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)

ATP and UTP induced a dual inotropic effect in rat left atria: first a decrease and then an increase in contractile tension were observed. PPADS, an antagonist of P2X receptors, inhibited positive inotropism induced by ATP and alpha,beta-meATP. Chiefly, we investigated intracellular mechanisms responsible for the positive inotropism. We tested cromakalim and glibenclamide, an activator and an inhibitor, respectively, of ATP-sensitive K(+) channels. These compounds did not influence the effects of ATP. IBMX, a phosphodiesterase inhibitor, and H-7, an inhibitor of protein kinase C and cAMP-dependent protein kinase, did not modify the inotropic effects of ATP. Instead, H-8, an inhibitor of cAMP- and cGMP-dependent protein kinases, strongly inhibited the positive effects of both ATP and UTP, suggesting the possible involvement of cGMP in the inotropism. Also, LY 83583, an inhibitor of cGMP production, reduced positive inotropism by alpha,beta-meATP, ATP and UTP. Moreover, 8-Br-cGMP (50 microM), a stable analogue of cGMP, inhibited positive inotropism by all nucleotides. Lastly, we determined intracellular cGMP levels by RIA; the cyclic nucleotide increased during positive inotropism induced by ATP and UTP. The results regarding positive inotropism suggest that: (a) ATP acts through P2X receptors, while UTP may act by P2X, but also through PPADS-insensitive receptors; and (b) changes in intracellular cGMP concentration are involved in this inotropic effect.
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PMID:Do ATP and UTP involve cGMP in positive inotropism on rat atria? 1123 39

The ubiquitin proteasome system is responsible for the proteolysis of important cell cycle and apoptosis-regulatory proteins. In this paper we report that the dipeptidyl proteasome inhibitor, phthalimide-(CH2)8CH-(cyclopentyl) CO-Arg(NO2)-Leu-H (CEP1612), induces apoptosis and inhibits tumor growth of the human lung cancer cell line A-549 in an in vivo model. In cultured A-549 cells, CEP1612 treatment results in accumulation of two proteasome natural substrates, the cyclin-dependent kinase inhibitors p21WAF1 and p27KIP1, indicating its ability to inhibit proteasome activity in intact cells. Furthermore, CEP1612 induces apoptosis as evident by caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Treatment of A-549 tumor-bearing nude mice with CEP1612 (10 mg/kg/day, i.p. for 31 days) resulted in massive induction of apoptosis and significant (68%; P < 0.05) tumor growth inhibition, as shown by terminal deoxynucleotidyltransferase-mediated UTP end labeling. Furthermore, immunostaining of tumor specimens demonstrated in vivo accumulation of p21WAF1 and p27KIP1 after CEP1612 treatment. The results suggest that CEP1612 is a promising candidate for further development as an anticancer drug and demonstrate the feasibility of using proteasome inhibitors as novel antitumor agents.
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PMID:CEP1612, a dipeptidyl proteasome inhibitor, induces p21WAF1 and p27KIP1 expression and apoptosis and inhibits the growth of the human lung adenocarcinoma A-549 in nude mice. 1124 20

1. Extracellularly added P(1),P(3)-di(adenosine-5') triphosphate (Ap(3)A), P(1),P(4)-di(adenosine-5') tetraphosphate (Ap(4)A), ATP, ADP, AMP and adenosine are growth inhibitory for rat C6 glioma cells. Analysis of nucleotide hydrolysis and the use of nucleotidase inhibitors demonstrated that the latter inhibition is due to hydrolysis of the nucleotides to adenosine. 2. Agonists of the P2Y(AC)(-)-receptor enhance the growth of C6 cells if their hydrolysis to adenosine is inhibited by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). In these conditions, the potency to stimulate cell growth parallels the ranking of the receptor agonists, i.e. 2-methylthioadenosine-5'-diphosphate (2MeSADP)>Ap(3)A>Ap(4)A. ATP and ADP are still hydrolysed in the presence of PPADS and have no proliferative effect on C6 cells. 3. The enhanced growth is due to a P2Y(AC)(-)-receptor-mediated activation of p42/44 mitogen-activated protein kinase (MAPK) as shown by immunoblotting and protein kinase assays for active MAPK and the use of the MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059. 4. The UTP-induced enhancement of the growth of C6 cells is due to activation of MAPK by a PPADS sensitive nucleotide receptor. 5. In conclusion, the effect of nucleotides on the growth of C6 cells is determined by ecto-nucleotidases and by activation of nucleotide receptors. Hydrolysis of nucleotides to adenosine induces growth inhibition while inhibition of the hydrolysis of agonists of the P2Y(AC)(-)-receptor enhances cell growth by activation of MAPK.
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PMID:P2Y(AC)(-)-receptor agonists enhance the proliferation of rat C6 glioma cells through activation of the p42/44 mitogen-activated protein kinase. 1156 59

Purines regulate intraocular pressure. Adenosine activates Cl(-) channels of nonpigmented ciliary epithelial cells facing the aqueous humor, enhancing secretion. Tamoxifen and ATP synergistically activate Cl(-) channels of pigmented ciliary epithelial (PE) cells facing the stroma, potentially reducing net secretion. The actions of nucleotides alone on Cl(-) channel activity of bovine PE cells were studied by electronic cell sorting, patch clamping, and luciferin/luciferase ATP assay. Cl(-) channels were activated by ATP > UTP, ADP, and UDP, but not by 2-methylthio-ATP, all at 100 microM. UTP triggered ATP release. The second messengers Ca(2+), prostaglandin (PG)E(2), and cAMP activated Cl(-) channels without enhancing effects of 100 microM ATP. Buffering intracellular Ca(2+) activity with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid or blocking PGE(2) formation with indomethacin inhibited ATP-triggered channel activation. The Rp stereoisomer of 8-bromoadenosine 3',5'-cyclic monophosphothioate inhibited protein kinase A activity but mimicked 8-bromoadenosine 3',5'-cyclic monophosphate. We conclude that nucleotides can act at >1 P2Y receptor to trigger a sequential cascade involving Ca(2+), PGE(2), and cAMP. cAMP acts directly on Cl(-) channels of PE cells, increasing stromal release and potentially reducing net aqueous humor formation and intraocular pressure.
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PMID:PGE(2), Ca(2+), and cAMP mediate ATP activation of Cl(-) channels in pigmented ciliary epithelial cells. 1160 Apr 25

1. Although accumulating studies have identified I kappa B kinase (IKK) to be essential for controlling NF-kappa B activity in response to several cytokines, the upstream kinases that control IKK activity are still not completely known. We have previously reported that G protein-coupled P2Y(6) receptor activation by UTP potentiates lipopolysaccharide (LPS)-induced I kappa B phosphorylation and degradation, and NF-kappa B activation in J774 macrophages. In this study, we investigated the upstream kinases for IKK activation by UTP and LPS. 2. In murine J774 macrophages, LPS-induced NF-kappa B activation was inhibited by the presence of PDTC, D609, Ro 31-8220, PD 098059 and SB 203580. 3. Accompanying NF-kappa B activation, LPS induced I kappa B degradation and IKK activation were reduced by PDTC, D609, Ro 31-8220 and PD 098059, but not by SB 203580. 4. Although UTP itself slightly induced IKK activation, this response was synergistic with LPS. BAPTA/AM and KN-93 (a calcium/calmodulin-dependent protein kinase (CaMK) inhibitor) attenuated UTP- but not LPS-stimulated IKK activity. Synergistic IKK activation between LPS and thapsigargin was further demonstrated in peritoneal macrophages. 5. LPS and UTP co-stimulation additively increased p65 NF-kappa B phosphorylation. In vitro kinase assays revealed that LPS and UTP induced extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase activation were respectively inhibited by PD098059 and SB 203580. 6. Taken together, we demonstration that Gq protein-coupled P2Y(6) receptor activation can potentiate LPS-stimulated IKK activity. While PKC and ERK participate in IKK activation by LPS and UTP, the phosphatidylinositide-phospholipase C-dependent activation of CaMK plays a major role in UTP potentiation of the LPS response.
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PMID:PKC- and ERK-dependent activation of I kappa B kinase by lipopolysaccharide in macrophages: enhancement by P2Y receptor-mediated CaMK activation. 1168 54

1. Using a Ca(2+) imaging system and fura-2 AM (5 microM) we showed that exposure of polarised monolayers of human bronchial epithelial cells (16HBE14o- cell line) to aldosterone produced a fast intracellular [Ca(2+)] ([Ca(2+)](i)) decrease, in 70 % of cells. Exposure to aldosterone (1 nM) reduced the [Ca(2+)](i) by 39 +/- 9 nM (n = 282, P < 0.0001) within 10 min, from a basal [Ca(2+)](i) of 131 +/- 19 nM (n = 282). 2. The effect of aldosterone on [Ca(2+)](i) was not affected by inhibitors of the classical genomic pathway, cycloheximide (1 microM) or spironolactone (10 microM). The aldosterone-induced [Ca(2+)](i) decrease was inhibited by thapsigargin (1 microM), pertussis toxin (24 h at 200 ng ml(-1)), the adenylate cyclase inhibitors 2',3'-dideoxyadenosine (200 microM) and MDL-12,330A hydrochloride (500 microM), and the protein kinase A inhibitor R(P)-adenosine 3',5'-cyclic monophosphorothioate (200 microM). In addition, treatment of 16HBE14o- monolayers with aldosterone (1 nM) inhibited by approximately 30 % the large and transient [Ca(2+)](i) increase induced by apical exposure to uridine triphosphate (UTP, 0.1 mM), a known secretagogue in airway epithelia. 3. Our results demonstrate for the first time that in human bronchial epithelial cells, aldosterone decreases [Ca(2+)](i) levels via a non-genomic mechanism. The hormone-induced changes to [Ca(2+)](i) involve stimulation of thapsigargin-sensitive Ca(2+)-ATPase, via G-protein-, adenylate cyclase- and protein kinase A-coupled signalling pathways.
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PMID:Rapid and non-genomic reduction of intracellular [Ca(2+)] induced by aldosterone in human bronchial epithelium. 1171 79

Mitogenic effects of the extracellular nucleotides ATP and UTP are mediated by P2Y(1), P2Y(2), and P2Y(4) receptors. However, it has not been possible to examine the highly expressed UDP-sensitive P2Y(6) receptor because of the lack of stable, selective agonists. In rat aorta smooth muscle cells (vascular smooth muscle cells; VSMC), UDP and UTP stimulated (3)H-labeled thymidine incorporation with similar pEC(50) values (5.96 and 5.69). Addition of hexokinase did not reduce the mitogenic effect of UDP. In cells transfected with P2Y receptors the stable pyrimidine agonist uridine 5'-O-(2-thiodiphosphate) (UDPbetaS) was specific for P2Y(6) with no effect on P2Y(1), P2Y(2), or P2Y(4) receptors. UDPbetaS stimulated [(3)H]thymidine and [(3)H]leucine incorporation and increased cell number in VSMC. Flow cytometry demonstrated that UDP stimulated cell cycle progression to both the S and G(2) phases. The intracellular signal pathways were dependent on phospholipase C, possibly protein kinase C-delta, and a tyrosine kinase pathway but independent of G(i) proteins, eicosanoids, and protein kinase A. The half-life of P2Y(6) receptor mRNA was <1 h by competitive RT-PCR. The mitogen-activated protein kinase kinase inhibitor PD-098059 significantly suppressed, whereas ATP and interleukin-1beta upregulated, expression of P2Y(6) receptor mRNA. The results demonstrate that UDP stimulates mitogenesis through activation of P2Y(6) receptors and that the receptor is regulated by factors important in the development of vascular disease.
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PMID:UDP acts as a growth factor for vascular smooth muscle cells by activation of P2Y(6) receptors. 1178 30

Stimulation of ovine airway epithelial cells with 10 microM ATP for 1 min at 25 degrees C transiently increased both cytoplasmic calcium (fura-2 epifluorescence microscopy) and ciliary beat frequency (CBF; differential interference contrast microscopy) with a similar time course. Identical purinergic stimulation of human airway epithelial cells at 25 or 35 degrees C, however, lead to an increase in CBF that outlasted the calcium transient at least 20 min. While a nitric oxide synthase inhibitor had no effect, pre-treatment of human cells with inhibitors of cAMP-dependent kinase (PKA), 10 microM myristoylated PKA-inhibitory peptide and 1 microM KT-5720, as well as an inhibitor of adenylyl cyclase, 1 mM SQ22536, blocked the prolonged, but not calcium-coupled CBF increase. Addition of PKA inhibitors after purinergic stimulation only partially reduced CBF from its elevated plateau. Prolonged CBF increases did not depend on adenosine production as 10 microM UTP had an effect similar to ATP and 8-sulphophenyl-theophylline did not block them. After increasing human CBF in a PKA-dependent manner to a stable plateau with forskolin (10 microM), ATP caused only a transient, calcium-coupled CBF increase. Calcium transients were necessary for both short-term and prolonged CBF changes as ATP failed to produce CBF increases after emptying calcium stores with 1 microM thapsigargin. These data suggest that in human, but not ovine airway epithelial cells, ATP-induced calcium transients activate a signalling cascade including adenylyl cyclase and PKA. The resulting prolonged CBF stimulation does not rely only on PKA activity, suggesting that the decay of CBF is influenced by ciliary phosphatase activity.
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PMID:Prolonged increase in ciliary beat frequency after short-term purinergic stimulation in human airway epithelial cells. 1179 Aug 25

ATP causes relaxation of the K(+)-contracted rat vas deferens. Possible sites of action were investigated. ATP and adenosine relaxed the vas deferens precontracted with 80 mM K(+); EC(50) values and maximal relaxations averaged, respectively, 760 microM and 56% for ATP and 74 microM and 30% for adenosine. The adenosine P1 receptor antagonist 8-(para-sulfophenyl)theophylline (8-SPT) reduced relaxations caused by adenosine and low concentrations of ATP, as did the Rp-diastereomer of adenosine 3',5'-cyclic phosphorothioate (Rp-cAMPS), an inhibitor of protein kinase A. The phosphodiesterase inhibitor 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) augmented responses to adenosine and low concentrations of ATP. alpha,beta-Methylene ADP, an inhibitor of 5'-nucleotidase, reduced relaxations caused by ATP to a similar extent as did 8-SPT. In the presence of an almost saturating concentration of adenosine, ATP caused further relaxation. Conversely, in the presence of ATP, adenosine had little effect. Like ATP, UTP and other nucleoside triphosphates relaxed the vas deferens. The P2 receptor antagonists reactive blue 2, acid blue 25 and 4,4'-diisothiocyanotostilbene-2,2'-disulphonate (DIDS) attenuated the relaxation caused by ATP; suramin, pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), Evans blue, trypan blue, reactive red 2 and brilliant blue G had no effect. Three non-selective inhibitors of protein kinases, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), staurosporine and (8R*,9S*,11S*)-(-)-9-hydroxy-9-carboxy-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one (K-252b), markedly reduced the relaxation caused by ATP. The results indicate that adenosine, derived from enzymatic dephosphorylation, contributes to the relaxant effect of ATP, presumably by activation of a smooth muscle adenosine receptor linked to the accumulation of cAMP and activation of protein kinase A. Yet, the main part of the response to ATP is mediated by a site distinct from the adenosine receptor. The pharmacological properties of this site differ from known P2 receptor subtypes. Possibly, the nucleotide-evoked relaxation is due to a phosphoryl transfer catalyzed by an ecto-protein kinase.
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PMID:Nucleotide-evoked relaxation of rat vas deferens: possible mechanisms. 1183 57

The carbamoyl phosphate synthetase domain of the multifunctional protein CAD catalyzes the initial, rate-limiting step in mammalian de novo pyrimidine biosynthesis. In addition to allosteric regulation by the inhibitor UTP and the activator PRPP, the carbamoyl phosphate synthetase activity is controlled by mitogen-activated protein kinase (MAPK)- and protein kinase A (PKA)-mediated phosphorylation. MAPK phosphorylation, both in vivo and in vitro, increases sensitivity to PRPP and decreases sensitivity to the inhibitor UTP, whereas PKA phosphorylation reduces the response to both allosteric effectors. To elucidate the factors responsible for growth state-dependent regulation of pyrimidine biosynthesis, the activity of the de novo pyrimidine pathway, the MAPK and PKA activities, the phosphorylation state, and the allosteric regulation of CAD were measured as a function of growth state. As cells entered the exponential growth phase, there was an 8-fold increase in pyrimidine biosynthesis that was accompanied by a 40-fold increase in MAPK activity and a 4-fold increase in CAD threonine phosphorylation. PRPP activation increased to 21-fold, and UTP became a modest activator. These changes were reversed when the cultures approach confluence and growth ceases. Moreover, CAD phosphoserine, a measure of PKA phosphorylation, increased 2-fold in confluent cells. These results are consistent with the activation of CAD by MAPK during periods of rapid growth and its down-regulation in confluent cells associated with decreased MAPK phosphorylation and a concomitant increase in PKA phosphorylation. A scheme is proposed that could account for growth-dependent regulation of pyrimidine biosynthesis based on the sequential action of MAPK and PKA on the carbamoyl phosphate synthetase activity of CAD.
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PMID:Growth-dependent regulation of mammalian pyrimidine biosynthesis by the protein kinase A and MAPK signaling cascades. 1187 54


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