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)

It has been known for a long time that heme oxygenase (HO) is a key enzyme in heme catabolism, and it was found to act as an oxidative-stress protein to produce carbon monoxide, which has similar actions to those of nitrogen monoxide. We examined transcriptional control of the HO gene in mouse M1 (myeloleukemia) cells during treatment with lipopolysaccharide (LPS; an oxidative reagent). Since the promoter region of this gene in human cells contains a 12-O-tetradecanoyl- phorbol-13-acetate(TPA)-responsive element (TRE) and a nuclear-factor-kappa B-responsive element. HO mRNA expression might be regulated by an oxidative activation pathway. We investigated activation of the HO gene after treatment of M1 cells with LPS. Upon treatment with LPS, H2O2 was produced, the nuclear proto-oncogenes fos and jun were activated, then the HO gene was activated. The extent of transcriptional activation of the fos, jun and HO genes in M1 cells treated with LPS was strongly reduced by a scavenger of oxygen radicals (N-acetyl-L-cysteine), but a specific inhibitor of protein kinase C only reduced transcriptional activation by 10-20%. These results suggest that LPS may be an oxidative reagent. Some oxidative reagents (e.g., H2O2) are strong activators of NF-kappa B, and therefore we treated M1 cells with H2O2. Essentially the same extends of transcriptional activation of the fos, jun and HO genes were observed as those observed after LPS treatment. Super-shift assays with DNA that contained the TRE motif revealed that the Fos and Jun proteins from nuclei of M1 cells treated with LPS and H2O2 bound weakly to the TRE motif, and, in assays with DNA that contained the NF-kappa B motif, nuclear protein from M1 cells treated with H2O2 or LPS bound strongly to the NF-kappa B motif. These results strongly suggest that the HO gene in M1 cells is mainly activated by LPS through oxidative activation of NF-kappa B due to production of H2O2.
 ...
PMID:Lipopolysaccharide activates transcription of the heme oxygenase gene in mouse M1 cells through oxidative activation of nuclear factor kappa B. 877 98

A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.
 ...
PMID:Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties. 889 41

We have previously shown that alpha2-adrenergic receptor-mediated coupling to phospholipase D (PLD) in vascular tissues requires a tyrosine kinase activity (Jinsi, A., Paradise, J., and Deth, R. C. (1996) Eur. J. Pharmacol. 302, 183-190). To further clarify this mode of regulation we reconstituted alpha2A/D-adrenergic receptor-stimulated PLD activity in PC12 cells expressing the cloned receptor. [3H]Myristic acid-labeled cells were lysed by nitrogen cavitation, and aliquots of subnuclear fraction were utilized in the PLD assay. Agonist-stimulated PLD activity was measured in the presence of 0.4% butanol as [3H]phosphatidylbutanol formation. Both GTP and its non-hydrolyzable analog guanosine 5'-O-(thiotriphosphate) stimulated PLD activity in a concentration- and time-dependent manner that required co-activation of protein kinase C by phorbol dibutyrate. Addition of epinephrine produced a 3-fold stimulation of PLD activity in the presence of GTP and GDP. This agonist-stimulated PLD activity was completely blocked by the alpha2-adrenergic receptor antagonist rauwolscine and by Clostridium botulinum toxin as well as by antibodies directed against either pp60(src), RhoA, or Ras GTPase-activating protein. These results indicate that coupling of the alpha2A/D-adrenergic receptor to PLD is complexly regulated by both the tyrosine kinase pp60(src) and the low molecular weight G protein RhoA.
 ...
PMID:Reconstitution of alpha2D-adrenergic receptor coupling to phospholipase D in a PC12 cell lysate. 916 13

As a part of studies on structure-activity relationships, several potential topoisomerase I inhibitors were prepared. Different analogues of the antitumor antibiotic rebeccamycin substituted on the imide nitrogen with a methyl group were synthesized. These compounds bore either the sugar residue of rebeccamycin, with or without the chlorine atoms on the indole moieties, or modified sugar residues (galactopyranosyl, glucopyranosyl, or fucopyranosyl) linked to the aglycone via a beta- or alpha-N-glycosidic bond. Their inhibitory properties toward protein kinase C, topoisomerase I, and topoisomerase II were examined, and their DNA-binding properties were investigated. Their in vitro antitumor activities against murine B16 melanoma and P388 leukemia cells were determined. Their antimicrobial activities were tested against Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, Gram-negative bacterium Escherichia coli, and yeast Candida albicans. These compounds are inactive toward topoisomerase II but inhibit topoisomerase I. A substitution with a methyl group on the imide nitrogen led to a loss of proteine kinase C inhibition in the maleimide indolocarbazole series but did not prevent topoisomerase I inhibition. Compounds possessing a beta-N-glycosidic bond, which fully intercalated into DNA, were more efficient at inhibiting topoisomerase I than their analogues with an alpha-N-glycosidic bond; however, both were equally toxic toward P388 leukemia cells. Dechlorinated rebeccamycin possessing a methyl group on the imide nitrogen was about 10 times more efficient in terms of cytotoxicity and inhibition of topoisomerase I than the natural metabolite.
 ...
PMID:Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. 934 21

1. An inward current (I[in]) was produced by gamma-aminobutyric acid (GABA) and muscimol, but not by baclofen, in an identifiable giant neuron type, v-LCDN (ventral-left cerebral distinct neuron), of an African giant snail (Achatina fulica Ferussac) under voltage clamp. 2. The pharmacological features of the excitatory GABA receptors in this Achatina neuron type, termed the Achatina muscimol II type GABA receptors, were mainly comparable to those of the mammalian GABA(C) receptors. 3. It was demonstrated in the present study that the following inhibitors for intracellular signal transduction systems showed no significant effect on the I(in) produced by GABA in this Achatina neuron type: H-7 [1-(5-isoquinolinyl sulfonyl)-2-methylpiperazine], an inhibitor of cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG) and protein kinase C (PKC); H-8 (N-[2-(methylamino)-ethyl]-5-isoquinolinesulfonamide), a PKA and PKG inhibitor; H-9 [N-(2-aminoethyl)-5-isoquinolinesulfonamide], a PKA inhibitor; staurosporine ((9alpha,10beta,11beta,13alpha)-(+)-2,3,10,11,12 ,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-d iindolo[1,2,3-gh: 3',2',1'-1m]pyrrolo[3,4-j] [1,7]benzodiazonin-1-one), a PKA and PKC inhibitor; KT5823 ((8R,9S, 11S)-9-methoxy-9-methoxycarbonyl-2N,8-dimethyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[c,d,e]- trinden-1-one), a PKG inhibitor; W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], a calmodulin inhibitor; ML-9 [1-(5-chloronaphthalene-1-sulfonyl-1H-hexahydro-1,4-diazepine hydrochloride], a myosin light-chain kinase inhibitor; genistein [5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one], a tyrosine protein kinase inhibitor; IBMX (3-isobutyl-1-methylxanthine), a cyclic nucleotide phosphodiesterase (PDE) inhibitor; fluphenazine nitrogen-mustard (2-chloroethyl)-4[3-(2-trifluoromethyl-10-phenothiazinyl)-propyl]p iperazine dihydrochloride), a calmodulin-dependent PDE inhibitor; calyculin A, a type 1 protein phosphatase inhibitor; and okadaic acid (9,10-deepithio-9,10-didehydroacanthifolicin), a type 1, 2A and 2B protein phosphatase inhibitor. 4. With these results, it was proposed that the excitatory Achatina muscimol II type GABA receptors in v-LCDN are not metabotropic but ionotropic.
 ...
PMID:Effects of inhibitors for intracellular signal transduction systems on the inward current produced by GABA in a snail neuron. 950 77

The indolocarbazole antibiotics staurosporine and rebeccamycin (1) are potent antitumor drugs targeting protein kinase C and topoisomerase I, respectively. To obtain staurosporine analogues from rebeccamycin, different structural modifications were performed: coupling of the sugar moiety to the second indole nitrogen, dechlorination and then reduction of the imide function to amide. The newly synthesized compounds (3-6) were tested for their abilities to bind to DNA and to inhibit topoisomerase I and protein kinase C. Their antiproliferative effects in vitro against B16 melanoma and P388 leukemia (including the related P388CPT cell line resistant to camptothecin) as well as their anti-HIV-1 and antimicrobial activities against various strains of microorganisms were determined. The cytotoxicity of the dechlorinated imide analogue 5 correlates well with its DNA binding and anti-topoisomerase I activities. These findings provide guidance for the development of new topoisomerase I-targeted antitumor indolocarbazoles equipped with a carbohydrate attached to the two indole nitrogens.
 ...
PMID:Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin. 980 30

Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.
 ...
PMID:Synthesis, mode of action, and biological activities of rebeccamycin bromo derivatives. 1034 33

Attachment of Salmonella typhimurium to epithelial surfaces elicit significant alterations in different cell signalling events which lead to the development of disease. The present investigation was conducted to evaluate the effect of immunization of rats with porins, on gut physiologic markers following challenge with S. typhimurium. Male albino Wistar rats were immunized with purified porins and challenged by intragastric infection with S. typhimurium. Electrolyte transport, levels of different second messengers and inflammatory mediators were studied. A net absorption of transepithelial fluxes of Na+ and Cl- in immunized-challenged group and secretion in infected group was found. Ca2+ and 3-O-methyl-D-glucose fluxes did not show any change. Significant increase in the levels of [Ca2+]i, cAMP, membrane form of protein kinase C, prostaglandins, NADPH oxidase, Glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, total oxygen free radicals, reactive nitrogen intermediates, citrulline and lipid peroxidation was found in the infected group. However, in the immunized-challenged group, the values of all the parameters were found to be almost the same as that of control as well as immunized groups. Na+, K+-ATPase and calmodulin levels were unaltered in all the groups of animals. The results of this study thus suggest that immunization of rats with purified Salmonella porins followed by subsequent challenge with the organism might be helpful for the prevention of multiple physiologic derangements in isolated ileal cells.
 ...
PMID:The effect of immunization with porins on gut pathophysiological response in rats infected with Salmonella typhimurium. 1063 Jun 36

Phosphatidylserine is one of the PKC modulators and thus it may play an important role in signal transduction. Regulation of the synthesis of this phospholipid is not yet clarified. The contrasting reports are possibly related to the existence of different enzymes which, in mammalian tissues, catalyse the exchange between free serine and the nitrogen base of a membrane phospholipid. This study demonstrates that serine base exchange reactions of commercially available lyophilised porcine platelets exhibit similar pH optima, temperature and Ca2+ dependence as observed in fresh tissues. Analysis of fatty acids composition of the three phospholipid classes involved in base exchange reactions also demonstrated a similarity with fresh platelets. Serine and ethanolamine base exchange enzyme activities were assayed in parallel in platelet lysate subjected to preincubation at various temperatures (30-60 degrees C). When dithioerithrol was omitted from the incubation medium, the two base exchange reactions were inhibited with a similar temperature-dependent pattern. Addition of the reducing agent enhanced the sensitivity to preincubation only for the serine base exchange reaction which was inhibited by 80% after preincubation at 45 degrees C. With respect to its regulation, porcine platelet serine base exchange enzyme(s) was inhibited by fluoroalluminate, a widely used G-protein activator, and stimulated by unfractionated heparin. Low mol. wt. heparin did not influence enzyme activity. Unfractionated heparin greatly stimulated SBEE activity assayed at pH 7.4, a pH value far from the optimal pH.
 ...
PMID:Serine base exchange enzyme in porcine lyophilised platelets: enzyme properties and modulation by AlF4- and different types of heparin. 1072 47

The Schizosaccharomyces pombe ran1/pat1 gene regulates the transition between mitosis and meiosis. Inactivation of Ran1 (Pat1) kinase is necessary and sufficient for cells to exit the cell cycle and undergo meiosis. The yeast two-hybrid interaction trap was used to identify protein partners for Ran1/Pat1. Here we report the identification of one of these, Cpc2. Cpc2 encodes a homologue of RACK1, a WD protein with homology to the beta subunit of heterotrimeric G proteins. RACK1 is a highly conserved protein, although its function remains undefined. In mammalian cells, RACK1 physically associates with some signal transduction proteins, including Src and protein kinase C. Fission yeast cells containing a cpc2 null allele are viable but cell cycle delayed. cpc2Delta cells fail to accumulate in G(1) when starved of nitrogen. This leads to defects in conjugation and meiosis. Copurification studies show that although Cpc2 and Ran1 (Pat1) physically associate, Cpc2 does not alter Ran1 (Pat1) kinase activity in vitro. Using a Ran1 (Pat1) fusion to green fluorescent protein, we show that localization of the kinase is impaired in cpc2Delta cells. Thus, in parallel with the proposed role of RACK1 in mammalian cells, fission yeast cpc2 may function as an anchoring protein for Ran1 (Pat1) kinase. All defects associated with loss of cpc2 are reversed in cells expressing mammalian RACK1, demonstrating that the fission yeast and mammalian gene products are indeed functional homologues.
 ...
PMID:Cpc2, a fission yeast homologue of mammalian RACK1 protein, interacts with Ran1 (Pat1) kinase To regulate cell cycle progression and meiotic development. 1080 44


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