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)

Transient cerebral ischemia demonstrates an increase in activated oxygen species in the brain that could lead to eventual neuronal cell death. Neuronal cells respond to oxygen free radicals through the restructuring of the cytoskeleton and membranes, mobilization of calcium and gene expression which play a role in cell injury. Ten min of bilateral carotid artery occlusion resulted in a decrease in calcium/calmodulin dependent protein kinase II (CaM kinase II) phosphorylation and activity detected in the brain immediately following ischemia and was partially restored within 24 h of reperfusion. Pretreatment of animals with an anesthetic dose of pentobarbital (40 mg/kg) resulted in partial protection of inactivation of CaM kinase II following ischemia. CaM kinase II activity was maintained following pretreatment of animals with alpha-phenyl N-tert-butyl nitrone (PBN), which traps oxygen free radicals. Infusion of superoxide dismutase or catalase prior to ischemia, blocked CaM kinase II inactivation. Blockage of calcium uptake with bepridil resulted in a marked protection of CaM kinase II inactivation. In addition, trifluoperazine, a calmodulin antagonist also diminished the inhibition of CaM kinase II phosphorylation in our model. These results suggest that ischemia and reperfusion injury results in the generation of activated oxygen and the mobilization of calcium which inactivate CaM kinase II. These results indicate that changes associated with protein kinase activity in the brain following an ischemic insult may have profound effects upon neurodegeneration and neuronal survival.
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PMID:Role of calcium in inactivation of calcium/calmodulin dependent protein kinase II after cerebral ischemia. 133 39

Flavonols are dietary compounds widely distributed in plants and characterized by a 2-phenyl-benzo(alpha)pyrane nucleus possessing hydroxyl and ketone groups at positions 3 and 4, respectively. Kaempferol, quercetin, and myricetin are flavonols that are further mono-, di-, or trihydroxylated on the phenyl ring, respectively. To test whether these ingested flavonols might exert a direct secretory effect on intestinal epithelial cells, monolayers of the T84 colonocyte cell line were mounted in Ussing chambers and examined for ion transport response. Twenty minutes after addition of 100 microM quercetin to either the serosal or mucosal side, the short-circuit current change was maximal at 16.6 microA/cm2. Kaempferol was less potent than quercetin, while myricetin and glycosylated quercetin (rutin) did not induce secretion. The secretion induced by quercetin did not seem to be mediated by the reactive oxygen species generated by quercetin through auto-oxidation and/or redox cycling (superoxide, hydrogen peroxide, and the hydroxyl radical) because it was neither enhanced by iron, nor inhibited by desferroxamine B or catalase (alone or in combination with superoxide dismutase). Like vasoactive intestinal peptide, quercetin induced a secretory response that was inhibited by barium chloride and bumetanide, and which exhibited synergism with carbachol. Quercetin also stimulated a modest increase in intracellular cAMP levels and the phosphorylation of endogenous protein substrates for cAMP-dependent protein kinase. Thus, quercetin is a potent stimulus of colonocyte secretion that resembles secretagogues which act via a cAMP-mediated signaling pathway.
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PMID:Stimulation of secretion by the T84 colonic epithelial cell line with dietary flavonols. 164 52

Oxidative stress plays an important role in various types of cell injury and tumor promotion. Cells respond to oxidative stress in many ways including changes in membrane organization, ion movements, and altered gene expression, all of which contribute to the subsequent fate of affected cells. In this study, we investigated the expression of the proto-oncogenes c-fos, c-myc, and c-jun, which play a key role in proliferation and differentiation, using primary cultures of rat proximal tubular epithelium exposed to oxidative stress generated by the xanthine/xanthine oxidase system. This system generates superoxide and H2O2 in the extracellular space stimulating the release of active oxygen species from inflammatory cells. c-fos mRNA was expressed within 15 min, peaked at 30 min, and returned to constitutive levels by 3 h. c-jun mRNA began to rise after 30 min, peaked at 120 min, and remained above the constitutive levels up to 180 min. c-myc mRNA expression was less affected by the treatment, with levels increasing gradually over the 180 min period. The expression of c-fos was inhibited by superoxide dismutase but not by catalase and was super-induced by cycloheximide. H2O2 alone did not induce any c-fos mRNA in this system. Chelation of extracellular ionized calcium by EGTA or of intracellular ionized calcium by Quin 2/AM resulted in a marked decrease of c-fos expression. Two protein kinase C inhibitors, H-7 and staurosporine, partly diminished the expression of c-fos, whereas a third, 2-aminopurine, which has a broader spectrum of inhibiting protein kinases, almost completely abolished it. A poly ADP-ribosylation inhibitor, 3-aminobenzamide, had no effect on c-fos expression in this system. Our results show that oxidative stress provokes sequential expression of c-fos, c-jun, and c-myc, mRNA in this order. This c-fos expression appears to be largely controlled by calcium ion movement, which could include protein kinase C activation. Another protein kinase or kinases also appear to play an important role.
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PMID:Role of [Ca2+]i in induction of c-fos, c-jun, and c-myc mRNA in rat PTE after oxidative stress. 174 Feb 41

We have investigated the phosphorylation of the ribosomal S6 protein which may be on the pathway of mitogenic stimulation in response to oxidants. Mouse epidermal cells JB6 (clone 41) were exposed to active oxygen generated extracellularly by glucose/glucose oxidase (producing H2O2) or xanthine oxidase (producing H2O2 plus superoxide) or active oxygen produced intracellularly by the metabolism of menadione (producing mostly superoxide). All three sources of active oxygen induced rapidly a protein kinase activity which phosphorylated S6 in cellular extracts prepared in the presence of the phosphatase inhibitor beta-glycerophosphate. Maximal activity was reached within 15 min of exposure, and phosphorylation occurred specifically at serine residues. Strong activation of the protein kinase activity was also observed by diamide which selectively oxidizes SH functions. The following observations characterize the reaction: 1) Extracellular addition of catalase but not Cu,Zn-superoxide dismutase was inhibitory, implicating H2O2 rather than superoxide as the active species. 2) Exposure of JB6 cells to reagent H2O2 or H2O2 released by glucose/glucose oxidase resulted in a measurable increase in intracellular free Ca2+. 3) The intracellular Ca2+ complexer quin 2 suppressed the reaction. 4) The calmodulin antagonist trifluoperazine prevented the activation of the protein kinase. 5) Exposure of cells to Mn2+ and La3+, which stimulate calmodulin-dependent activities, potently increased the S6 kinase activity of the cell extracts. 6) Desalted extracts strictly required the addition of Mg2+ and their activity was inhibited by Mn2+. In contrast, the phosphorylation of a 95-kDa protein was strongly stimulated by Mn2+. 7) For several agonists, i.e. active oxygen, phorbol 12-myristate 13-acetate, and serum, tryptic peptide analysis yielded the same phosphopeptides, suggesting that a common S6 kinase is involved in these reactions. From these data we propose that oxidants induce an increase in intracellular free Ca2+ which activates a Ca2+/calmodulin-dependent protein kinase and, as a consequence, an S6 kinase.
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PMID:Oxidants induce phosphorylation of ribosomal protein S6. 314 21

Interferon exhibits pleotropic effects on homologous cells. Interferons may be used clinically for both antiviral and antitumor therapy. A better understanding of how interferon achieves its hormonal effects should be useful in developing more judicious and specific applications of these natural substances in therapy. Interferon induces increased activity of two enzymes, 2'5'-oligoadenylate synthetase and a protein kinase, that depend on double-stranded RNA for activation. 2'5' A polymerizes ATP into a novel 2'5'-linked oligonucleotide, which in turn can activate a latent cellular nuclease (RNase L) which degrades mRNA. The second dsRNA-dependent enzyme, a protein kinase, phosphorylates a protein of approximately 67,000 daltons as well as the small subunit of eukaryotic initiation factor (eIF-2). The phosphorylation of eIF-2 results in the inhibition of protein synthesis. The extent of sensitivity to exogenous interferon could be influenced by several factors, including the number of cell surface receptors for interferon and the rate and efficiency at which ligand binding and "processing" is achieved. Prostaglandins, cyclic nucleotides, and oxygen-free radicals could participate in modulation of interferon action at this level. Interferon induces specific changes in the composition of membrane lipids. These changes included loss of unsaturated fatty acids from phospholipids, significant increases in levels of unesterified fatty acids, and moderate increases in concentrations of triglycerides and cholesterol esters. The changes were absent in cells treated with interferon in the presence of inhibitors of fatty acid cyclooxygenase or superoxide dismutase. Whether or not interferon-associated lipid changes directly participate in interferon action is not yet clear. Apparent diversity in its mechanistic approach to virus inhibition may be the key to the success of interferon as a wide-spectrum antiviral agent. Heterogeneity in molecular species of interferon may signify its molecular evolutionary adaptations to specific needs and the eventual development of a "fool-proof" system that we now perceive as the "interferon-system." The observed pleotropic effects may be due to linkage to a broader cellular machinery that operates to identify and effectively handle "foreign" substances.
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PMID:Interferon-induced biochemical changes in cell membranes: possible role of cellular enzyme superoxide dismutase. 619 67

Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decreased NO (and hence cGMP) levels following pulmonary reperfusion, leading to increased pulmonary vascular resistance and leukostasis. Using an orthotopic rat model of lung transplantation, a porphyrinic microsensor was used to make direct in vivo measurements of pulmonary NO. NO levels measured at the surface of the transplanted lung plummeted immediately upon reperfusion, with levels moderately increased by topical application of superoxide dismutase. Because cGMP levels declined in preserved lungs after reperfusion, this led us to buttress the NO pathway by adding a membrane-permeant cGMP analog to the preservation solution. Compared with grafts stored in its absence, grafts stored with supplemental 8-Br-cGMP and evaluated 30 min after reperfusion demonstrated lower pulmonary vascular resistances with increased graft blood flow, improved arterial oxygenation, decreased neutrophil infiltration, and improved recipient survival. These beneficial effects were dose dependent, mimicked by the type V phosphodiesterase inhibitor 2-o-propoxyphenyl-8-azapurin-6-one, and inhibited by a cGMP-dependent protein kinase antagonist, the R isomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate. Augmenting the NO pathway at the level of cGMP improves graft function and recipient survival following lung transplantation.
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PMID:The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation. 752 50

Heme-hemopexin or cobalt protoporphyrin (CoPP)-hemopexin (a model ligand for hemopexin receptor occupancy) is shown to increase transcription of the metallothionein-1 (MT-1) gene by activation of a signaling pathway. Promoter deletion analysis followed by transient transfection assays show that 110 base pairs (-153 to -43) of 5'-flanking region of the murine MT-1 promoter are sufficient for increasing transcription in response to heme-hemopexin or to CoPP-hemopexin in mouse hepatoma cells. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), prevented the increase in MT-1 transcription by heme-hemopexin, CoPP-hemopexin, or phorbol 12-myristate 13-acetate, but the protein kinase A inhibitor, HA1004, was without effect. N-Acetylcysteine (NAC) and glutathione, as well as superoxide dismutase and catalase, inhibited both the increase in endogenous MT-1 mRNA and the activation of reporter gene activity by heme-hemopexin, CoPP-hemopexin, and phorbol 12-myristate 13-acetate. In sum, these data suggest that reactive oxygen intermediates are generated by heme-hemopexin via events associated with receptor binding, including protein kinase C activation. Induction of heme oxygenase-1 expression, in contrast to MT-1, is significantly less sensitive to NAC. Deletion and mutation analyses of the MT-1 proximal promoter revealed that the sequence 5'-GTGACTATGC-3' (from -98 to -89 base pairs) is, in part, responsible for the hemopexin-mediated regulation of MT-1 which is inhibited by H7. Regulation via this element is also induced by H2O2 showing that it is an antioxidant response element. Heme itself acts via more distal elements on the MT-1 promoter. In contrast to NAC and glutathione, diethyl dithiocarbamate and pyrrolidine dithiocarbamate, which inactivate reactive oxygen intermediates and chelate Zn(II), synergistically augment the induction of MT-1 mRNA levels and reporter gene activity in response to heme-hemopexin via the antioxidant response element by both metal-responsive element-dependent and -independent mechanisms.
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PMID:Mechanism of metallothionein gene regulation by heme-hemopexin. Roles of protein kinase C, reactive oxygen species, and cis-acting elements. 759 95

1. Zinc-protoporphyrin-IX (ZnPP-IX) is an inhibitor of the enzyme heme-oxygenase-2 (HO-2) and consequently has been used to examine the role of carbon monoxide production in neural tissues. We have measured voltage-gated Ca current in AtT-20 pituitary cells using the whole-cell patch-clamp technique and have assessed the effects of extracellularly applied ZnPP-IX and related compounds. 2. Ca currents evoked by depolarizing steps from a holding potential of -90 mV were of the high-threshold, slowly inactivating type. Fifty-six percent of this current was blocked by 10 microM nifedipine and 16% by 3 microM omega-conotoxin with the remainder resistant to both drugs in combination, suggesting that the total Ca current was a mixture of L, N, and possibly P-type conductances. 3. Bath application of ZnPP-IX resulted in an irreversible, dose-dependent attenuation of Ca current. Five micromolar ZnPP-IX produced a 62% reduction of peak current amplitude with no shift in the current-voltage relation, 0.5 microM produced a 19% reduction, and 0.05 microM produced a variable response, either a small transient attenuation or potentiation. 4. The attenuation of Ca current by 5 microM ZnPP-IX could be nearly completely blocked by co-application of superoxide dismutase in the bath (90 U/ml) but not by addition of an inhibitor of cGMP-dependent protein kinase to the internal saline (KT5823, 1 microM). 5. Other inhibitors of heme-oxygenase with similar potency such as tin-protoporphyrin-IX (Sn-PP-IX) and Zn-deuteroporphyrin-bis-glycol (ZnBG) did not attenuate Ca current when applied at 5microM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Protoporphyrins modulate voltage-gated Ca current in AtT-20 pituitary cells. 790 35

The effect of an inhibitor of protein kinase, HA1077 [1-(5-isoquinolinesulfonyl)-homopiperazine HCl], and its hydroxylated metabolite, HA1100, on the activation of NADPH oxidase in human neutrophils were studied. Cells were preincubated with each drug for 10 min and then activated by treatment with phorbol myristate acetate (PMA) or formylmethionyl leucyl phenylalanine (FMLP). After activation, the rate of superoxide dismutase-inhibitable reduction of cytochrome c was estimated. HA1077 and HA1100 inhibited the PMA-induced production of O2- by neutrophil NADPH oxidase in a concentration-dependent manner (IC50 = 15 and 24 microM, respectively). The sensitivity of the FMLP-induced production of O2- to these drugs was similar. The production of O2- in 1,25-dihydroxyvitamin D3-treated HL-60 cells, which differentiated to macrophage-like cells, was also inhibited by the drugs. The extent of inhibition by HA1077 was almost the same as that by a calmodulin inhibitor (W-7) and by inhibitors of protein kinase (H-7 and H-8). In a cell-free lysate of neutrophils, the NADPH-dependent production of O2- can be induced by sodium dodecyl sulfate (SDS). HA1077 at 100 microM had only a weak inhibitory effect on the cell-free, SDS-induced production of O2-, an indication that HA1077 inhibits the activation of NADPH oxidase, not the actual activity. The effects of H-7 and H-8 were similar to that of HA1077, whereas W-7 inhibited the production of O2- by the cell-free extract of HL-60 cells. This action of HA1077 could explain, in part, its ability to protect neuronal cells from death after ischemia.
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PMID:Inhibition by the protein kinase inhibitor HA1077 of the activation of NADPH oxidase in human neutrophils. 824 Apr

Ischemia and reperfusion lead to the rapid induction of proto-oncogenes in the heart and subsequent induction of genes with cardioprotective functions. The activity of the transcription factors c-Jun and ATF-2 can be stimulated by activation of c-Jun amino-terminal kinase (JNK) in response to a variety of stresses. Here we show that ischemia and reperfusion led to the activation of JNK and also of the distantly-related mitogen activated protein kinase (MAPK). Activation of JNK, but not (MAPK), was abolished by removal of calcium from the perfusate immediately prior to ischemia. In contrast, infusion of the hydrogen peroxide scavenger catalase abolished activation of MAPK in response to ischemia and reperfusion, but activation of JNK was inhibited significantly by catalase only when superoxide dismutase was also present. Hydrogen peroxide infusion activated MAPK but not JNK, supporting a role for hydrogen peroxide produced during reperfusion in MAPK activation. We conclude that while ischemia and reperfusion activate both JNK and MAPK, the mechanisms of activation are different for the 2 kinases. Activation of these kinases is likely to contribute to altered gene expression in response to ischemia and reperfusion.
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PMID:Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat heart. 857 81


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