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)

Treatment of B16 mouse melanoma cells with all-trans-retinoic acid (ATRA) results in inhibition of cell proliferation and induction of differentiation. Accompanying these events is an induction of retinoic acid receptor beta (RARbeta) expression, an increase in protein kinase Calpha (PKCalpha) expression, and enhanced activator protein-1 (AP-1) transcriptional activity. These cells express nuclear RARalpha and RARgamma and nuclear retinoid X receptors (RXR) alpha and beta constitutively. We tested the ability of receptor-selective retinoids to induce the biochemical changes found in ATRA-treated melanoma cells and also tested their effectiveness in decreasing anchorage-dependent and -independent growth. The RXR-selective ligand (2E,4E)-6-(5,6,7,8-tetrahydro-3,5,5,8, 8-pentamethyl-2-naphthalenyl)-3,7-dimethyl-2,4,6-octatrienoic acid (SR11246) was most effective at inhibiting anchorage-dependent growth, whereas the RARgamma-selective ligand 6-[(5,6,7, 8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)(hydroxyimino)methyl]-2-naphthalen ecarbo xylic acid (SR11254) was most potent at inhibiting anchorage-independent growth. In contrast, 4-(5,6,7,8-tetrahydro-5,5, 8,8-tetramethyl-2-naphthalenecarboxamido)-benzoic acid (Am580), an RARalpha-selective ligand, was the most effective receptor-selective agonist for inducing RARbeta mRNA and increasing the amount of PKCalpha protein. All of the retinoids induced a concentration-dependent increase in AP-1 transcriptional activity, with little difference in effectiveness among the receptor-selective retinoids. A synergistic increase in the amount of PKCalpha was found when an RAR-selective agonist was combined with an RXR-selective agonist. One possible explanation for this result is that an RXR-RAR heterodimer in which both receptors are liganded is required for maximum expression of this critical component of the ATRA-induced differentiation pathway. Our data suggest that synthetic retinoids can activate different growth and differentiation pathways preferentially in B16 melanoma cells, due, most likely, to their ability to activate a different subset of receptors.
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PMID:Effect of receptor-selective retinoids on growth and differentiation pathways in mouse melanoma cells. 1073 27

Secretin stimulates bicarbonate secretion from pancreatic duct cells, but what influence secretin exerts on intestinal tissues remains to be clarified. The aim of this study is to examine effects of secretin on ion transport in intestinal epithelial Caco-2 cells. We mounted monolayers of Caco-2 cells grown on permeable supports for 21-28 d in a Ussing chamber and measured short-circuit currents (I(sc)). Addition of secretin (5-100 nM) to the basolateral solution dose-dependently induced biphasic increases of I(sc) (transient and sustained phase). Dibutyryl cyclic AMP (200 microM), forskolin (10 microM), and 3-isobutyl-1-methylxanthine (IBMX, 1 mM) also induced I(sc) responses similar to the administration of secretin. Addition of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB, 100 microM) or benzamil (100 microM) to the apical solution markedly reduced the secretin-induced I(sc) increase in the transient phase. A selective antagonist of cAMP-dependent protein kinase (PKA), N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89, 1 microM), and a membrane permeable Ca(2+) chelator, 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM, 10 microM) reduced the secretin-induced I(sc). Basolateral addition of 4, 4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS, 1 mM) suppressed the sustained phase I(sc) increase. Secretin also induced alkalinization of the apical solution (DeltapH, 0.053 +/- 0.013). The alkalinization did not occur when DIDS (1 mM) was added to the basolateral solution or Na(+) was removed from the solutions. Taken together, our observations suggest: (1) secretin stimulates a benzamil-sensitive Na(+) influx and an NPPB-sensitive Cl(-) efflux across the apical membrane through PKA-dependent and Ca(2+)-sensitive pathways; and (2) secretin also induces alkalinization of the apical solution through the activation of a DIDS-sensitive Na(+)-HCO(3)(-) cotransport in the basolateral membrane of Caco-2 cells.
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PMID:Activation of transepithelial ion transport by secretin in human intestinal Caco-2 cells. 1088 Aug 78

Effects of HCO(3)(-) on protein kinase C (PKC)- and protein kinase A (PKA)-induced anion conductances were investigated in Necturus gallbladder epithelial cells. In HCO(3)(-)-free media, activation of PKC via 12-O-tetradecanoylphorbol 13-acetate (TPA) depolarized apical membrane potential (V(a)) and decreased fractional apical voltage ratio (F(R)). These effects were blocked by mucosal 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), a Cl(-) channel blocker. In HCO(3)(-) media, TPA induced significantly greater changes in V(a) and F(R). These effects were blocked only when NPPB was present in both mucosal and basolateral compartments. The data suggest that TPA activates NPPB-sensitive apical Cl(-) conductance (g(Cl)(a)) in the absence of HCO(3)(-); in its presence, TPA stimulated both NPPB-sensitive g(Cl)(a) and basolateral Cl(-) conductance (g(Cl)(b)). Activation of PKA via 3-isobutyl-1-methylxanthine (IBMX) also decreased V(a) and F(R); however, these changes were not affected by external HCO(3)(-). We conclude that HCO(3)(-) modulates the effects of PKC on g(Cl)(b). In HCO(3)(-) medium, TPA and IBMX also induced an initial transient hyperpolarization and increase in intracellular pH. Because these changes were independent of mucosal Na(+) and Cl(-), it is suggested that TPA and IBMX induce a transient increase in apical HCO(3)(-) conductance.
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PMID:Effect of HCO(3)(-) on TPA- and IBMX-induced anion conductances in Necturus gallbladder epithelial cells. 1102 86

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.
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PMID:Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. 1134 29

Epithelia of humans and mice with cystic fibrosis are unable to secrete chloride in response to a chloride gradient or to cAMP-elevating agents. Bioelectrical properties measured using the nasal transepithelial potential difference (TEPD) assay are believed to reflect these cystic fibrosis transmembrane conductance regulator (CFTR)-dependent chloride transport defects. Although the response to forskolin is CFTR mediated, the mechanisms responsible for the response to a chloride gradient are unknown. TEPD measurements performed on inbred mice were used to compare the responses to low chloride and forskolin in vivo. Both responses show little correlation between or within inbred strains of mice, suggesting they are mediated through partially distinct mechanisms. In addition, these responses were assayed in the presence of several chloride channel inhibitors, including DIDS, diphenylamine-2-carboxylate, glibenclamide, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and a protein kinase A inhibitor, the Rp diastereomer of adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). The responses to low chloride and forskolin demonstrate significantly different pharmacological profiles to both DIDS and Rp-cAMPS, indicating that channels in addition to CFTR contribute to the low chloride response.
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PMID:Examining basal chloride transport using the nasal potential difference response in a murine model. 1159 9

Characteristics of pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increase of Ca(2+) entry and catecholamine (CA) release were studied in bovine adrenal medullary chromaffin cells. PACAP induced intracellular free Ca(2+) concentration ([Ca(2+)](i)), showing an initial transient [Ca(2+)](i) rise followed by a sustained rise and CA release, which were not blocked by the blocking agents for nicotinic acetylcholine receptor (nAChR) channel, the voltage-dependent Ca(2+) channel (VOC), or the Na(+) channel. The sarcoendoplasmic Ca(2+)-ATPase inhibitors thapsigargin and cyclopiazonic acid did not affect the PACAP-induced sustained rise of [Ca(2+)](i), but did inhibit the initial [Ca(2+)](i) rise. In cells pretreated with cyclopiazonic acid or membrane-permeable, low-affinity Ca(2+) chelator N',N',N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, PACAP further stimulated the entry of Ca(2+) or Mn(2+), whereas these treatments masked [Ca(2+)](i) dynamics induced by bradykinin. PACAP-induced sustained [Ca(2+)](i) rise and Mn(2+) entry were enhanced by acidic extracellular solution and reduced by alkalinization, whereas thapsigargin-induced Mn(2+) entry was regulated by the opposite. PACAP-induced [Ca(2+)](i) rise and Mn(2+) entry were not affected by blockers of cAMP-dependent protein kinase, phospholipase C, or protein kinase C. All store-operated Ca(2+) channel (SOC) blocking agents tested inhibited thapsigargin-induced Mn(2+) entry. 1(beta-[3-(4-Methoxyphenyl)-propoxy]-4-methoxyphenylethyl)-1H-imidazole hydrochloride (SK&F 96365), (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide, and econazole inhibited PACAP-induced Ca(2+) or Mn(2+) entry, whereas GdCl(3), 7,8-benzoflavone, nor-dihydroguaiaretic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, fulfenamic acid, and niflumic acid did not. SK&F 96365 and econazole but not GdCl(3) inhibited PACAP-induced CA release. These results suggest that PACAP activates a novel Ca(2+) entry pathway associated with sustained CA release independent of the nAChR channel, VOC and SOC, activated by acid pH, with different sensitivity to blockers of SOC. This pathway may provide a useful model for the study of receptor-operated Ca(2+) entry.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces a sustained increase in intracellular free Ca(2+) concentration and catechol amine release by activating Ca(2+) influx via receptor-stimulated Ca(2+) entry, independent of store-operated Ca(2+) channels, and voltage-dependent Ca(2+) channels in bovine adrenal medullary chromaffin cells. 1218 54

Cystic fibrosis transmembrane conductance regulator (CFTR) is a protein kinase A (PKA) and ATP regulated Cl- channel. Studies using mostly ex vivo systems suggested diphenylamine-2-carboxylate (DPC), 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and glybenclamide inhibit CFTR Cl- conductance (CFTR GCl). However, the properties of inhibition in a native epithelial membrane have not been well defined. The objective of this study was to determine and compare the inhibitory properties of the aforementioned inhibitors as well as the structurally related anion-exchange blockers (stilbenes) including 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS) in the microperfused intact and basilaterally permeabilized native sweat duct epithelium. All of these inhibitors blocked CFTR in a dose-dependent manner from the cytoplasmic side of the basilaterally permeabilized ducts, but none of these inhibitors blocked CFTR GCl from the luminal surface. We excluded inhibitor interference with a protein kinase phosphorylation activation process by "irreversibly" thiophosphorylating CFTR prior to inhibitor application. We then activated CFTR GCl by adding 5 mM ATP. At a concentration of 10(-4) M, NPPB, DPC, glybenclamide, and DIDS were equipotent and blocked approximately 50% of irreversibly phosphorylated and ATP-activated CFTR GCl (DIDS = 49 +/- 10% > NPPB = 46 +/- 10% > DPC = 38 +/- 7% > glybenclamide = 34 +/- 5%; values are mean +/- SE expressed as % inhibition from the control). The degree of inhibition may be limited by inhibitor solubility limits, since DIDS, which is soluble to 1 mM concentration, inhibited 85% of CFTR GCl at this concentration. All the inhibitors studied primarily blocked CFTR from the cytoplasmic side and all inhibition appeared to be independent of metabolic and phosphorylation processes.
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PMID:Effect of anion transport blockers on CFTR in the human sweat duct. 1220 48

Previous studies indicate that a continual source of adenosine 5[prime]-triphosphate is required for both opening and closing of stomata. However, vanadate (Na3VO4 at 500 [mu]M) as well as a light/dark transition induced stomatal closing in epidermal peels of Commelina communis L., showing that the stoppage or even the decrease of the activity of the plasma membrane H+-adenosine 5[prime]-triphosphatase is sufficient to induce stomatal closure. Furthermore, stomatal closing in response to Na3VO4 or a light/dark transition was suppressed by inhibitors of metabolism (10 [mu]M carbonyl cyanide m-chlorophenylhydrazone) and of protein kinases (20 [mu]M 1-[5-iodonaphthalene-1-sulfonyl]-1H-hexa-hydro-1,4-diaz-epine), calmodulin antagonists (20 [mu]M N-[6-aminohexyl]-5-chloro-1-naphthalenesulfonamide), and the anion channel blocker 5-nitro-2,3-phenylpropyllamino benzoic acid (50 [mu]M). These data suggest that the slow, outward rectifying anion channel, whose opening would be related to the membrane potential, and at least one step requiring a protein phosphorylation by a Ca2+-calmodulin-dependent protein kinase of the myosin light chain kinase type might be implicated in the induction of stomatal closing by vanadate or a light/dark transition.
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PMID:Induction of Stomatal Closure by Vanadate or a Light/Dark Transition Involves Ca2+-Calmodulin-Dependent Protein Phosphorylations. 1222 7

We previously reported that dieldrin, one of the potential environmental risk factors for development of Parkinson's disease, induces apoptosis in dopaminergic cells by generating oxidative stress. Here, we demonstrate that the caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) mediates as well as regulates the dieldrin-induced apoptotic cascade in dopaminergic cells. Exposure of PC12 cells to dieldrin (100-300 microM) results in the rapid release of cytochrome C, followed by the activation of caspase-9 and caspase-3 in a time- and dose-dependent manner. The superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride significantly attenuates dieldrin-induced cytochrome C release, indicating that reactive oxygen species may contribute to the activation of pro-apoptotic factors. Interestingly, dieldrin proteolytically cleaves native PKCdelta into a 41 kDa catalytic subunit and a 38 kDa regulatory subunit to activate the kinase. The dieldrin-induced proteolytic cleavage of PKCdelta and induction of kinase activity are completely inhibited by pretreatment with 50-100 microM concentrations of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), indicating that the proteolytic activation of PKCdelta is caspase-3-dependent. Additionally, Z-VAD-FMK, Z-DEVD-FMK or the PKCdelta specific inhibitor rottlerin almost completely block dieldrin-induced DNA fragmentation. Because dieldrin dramatically increases (40-80-fold) caspase-3 activity, we examined whether proteolytically activated PKCdelta amplifies caspase-3 via positive feedback activation. The PKCdelta inhibitor rottlerin (3-20 microM) dose-dependently attenuates dieldrin-induced caspase-3 activity, suggesting positive feedback activation of caspase-3 by PKCdelta. Indeed, delivery of catalytically active recombinant PKCdelta via a protein delivery system significantly activates caspase-3 in PC12 cells. Finally, overexpression of the kinase-inactive PKCdelta(K376R) mutant in rat mesencephalic dopaminergic neuronal cells attenuates dieldrin-induced caspase-3 activity and DNA fragmentation, further confirming the pro-apoptotic function of PKCdelta in dopaminergic cells. Together, we conclude that caspase-3-dependent proteolytic activation of PKCdelta is a critical event in dieldrin-induced apoptotic cell death in dopaminergic cells.
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PMID:Dieldrin induces apoptosis by promoting caspase-3-dependent proteolytic cleavage of protein kinase Cdelta in dopaminergic cells: relevance to oxidative stress and dopaminergic degeneration. 1283 55

Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)amino]-azepan-4-yl ester (1) (IC(50) (PKB-alpha) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl]-isonicotinamide (4), (3R,4R)-N-[4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl]-isonicotinamide (5), N-[(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl]-azepan-3-yl)-isonicotinamide (6), N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl]-isonicotinamide (7), and N-[(3R,4S)-4-(4-[trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl]-vinyl]-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1) Compound 4 was found to be plasma stable and highly active (IC(50) (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.
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PMID:Structure-based optimization of novel azepane derivatives as PKB inhibitors. 1499 27


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