EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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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 that anoxic preconditioning (APC) has protective effects not only on cardiomyocyte, but also on vasculature. However, the effects of APC on vascular smooth muscle cells (VSMC) is unknown. On the model of anoxia/reoxygenation (A/R) injury of rabbit VSMC, the effect of APC was observed. It was found that APC could increase the survival rate of VSMC after A/R injury, lower the leakage of lactate dehydrogenase (LDH) and protein from cells, and attenuate peroxidation injury and calcium overload of VSMC. The results also showed that PMA, an activator of protein kinase C (PKC), could mimic, but H7 or polymyxin B (inhibitors of PKC) could abolish the above protective effect of APC. It is suggested that the protective effect of APC on VSMC during A/R injury might be due to the activation of PKC.
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PMID:[Protein kinase C involved in the protecttve effect of anoxic preconditioning on vascular smooth muscle cells]. 1007 63

Using conscious rabbits, we examined the effect of ischemic preconditioning (PC) on p44 and p42 mitogen-activated protein kinases (MAPKs). We found that both isoforms contribute significantly to total MAPK activity in the heart (in-gel kinase assay: p44, 59 +/- 1%; p42, 41 +/- 1%). Ischemic PC (6 cycles of 4-min occlusion/4-min reperfusion) elicited a pronounced increase in total cellular MAPK activity (+89%). This increase, which occurred exclusively in the nuclear fraction, was contributed by both isoforms (in-gel kinase assay: p44, +97%; p42, +210%) and was accompanied by migration of the two proteins from the cytosolic to the nuclear compartment. In control rabbits, MAPK kinase (MEK)1 and MEK2, direct activators of p44 and p42 MAPKs, were located almost exclusively in the cytosolic fraction. Ischemic PC induced a marked increase in cytosolic MEK activity (+164%), whereas nuclear MEK activity did not change, indicating that MEK-induced activation of MAPKs occurred in the cytosolic compartment. Activation of MAPKs after ischemic PC was completely blocked by the protein kinase C (PKC) inhibitor chelerythrine. Selective overexpression of PKC-epsilon in adult rabbit cardiomyocytes induced activation of both p44 and p42 MAPKs and reduced lactate dehydrogenase release during simulated ischemia-reperfusion, which was abolished by the MEK inhibitor PD-98059. The results demonstrate that 1) ischemic PC induces a rapid activation of p44 and p42 MAPKs in hearts of conscious rabbits; 2) the mechanism of this phenomenon involves activation of p44 and p42 MAPKs in the cytosol and their subsequent translocation to the nucleus; and 3) it occurs via a PKC-mediated signaling pathway. The in vitro data implicate PKC-epsilon as the specific isoform responsible for PKC-induced MAPK activation and suggest that p44/p42 MAPKs contribute to PKC-epsilon-mediated protection against simulated ischemia. The results are compatible with the hypothesis that p44 and p42 MAPKs may play a role in myocardial adaptations to ischemic stress.
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PMID:PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. 1033 Feb 29

Growing evidence exists that ATP-sensitive mitochondrial potassium channels (MitoKATP channel) are a major contributor to the cardiac protection against ischemia. Given the importance of mitochondria in the cardiac cell, we tested whether the potent and specific opener of the MitoKATP channel diazoxide attenuates the lethal injury associated with Ca2+overload. The specific aims of this study were to test whether protection by diazoxide is mediated by MitoKATP channels; whether diazoxide mimics the effects of Ca2+ preconditioning; and whether diazoxide reduces Ca2+ paradox (PD) injury via protein kinase C (PKC) signaling pathways. Langendorff-perfused rat hearts were subjected to the Ca2+ PD (10 minutes of Ca2+ depletion followed by 10 minutes of Ca2+ repletion). The effects of the MitoKATP channel and other interventions on functional, biochemical, and pathological changes in hearts subjected to Ca2+ PD were assessed. In hearts treated with 80 micromol/L diazoxide, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca2+ PD; peak lactate dehydrogenase release was also significantly decreased, although ATP content was less depleted. The cellular structures were well preserved, including mitochondria and intercalated disks in diazoxide-treated hearts compared with nontreated Ca2+ PD hearts. The salutary effects of diazoxide on the Ca2+ PD injury were similar to those in hearts that underwent Ca2+ preconditioning or pretreatment with phorbol 12-myristate 13-acetate before Ca2+ PD. The addition of sodium 5-hydroxydecanoate, a specific MitoKATP channel inhibitor, or chelerythrine chloride, a PKC inhibitor, during diazoxide pretreatment completely abolished the beneficial effects of diazoxide on the Ca2+ PD. Blockade of Ca2+ entry during diazoxide treatment by inhibiting L-type Ca2+ channel with verapamil or nifedipine also completely reversed the beneficial effects of diazoxide on the Ca2+ PD. PKC-delta was translocated to the mitochondria, intercalated disks, and nuclei of myocytes in diazoxide-pretreated hearts, and PKC-alpha and PKC-epsilon were translocated to sarcolemma and intercalated disks, respectively. This study suggests that the effect of the MitoKATP channel is mediated by PKC-mediated signaling pathway.
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PMID:Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium. 1034 90

The mechanisms of neuronal degeneration following hypoxia/ischemia remain undefined, but the processes include increases in neurotransmitter release, elevation of cytosolic-free calcium concentration, and changes in signal transduction pathways. Activation of the multigene family of protein kinase C (PKC) has been associated with the release of neurotransmitter and the survival of neurons. Therefore, to understand which PKC isozymes are involved in hypoxia/ischemia-induced neuronal degeneration, we examined PKC isozymes after chemical hypoxia (i.e., KCN exposure) in PC12 cells. Cell toxicity, as measured by lactate dehydrogenase (LDH) release, was increased significantly by KCN in glucose-free DMEM and was exaggerated by acute 12-O-tetradecanoyl phorbol-13-acetate (TPA) pretreatment. Under parallel conditions, KCN elevated cytosolic-free calcium ([Ca2+]i) in glucose-free but not in glucose containing DMEM, and TPA pretreatment did not exaggerate KCN's effect on [Ca2+]i. Thus, increases in [Ca2+]i are not sufficient for the synergistic toxic effect of KCN and TPA. In the glucose-free DMEM, selective PKC isozyme inhibitor Go 6976 at 10 nM completely inhibited KCN-induced LDH release and at higher concentrations (1 microM) inhibited the basal levels of LDH release. The protein levels of PKCs in the nuclear, membrane, and cytosolic fractions were measured by Western blot analysis using antibodies against specific isoforms. Two Ca2+-dependent (-alpha, -gamma) and four Ca2+-independent (-delta, -epsilon, -zeta, and -lambda) isozymes were identified and two isozymes (-beta and -theta) were not detected in the subcellular fractions of PC12 cells. Treatment of the cells with TPA significantly activated translocation of conventional PKC-gamma from the cytosol to the membrane and nuclear fractions and other PKC isozymes (-alpha, -delta, and -epsilon) from the cytosol to the membrane, but not atypical PKC-zeta and -lambda. Although only the levels in the nuclear PKC-gamma but not other PKC isozymes were increased significantly following KCN, the levels of cPKC-alpha and -gamma in the membrane mainly- and those and PKC-epsilon in the nucleus-were increased when KCN was combined with TPA. In addition, this condition (TPA + KCN) did not affect the TPA insensitive atypical isozymes, PKC-zeta or -lambda. Taking the results together, differential activation/translocation of PKC isozymes by KCN and TPA is important in the regulation of chemical hypoxia-induced cell injury in PC12 cells.
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PMID:Selective subcellular redistributions of protein kinase C isoforms by chemical hypoxia. 1037 22

Cellular adaptation to hypoxia involves regulation of specific genes such as vascular endothelial growth factor (VEGF), erythropoietin (EPO) and hypoxia inducible factor (HIF)-1 . In this study, we have evaluated the protective effect of picroliv (a purified iridoid glycoside fraction from roots of Picrorhiza kurrooa with hepatoprotective, anti-inflammatory and antioxidant properties) against hypoxic injury by examining lactate dehydrogenase (LDH) release in Hep 3B and Glioma cells. The expression of hypoxia regulated genes, VEGF and HIF-1 was studied in human umbilical vein endothelial cells (HUVEC), Hep 3B and Glioma cells. Picroliv reduced the cellular damage caused by hypoxia as revealed by a significant reduction in LDH release compared to untreated control. The expression of VEGF and HIF-1 subunits (HIF-1alpha and HIF-1beta) was enhanced by treatment with picroliv during normoxia and hypoxia in HUVEC and Hep 3B cells and on reoxygenation the expression of these genes was significantly reduced as revealed by mRNA analysis using RT-PCR. Simultaneous treatment with picroliv during hypoxia inhibited VEGF and HIF-1 expression in Glioma cells whereas the expression was not reduced by picroliv treatment during reoxygenation as evidenced by both RT-PCR and Northern hybridization. VEGF expression as revealed by immunofluorescence studies correlates well with the regulations observed in the mRNA expression. We have also examined the kinase activity of tyrosine phosphorylated proteins and protein kinase C (PKC) in Glioma cells treated with picroliv during hypoxia/reoxygenation. A selective inhibition of protein tyrosine kinase activity leading to tyrosine dephosphorylation of several proteins including 80 kd protein, and a reduction in PKC was seen in cells treated with picroliv and hypoxia. These findings suggest that picroliv may act as a protective agent against hypoxia/reoxygenation induced injuries, and the underlying mechanism may involve a novel signal transduction pathway.
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PMID:Picroliv -- a natural product protects cells and regulates the gene expression during hypoxia/reoxygenation. 1039 Nov 50

We investigated the relationship between tension development and the cytosolic free Ca2+ level ([Ca2+]i) on exposure of the endothelium-denuded isolated rat aorta to palmitoyl-L-alpha-lysophosphatidylcholine. Lysophosphatidylcholine concentration-dependently induced a gradual increase in [Ca2+]i. Application of 10(-4) M lysophosphatidylcholine induced a large and sustained tonic increase in [Ca2+]i (the peak [Ca2+]i was 125.2 +/- 11.5% of the 80 mM K+-induced response) but only a small contraction (4.0 +/- 1.4% of the 80 mM K+ induced contraction). The sustained increase in [Ca2+]i was attenuated when extracellular Ca2+ was removed but it was unaffected by verapamil or 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H-7). Digitonin also produced a gradual increase in [Ca2+]i but with a pronounced contraction. Triton X-100 (0.1%) produced a marked elevation in [Ca2+]i with no detectable contraction. Triton X-100, however, caused a rapid leakage of fura PE-3. Treatment with 10(-4) M lysophosphatidylcholine for 1 or 2 h did not affect the contractile response induced by 80 mM K+ and this treatment did not release lactate dehydrogenase from the rat aorta. Treatment with lysophosphatidylcholine did not affect either the cyclic AMP level or the cyclic GMP level in endothelium-denuded aortic tissues. These results show that in the rat aorta lysophosphatidylcholine produces a large increase in [Ca2+]i (possibly in a non-contractile compartment) which does not induce contraction. Thus, the increase in [Ca2+]i induced by lysophosphatidylcholine (i) requires external Ca2+ but is not due to an increased Ca2+ influx through voltage-dependent L-type Ca2+ channels, (ii) is not primarily due to protein kinase C activation and (iii) is probably not due to a detergent action (like those of digitonin and triton X-100). The relative lack of a contractile response to lysophosphatidylcholine is not due to formation of cyclic AMP or cyclic GMP.
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PMID:Marked dissociation between intracellular Ca2+ level and contraction on exposure of rat aorta to lysophosphatidylcholine. 1047 30

In a previous work, we reported that lactate dehydrogenase A4 (LDH A4) activity is a key step in the stimulatory effect of epidermal growth factor (EGF) on lactate production in cultured Sertoli cells. Here, we further investigated the regulatory mechanisms involved in EGF action on LDH A mRNA expression. Steady-state levels of LDH A mRNA analyzed by Northern blot hybridization were induced to 2. 9-fold in response to a 36-h incubation with EGF (ED(50) = 4 ng/ml, 0.63 x 10(-9) M). Whether EGF-induced increases of LDH A mRNA levels are the result of increased transcription and/or altered mRNA stability was investigated. The decay curves for the 1.5-kilobase LDH A mRNA transcript in Sertoli cells were not different in the absence or presence of EGF, suggesting that EGF did not affect LDH A mRNA stability. Inhibitors of protein synthesis (cycloheximide) and RNA synthesis (actinomycin D, and 5,6-dichloro-1-beta-ribofuranosyl benzimidazole) completely abrogated the EGF-induced LDH A mRNA expression, indicating that EGF increased LDH A mRNA levels through a transcriptional mechanism, which probably involves protein synthesis. Finally, the partial inhibitory effect of a protein kinase C (PKC) inhibitor, bisindolylmaleimide, on EGF-stimulated LDH A mRNA supports a partial involvement of PKC in the action of the growth factor. Since EGF is produced in Sertoli and in germ cells, its action is probably exerted in a context of a local control. As EGF also regulates other parameters involved in glucose metabolism, its effect on LDH A might be viewed in a general context related to the control of energy metabolism by the growth factor in the testicular cells.
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PMID:Epidermal growth factor regulates glucose metabolism through lactate dehydrogenase A messenger ribonucleic acid expression in cultured porcine Sertoli cells. 1049 55

Besides playing an important role in the maintenance of cell membrane phospholipids, phospholipases A2 (PLA2) are responsible for the release of arachidonic acid (AA) which is a precursor for prostaglandin biosynthesis. The cytosolic PLA2 has been the focus of recent studies, probably due to its ability to respond to protein kinases and changes in intracellular calcium levels. In this study, we examined agents for stimulation of the cytosolic phospholipase A2 in immortalized astrocytes (DITNC). Incubation of DITNC cells with [14C]arachidonic acid (AA) resulted in a time-dependent uptake of the label into phospholipids (PL) and neutral glycerides. In prelabeled cells, release of labeled AA could be stimulated by calcium mobilizing agents such as calcium ionophore A23187 (4-20 microM) and thimerosal (100 microM), and by phorbol myristate acetate (PMA, 100 nM), an agent for activation of protein kinase C. The release of AA could also be stimulated by ATP (200 microM), probably through activation of the purinergic receptor but not by glutamate (1 mM). The stimulated release of AA was dependent on extracellular Ca2+ and was inhibited by mepacrine (50 microM), a non-specific PLA2 inhibitor. Western blot analysis further confirmed the presence of an 85 kDa cPLA2 in both membrane and cytosol fractions of these cells and stimulation by A23187 resulted in translocation of this protein to the membrane fraction. Besides labeled fatty acids, A23187 also stimulated the concomitant release of labeled PL into the culture medium and this event was accompanied by the increased release in lactate dehydrogenase (LDH). Results thus revealed that besides activation of cPLA2, the calcium ionophore A23187 is capable of perturbating cell membrane integrity.
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PMID:Studies on the cytosolic phospholipase A2 in immortalized astrocytes (DITNC) revealed new properties of the calcium ionophore, A23187. 1049 24

This study compares the effects of heat and osmotic stress on heat stress protein (HSP) production while examining the putative protective action of HSPs on modulation of Na(+),K(+),Cl(-) and Na(+),P(i) cotransporters in Madin-Darby canine kidney (MDCK) epithelial cells by severe heat stress (46 degrees C, 15 min). Preconditioning heat stress (43 degrees C, 20 min) followed by 4 h recovery at 37 degrees C led to a 35-fold increase of HSP70 mRNA expression measured by Northern blot analysis. The protein content of HSP70 and HSP27, assessed by Western blots, was augmented by 5- and 2-fold, respectively, after 6 h of recovery. In contrast to preconditioning heat stress, hyperosmotic stress (520 vs. 320 mosm) elevated HSP70 mRNA content only by 7-fold and did not significantly affect the protein content of HSP70 or HSP27. Neither cell survival, assessed as lactate dehydrogenase (LDH) release, nor the basal activities of the ion transporters and their modulation by protein kinase C, P(2)-purinoceptor and cell volume were altered by preconditioning heat stress. Severe heat stress increased extracellular LDH content from 3+/-2 to 23+/-5% and enhanced Na(+),K(+),Cl(-) and Na(+),P(i) cotransport activity by 2-3-fold. The volume- and protein kinase C-dependent regulation of these carriers was abolished by severe heat stress while regulation by P(2)-purinoceptors was preserved. Preconditioning heat stress diminished severe heat stress-induced LDH release to 11+/-4% but did not protect Na(+),K(+),Cl(-) and Na(+),P(i) cotransporters from activation by severe heat stress and did not prevent severe heat stress-induced inactivation of protein kinase C- and volume-dependent signaling pathways. These results show that in MDCK cells, preconditioning heat stress-induced HSPs are not involved in the regulation of Na(+),K(+),Cl(-) and Na(+),P(i) cotransporters and do not protect them from modulation by severe heat stress.
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PMID:Heat stress preconditioning does not protect renal epithelial Na(+),K(+),Cl(-) and Na(+),P(i) cotransporters from their modulation by severe heat stress. 1056 81

Activation of protein kinase C (PKC) and protein kinase A (PKA) in rat C6 glioma cells increases the half-life of short-lived lactate dehydrogenase (LDH)-A mRNA about 5- and 8-fold, respectively. PKA and PKC act synergistically and prolong LDH-A mRNA half-life more than 21-fold. Similar effects were observed after transfection and transcription of a globin/lactate dehydrogenase minigene consisting of a beta-globin expression vector in which the 3'-untranslated region (UTR) of beta-globin had been replaced with the LDH-A 3'-UTR. Synergism was only obtained by transcription of minigenes containing the entire 3'-UTR and did not occur when truncated 3'-UTR fragments were analyzed. Additional mutational analyses showed that a 20-nucleotide region, named PKC-stabilizing region (PCSR), is responsible for mediating the stabilizing effect of PKC. Previous studies (Tian, D., Huang, D., Short, S., Short, M. L., and Jungmann, R. A. (1998) J. Biol. Chem. 273, 24861-24866) have demonstrated the existence of a cAMP-stabilizing region in LDH-A 3'-UTR. Sequence analysis of PCSR identified a 13-nucleotide AU-rich region that is common to both cAMP-stabilizing region and PCSR. These studies identify a specific PKC-responsive stabilizing element and indicate that interaction of PKA and PKC results in a potentiating effect on LDH-A mRNA stabilization.
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PMID:Structural determinants for post-transcriptional stabilization of lactate dehydrogenase A mRNA by the protein kinase C signal pathway. 1077 97

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