on an increase in intracellular Ca2+ followed by activation of the calmodulin, but not by a PKC or PKA pathway.
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PMID:Regulation of immune complexes binding of macrophages by pectic polysaccharide from Bupleurum falcatum L.: pharmacological evidence for the requirement of intracellular calcium/calmodulin on Fc receptor up-regulation by bupleuran 2IIb. 760 71

The effects of lysophosphatidylcholine (LPC), a vasoactive phospholipid, on intracellular free calcium concentration ([Ca2+]i), DNA synthesis and cytotoxicity of vascular smooth muscle cells (VSMC) were studied. LPC from 10(-7) to 10(-5) mol/l dose-dependently induced a sustained increase in [Ca2+]i. In contrast to the response of [Ca2+]i induced by angiotensin II, that induced by LPC was totally abolished when extracellular Ca2+ was removed, was not affected by pretreatment of the cells with islet-activating protein, and was not desensitized by repeated addition. 8-(N,N-Diethylamino)octyl 3,4,5-trimethoxybenzoic acid (TMB-8), an inhibitor of Ca2+ release from intracellular Ca2+ stores, 1-(5-isoquinolinesulfonyl)-2-methylpiperadine dihydrochloride (H-7), an inhibitor of protein kinase C, KT5823, an inhibitor of protein kinase G, and Ca2+ channel blockers failed to suppress the LPC-induced increase in [Ca2+]i. LPC at 10(-5) mol/l caused significant stimulation of [3H]thymidine incorporation into VSMC, and at concentrations of 10(-5) mol/l and higher dose-dependently stimulated release of lactate dehydrogenase in cell culture supernatants. Moreover, digitonin mimicked the effects of LPC on [Ca2+]i, and also caused similar effects to those of LPC on DNA synthesis and cytotoxicity in VSMC. These observations suggest that LPC causes both cell growth and cell injury of VSMC, at least partly, through its detergent action, causing membrane leakiness and resultant [Ca2+]i overload in vitro, thus indicating the possible participation of LPC in atherosclerosis and/or injury of the vascular wall.
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PMID:Lysophosphatidylcholine causes Ca2+ influx, enhanced DNA synthesis and cytotoxicity in cultured vascular smooth muscle cells. 777 68

A 64-kDa protein was purified from an octyl glucoside/cholate extract of spinach thylakoids. N-Terminal analysis yielded 23 residues of sequence, of which the first 15 were identical to a sequence reported [Gal, A., Herrmann, R. G., Lottspeich, F., & Ohad, I. (1992) FEBS Lett. 298, 33-35] for a protein kinase with specificity toward the photosystem II light-harvesting complex (LHC-II). We report the complete sequence of this 64-kDa protein, deduced from cDNA clones. The transit peptide has a chloroplast import signal at the N-terminus and a C-terminal hydrophobic span bounded by basic amino acids that predicts localization of the protein to the thylakoid lumen. The mature protein sequence is about 50% identical to several polyphenol oxidases (PPOs). Canonical protein kinase motifs are absent, as are sequences characteristic of ATP-binding sites. The mature protein resembles arthropodan hemocyanin (Hc), possessing three major domains. The N-terminal domain is rich in cysteine residues and predicted alpha-helices. The central domain has a conserved motif, N-terminal to a presumptive Cu-A site, that is not found in tyrosinases or Hc and is proposed as the provider of a third imidazole ligand to Cu-A. An unusual 13-residue, glutamine-rich link begins a C-terminal domain containing 7 predicted beta-strands which, by analogy with Hc, may form an antiparallel beta-barrel. We conclude that this 64-kDa polypeptide is a lumenal PPO and the precursor of a 42.5-kDa PPO form described previously [Golbeck, J. H., & Cammarata, K. V. (1981) Plant Physiol. 67, 977-984].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Spinach thylakoid polyphenol oxidase: cloning, characterization, and relation to a putative protein kinase. 779 29

Interleukin-13 (IL-13), a novel cytokine produced by activated lymphocytes modulates some monocyte functions, but no data is available concerning the signal transduction pathway. We show here, the inhibitory effect of IL-13 on 12-O-tetradecanoylphorbol-13-acetate (TPA)-triggered reactive oxygen intermediate production in human monocytes and the signals involved in this response. Our results show that IL-13 produces rapid and transient phosphoinositide hydrolysis and intracellular Ca2+ mobilization. Furthermore, IL-13 induces intracellular cAMP accumulation through inositol 1,4,5-trisphosphate-dependent Ca2+ mobilization. Metabolic inhibitors were used to relate the first steps in signaling pathways to the inhibitory effect of IL-13 on TPA-triggered reactive oxygen intermediate production. Indeed, inhibitors of phospholipase C (neomycin), intracellular Ca2+ mobilization (8-[N,N-diethylamino]-octyl 3,4,5-trimethoxybenzoate hydrochloride), adenylate cyclase (delta 9-tetrahydrocannabinol), and protein kinase A (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) impair the IL-13 inhibitory response. Altogether these observations indicate that modulatory effect of IL-13 on the TPA-induced oxidative burst is the result of the intracellular cAMP accumulation through an inositol 1,4,5-trisphosphate-induced Ca2+ mobilization-dependent pathway.
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PMID:Interleukin-13 inhibits protein kinase C-triggered respiratory burst in human monocytes. Role of calcium and cyclic AMP. 789 Jun 16

The induction mechanism of gamete formation (gametogenesis) in a rodent malaria parasite, Plasmodium berghei, was investigated using Ca2+ antagonists, protein kinase inhibitors and amiloride, an inhibitor of monovalent cation/H+ exchange. Treatment with 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, a Ca2+ release inhibitor) and W-7/W-66 (calmodulin inhibitors) blocked formation of male gametes by inhibiting DNA synthesis from 1.5C to 8C level. In contrast, inhibitors of cAMP/cGMP-dependent protein kinases such as H-8, H-87, H-89 and staurosporine also ceased the development of gametocytes, but DNA synthesis in male gametocytes occurred as in the controls. Electron microscopy revealed that male gametocytes treated with TMB-8 and W-7 failed to enlarge nuclei and to form axonemes in the cytoplasm. In female gametocytes, treatment with both Ca2+ antagonists resulted in a dramatic morphological change in the endoplasmic reticulum (ER), which is thought to be a Ca2+ store. The ER network condensed near nuclei and was laminated by the abnormal attachment of ribosomes between two ER membranes. On the other hand, male gametocytes treated with protein kinase inhibitors or amiloride had enlarged nuclei and axonemes, but failed to develop further. The ER network in female gametocytes treated with these inhibitors was similar to that in the controls.
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PMID:The roles of Ca2+/calmodulin- and cGMP-dependent pathways in gametogenesis of a rodent malaria parasite, Plasmodium berghei. 838 16

Purification of the lens fiber cell membrane proteins MP20 and MP26, and the partial co-purification of the lens connexin-related proteins MP70 and connexin 46 has been achieved using anion- and cation-exchange chromatography of lens fiber cell membrane proteins solubilized in n-octyl-beta-D-glucopyranoside (octyl glucoside). The apparent molecular weights of the solubilized protein-detergent complexes were significantly greater than that expected for the monomeric proteins. The purified proteins retained their ability to be phosphorylated by cAMP-dependent protein kinase, and to bind calmodulin in a calcium and magnesium dependent manner. The heterobifunctional covalent chemical crosslinking agent N-5-azido-2-nitro-benzoyloxysuccinimide (ANB-NOS), and the thiol oxidant cupric phenanthroline were used to identify the oligomeric states of these proteins. Crosslinking of either the purified proteins or native lens membranes generated a ladder of crosslinked MP20 or MP26 homo-oligomers. The largest detectable crosslinked homo-oligomer of MP20 was at least a hexamer, while for MP26 the largest crosslinked homo-oligomer was at least a tetramer. The possible oligomeric states of MP70 and connexin 46 could not be determined with the crosslinking reagents used in this study. The procedure described here for the purification of detergent-solubilized major lens proteins should provide a valuable approach in future studies aimed at clarifying the roles of these different lens membrane proteins.
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PMID:Purification and oligomeric state of the major lens fiber cell membrane proteins. 852 19

The cellular regulation mechanism of Na-K-Cl cotransport was studied in dispersed acinar cells of the guinea pig nasal gland by a microfluorimetric imaging method using the Na(+)-sensitive dye sodium-binding benzofuran isophthalate. Addition of 1 micron acetylcholine (ACh) induced an immediate increase in intracellular Na+ concentration ([Na+]i) by 36.7 +/- 9.9 mM, which was almost completely abolished by the addition of atropine. The increased [Na+]i after cholinergic stimulation was due to the external (Cl-)-dependent cotransport system (about 80% of the total Na+ influx) and the dimethyl amiloride-sensitive (Na+)-H+ exchange system (of about 20%). The ACh-induced increase in [Na+]i was dependent on extracellular Ca2+ and was prevented by pretreatment with 8-(N, N-diethylamino)octyl-3,4,5-trimethoxybenzoate or O-O'-bis(2-aminophenyl)ethyleneglycol-N, N, N', N'-tetraacetic acid tetraacetoxymethylester. Addition of 1 microns ionomycin mimicked the ACh-induced increase in [Na+]i which was dependent on external Cl-. Moreover, both a calmodulin antagonist trifluoperazine and a myosin light chain kinase inhibitor ML-7 reduced the ACh-induced response in [Na+]i. However, the following treatment did not affect the basal [Na+]i nor the ACh-induced increase in [Na+]i: (i) addition of dibutyryl cAMP, 8-Br-cGMP, or phorbol 12-myristate 13-acetate, (ii) pretreatment of protein kinase inhibitors, H-89, H-8, H-7 or chelerythrine, (iii) prevention of cytosolic Cl- efflux by the addition of diphenylamine-2-carboxylic acid or, (iv) prevention of cytosolic K+ efflux by the addition of charybdotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular mechanisms in activation of Na-K-Cl cotransport in nasal gland acinar cells of guinea pigs. 856 45

We investigated the ability of N-octanoyl-sphingosine (C8-Cer) stereoisomers, N-octanoyl-DL-erythro-dihydrosphingosine (DL-e-DHC8-Cer), and a new ceramide derivative, N-octyl-D-erythro-sphingosine (D-e-C8-Ceramine), to induce apoptosis in U937 cells. We found the C8-Cer stereoisomers to be stereospecific with the D- and L-threo stereoisomers being severalfold more potent than the erythro in inducing nucleosomal fragmentation. The order of potency was: D-t-C8-Cer = L-t-C8-Cer > L-e-C8-Cer > D-e-C8-Cer > DL-e-DHC8-Cer. The importance of the carbonyl group in apoptosis was investigated by using a new ceramide derivative, D-e-C8-Ceramine, in which the carbonyl group was replaced by a methylene group. The carbonyl group was not necessary for triggering apoptosis. In fact, replacement of the carbonyl group decreased substantially the time required for cells to die, with maximum DNA fragmentation occurring at 6 h as opposed to the 18 h required by D-e-C8-Cer. To explore possible mechanisms by which these compounds trigger the apoptotic pathway, we tested their ability to increase the endogenous levels of cellular ceramide and to differentially activate a ceramide-activated protein kinase (CAPK). While the potent DNA fragmentation-inducing compounds D-e-C8-Ceramine and L-t-C8-Cer failed to increase the cellular ceramide levels, D-e-C8-Cer, D-t-C8-Cer and D-e-C8-Ceramine activated the CAPK equally. These studies suggest that the DNA fragmentation-inducing ability of the threo stereoisomers and D-e-C8-Ceramine cannot be attributed either to an increase in the activity of CAPK, or, as illustrated by D-e-C8-Ceramine and L-t-C8-Cer, to the differential elevation of endogenous ceramide. The phosphatase inhibitor okadaic acid failed to protect U937 cells from apoptosis induced by D-e-C8-Cer.
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PMID:Stereospecific induction of apoptosis in U937 cells by N-octanoyl-sphingosine stereoisomers and N-octyl-sphingosine. The ceramide amide group is not required for apoptosis. 861 51

Granulocyte colony stimulating factor (G-CSF) regulates survival, proliferation, differentiation, and activation of myeloid cells. It binds to a high affinity receptor (G-CSF-R) expressed on myeloid cells, for which the signal transduction mechanisms other than protein tyrosine kinase (PTK) activation have not been completely identified. We explored the potential involvement of protein kinase-C (PKC) in G-CSF-R signal transduction. In this report, we provide direct evidence of PKC activation by G-CSF-R. G-CSF treatment of peripheral blood neutrophils, granulocytic cell lines (HL-60, NFS-60, KG-1), and monocytic cell lines (WEHI-3B,U-937) resulted in PKC activation. Chelerythrine chloride and HA-100, an isoquinolinesulfonamide derivative, the specific inhibitors of PKC, 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid (BAPTA), a chelator of intracellular calcium, and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8), an inhibitor of intracellular calcium release, blocked G-CSF-induced PKC activation in HL-60 cells, and reduced CD11b upregulation in neutrophils, but did not affect ligand-binding or down-modulation of G-CSF-R. Methyl 2,5-dihydroxycinnamate (MDHC), a potent inhibitor of protein tyrosine kinases (PTK), also inhibited PKC activation in response to G-CSF treatment, suggesting that PKC activation may occur downstream of PTK activation. Our results demonstrate the involvement of PKC in G-CSF-R signal transduction, and suggest a common signaling pathway in myeloid cells of granulocytic and monocytic lineages.
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PMID:Granulocyte colony-stimulating factor-induced activation of protein kinase-C in myeloid cells. 925 86


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