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)

Mitogen activation of human peripheral lymphocytes leads to a switch in the isozymes of LDH; resting cells contain low activities of only the B4 and B3A forms, whereas activated cells contain high activities of the A4 and A3B forms. B4 LDH is not altered in activated cells. In this study we show that the appearance of the A subunits occurs concomitantly with a several fold increase in the steady state levels of LDH-A mRNA. Responses in LDH-A mRNA are observed within 12 hrs of activation, and are, thus, associated with the G0/G1 transition or with early G1 (Marjanovic et al. Exp. Cell Res. (1991) 193: 425-431). Maximal expression of LDH-A mRNA requires both phorbol ester and concanavalin A, implying a complex regulatory pathway involving cascade systems activated through both the antigen receptor (TR) and protein kinase C.
 ...
PMID:Regulation of the expression of lactate dehydrogenase isozymes in human lymphocytes. 158 5

During T-lymphocyte differentiation in the thymus, the majority of thymocytes die by apoptosis in situ. This process is characterized by internucleosomal DNA fragmentation and is induced by a number of stimuli including glucocorticoids, calcium ionophore, cAMP and 12-o-tetradecanoylphorbol 13-acetate (TPA). In this study, the effect of cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon gamma (IFN-gamma) on the programmed cell death of thymocytes was examined by measuring DNA fragmentation and LDH release. TNF-alpha and IFN-gamma had no effect on DNA fragmentation in control and TPA, or A23187-treated thymocytes. Both human and murine rTNF-alpha enhanced cAMP-induced programmed cell death dose-dependently, but IFN-gamma had no effect on the process. TNF-alpha did not stimulate cAMP accumulation in control or 2-chloroadenosine-treated thymocytes. TPA markedly stimulated cAMP-induced DNA fragmentation as a result of 6 h incubation, whereas TNF-alpha did not. Thus TNF-alpha did not appear to activate protein kinase C directly. The effect of TNF-alpha was observed in the cell preparations from which adherent cells had been removed, suggesting that cytokines secreted by adherent cells in response to TNF-alpha are not involved in the process. The enhancement of cAMP-induced DNA fragmentation was observed in CD4+CD(8+)-double positive cells, but not in CD4+CD(8-)-single positive cells. The results of the present study indicate that a physiological cytokine, TNF-alpha, may modulate programmed cell death in immature thymocytes in concert with cAMP.
 ...
PMID:Tumour necrosis factor-alpha enhances cAMP-induced programmed cell death in mouse thymocytes. 826 Jun

The effects of the inhibitors of topoisomerase I and II, camptothecin and etoposide, as well as novobiocin and adriamycin, on the DNA fragmentation and viability of mouse thymocytes in primary culture were examined. All inhibitors were shown to produce dose-dependent internucleosomal DNA cleavage by resolving isolated DNA by agarose-gel electrophoresis. The DNA fragmentation seemed to precede cell death, determined on the basis of LDH release, by a few hours. Etoposide-induced DNA fragmentation progressively increased after incubation and was enhanced by pretreatment with phorbol 12,13-dibutyrate, a phorbol ester capable of activating protein kinase C, whereas camptothecin-induced DNA fragmentation increased progressively after 12 h incubation and was unaffected by phorbol 12,13-dibutyrate-pretreatment. The process was also energy-dependent and required RNA and protein synthesis and protein phosphorylation, since it was inhibited by sodium azide, actinomycin D, cycloheximide and 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine hydrochloride, a protein kinase inhibitor. DNA fragmentation was also inhibited by zinc ions, suggesting the involvement of a specific endonuclease in DNA cleavage. These phenomena are similar to those detected in thymocytes undergoing apoptosis following exposure to glucocorticoids (Cohen, J.J. and Duke, R.C. (1984) J. Immunol. 132, 38-42). Considering that topoisomerases function in cellular proliferation and differentiation by altering DNA topology, the results suggest that topoisomerases have important roles in T-lymphocyte ontogeny in the thymus and are in part involved in the elimination of autoreactive or harmful cells by an apoptotic process.
 ...
PMID:Topoisomerase inhibitors induce apoptosis in thymocytes. 838 Mar 39

We tested the hypothesis that anoxic preconditioning could protect coronary endothelial cells against anoxic and reoxygenation injury and that this preconditioning effect could be mediated by an adenosine A2 receptor via the protein kinase C (PKC) pathway. Cells were preconditioned with 10-minute anoxia and 10-minute reoxygenation and were then subjected to anoxia for 60 minutes, followed by 120 minutes of reoxygenation. In some groups, the preconditioning effect was prevented by 8-sulfophenyltheophylline (SPT [50 mumol/L], a nonselective adenosine receptor antagonist), or calphostin C (100 nmol/L, a PKC inhibitor). In other groups, 2-p-(2-carboxyethyl)phenethylamino-5'N-ethylcarboxyamido- adenosine (CGS-21680 [20 nmol/L], an adenosine A2 receptor agonist, R-(--)-N6-(2-phenylisopropyl)-adenosine (R-PIA [50 nmol/L], an adenosine A1 receptor agonist), or 4 beta-phorbol 12-myristate 13-acetate (PMA [100 nmol/L], a PKC activator) was given as a pretreatment to mimic the preconditioning effect. Endothelial cells were also pretreated with 100 nmol/L calphostin C to confirm whether inhibition of PKC can block the effects of adenosine A2 receptor activation by CGS-21680 on anoxia and reoxygenation injury. Preconditioning reduced LDH release, increased adenosine release, promoted translocation of PKC from cytosol to membrane, increased cell viability, and preserved ATP content and cell morphology. Pretreatment with either CGS-21680 or PMA resulted in protection similar to that seen with anoxic preconditioning. The protection was totally abolished by SPT or calphostin C. The results suggest that (1) preconditioning protects coronary endothelial cells against anoxia and reoxygenation injury, (2) the protection is probably mediated by activation of adenosine A2 receptors through the PKC pathway, and (3) the preservation of endothelial cells may be one of the mechanisms of myocardial preconditioning.
 ...
PMID:Preconditioning of bovine endothelial cells. The protective effect is mediated by an adenosine A2 receptor through a protein kinase C signaling pathway. 860 8

Excess vascular oxidative stress has been linked to impaired endothelium-dependent arterial relaxation in hypercholesterolemia. alpha-Tocopherol (AT) preserves endothelial function in hypercholesterolemia although the mechanism(s) for this protective effect is (are) not known. We examined the tissue-specific effects of AT on oxidized LDL (ox-LDL)-mediated endothelial dysfunction in male New Zealand White rabbits. Animals consumed chow deficient in (< 10 IU/kg) or supplemented with (1,000 IU/kg) AT for 28 d. Exposure of thoracic aortae from AT-deficient animals to ox-LDL (0-500 microg/ml) for 4 h produced dose-dependent inhibition of acetylcholine-mediated relaxation (P < 0.05) while vessels derived from animals consuming AT were resistant to ox-LDL-mediated endothelial dysfunction. Animals consuming AT demonstrated a 100-fold increase in vascular AT content and this was strongly correlated with vessel resistance to endothelial dysfunction from ox-LDL (R = 0.67; P = 0.0014). These results were not explained by an effect of AT on ox-LDL-mediated cytotoxicity by LDH assay or scanning electron microscopy. Vascular incorporation of AT did produce resistance to endothelial dysfunction from protein kinase C stimulation, an event that has been implicated in the vascular response to ox-LDL. Human aortic endothelial cells loaded with AT also demonstrated resistance to protein kinase C stimulation by both phorbol ester and ox-LDL. Thus, these data indicate that enrichment of vascular tissue with AT protects the vascular endothelium from ox-LDL-mediated dysfunction, at least in part, through the inhibition of protein kinase C stimulation. These findings suggest one potential mechanism for the observed beneficial effect of AT in preventing the clinical expression of coronary artery disease that is distinct from the antioxidant protection of LDL.
 ...
PMID:Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation. 875 49

In the present study, we investigated the regulatory action of tumor necrosis factor-alpha (TNFalpha) on lactate dehydrogenase A (LDH A), a key enzyme involved in lactate production. To this end, use was made of a primary culture system of porcine testicular Sertoli cells. TNFalpha stimulated LDH A messenger RNA (mRNA) expression in a dose (ED50 = 2.5 ng/ml; 0.1 nM TNFalpha)-dependent manner. This stimulatory effect was time dependent, with an effect detected after 6 h of TNFalpha treatment and maximal after 48 h of exposition (5-fold; P<0.001). The direct effect of TNFalpha on LDH A mRNA could not be accounted for by an increase in mRNA stability (half-life = 9 h), but was probably due to an increase in LDH A gene transcription. Inhibitors of protein synthesis (cycloheximide), gene transcription (actinomycin D and dichlorobenzimidazole riboside), tyrosine kinase (genistein), and protein kinase C (bisindolylmaleimide) abrogated completely (actinomycin D, dichlorobenzimidazole riboside, cycloheximide, and genistein) or partially (bisindolylmaleimide) TNFalpha-induced LDH A mRNA expression. These observations suggest that the stimulatory effect of TNFalpha on LDH A mRNA expression requires protein synthesis and may involve a protein tyrosine kinase and protein kinase C. In addition, we report that LDH A mRNA levels were increased in Sertoli cells treated with FSH. However, although the cytokine enhances LDH A mRNA levels through increased gene transcription, the hormone exerts its stimulatory action through an increase in LDH A mRNA stability. The regulatory actions of the cytokine and the hormone on LDH A mRNA levels and therefore on lactate production may operate in the context of the metabolic cooperation between Sertoli and postmeiotic germ cells in the seminiferous tubules.
 ...
PMID:Tumor necrosis factor-alpha stimulates lactate dehydrogenase A expression in porcine cultured sertoli cells: mechanisms of action. 1038 97

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.
 ...
PMID:Epidermal growth factor regulates glucose metabolism through lactate dehydrogenase A messenger ribonucleic acid expression in cultured porcine Sertoli cells. 1049 55

The present study is designed to investigate the mechanism of the cardioprotective effect of ischaemic preconditioning. Isolated perfused rat heart was subjected to global ischaemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analysed for LDH and CK release to assess the degree of cardiac injury. Myocardial infarct size was estimated macroscopically using TTC staining. Four episodes of ischaemic preconditioning markedly reduced LDH and CK release in the coronary effluent and decreased myocardial infarct size. Administration of prazosin (alpha(1)adrenoceptor antagonist) before global ischaemia reduced the extent of ischaemia-reperfusion induced myocardial injury. The cardioprotective effect of ischaemic preconditioning was abolished by prazosin and colchicine (microtubule disaggregator). On the basis of these results, it may be concluded that the cardioprotective effects of ischaemic preconditioning may be mediated through stimulation of alpha(1)adrenoceptors and translocation of PKC.
 ...
PMID:Possible mechanism of cardioprotective effect of ischaemic preconditioning in isolated rat heart. 1081 32

Release of neurotransmitters, including dopamine and glutamate, has been implicated in hypoxia/ischemia-induced alterations in neuronal function and in subsequent tissue damage. Although extensive studies have been done on the mechanism underlying the changes in glutamate release, few have examined the mechanism that is responsible for the changes in catecholamines. Rat pheochromocytoma-12 (PC12) cells synthesize, store, and release catecholamines including DA and NE. Therefore, we used HPLC and ED to evaluate extracellular DA and NE concentrations in a medium during chemical hypoxia in PC12 cells. Chemical hypoxia produced by KCN induced differential release of DA and NE. Under normal glucose conditions, KCN induced release of NE, but not DA. Under glucose-free conditions, KCN-induced release of DA was elevated transiently, whereas the release of NE increased progressively. Under parallel conditions, KCN biphasically elevated the level of cytosolic free calcium ([CA(2+)](i)) in glucose-free DMEM, peaking at 95 +/- 18 nM at 1,107 +/- 151 s, followed by a new plateau level at 249 +/- 24 nM sustained from 4,243 +/- 466 to 5,263 +/- 440 s. Cell toxicity, as measured by LDH release, was increased significantly by KCN in glucose-free DMEM but was diminished in the presence of glucose, and was correlated with DA release by chemical hypoxia. The protein kinase C (PKC) inhibitor GO6976 or staurosporine inhibited KCN-induced LDH release as well as the release of NE and DA. Taken together, selective activation of DA but not NE was correlated with the LDH release by chemical hypoxia, and was diminished with GO6976 or staurosporine. These results suggest that selective activation of PKC isoforms is involved in the chemical hypoxia-induced DA release, which may lead to neuronal cell toxicity.
 ...
PMID:Differential alteration of catecholamine release during chemical hypoxia is correlated with cell toxicity and is blocked by protein kinase C inhibitors in PC12 cells. 1096 47

Activation of protein kinase C (PKC) and more recently mitogen-activated protein kinases (MAPKs) have been associated with the cardioprotective effect of ischemic preconditioning. We examined the interplay between these kinases in a characterized model of ischemic preconditioning in cultured rat neonatal ventricular cardiocytes where ectopic expression of active PKC-delta results in protection. Two members of the MAPK family, p38 and p42/44, were activated transiently during preconditioning by brief simulated ischemia/reoxygenation. Overexpression of active PKC-delta, rather than augmenting, completely abolished this activation. We therefore determined whether a similar process occurred during lethal prolonged simulated ischemia. In contrast to ischemia, brief, lethal-simulated ischemia activated only p38 (2.8+/-0.45 vs. basal, P<0.01), which was attenuated by expression of active PKC-delta or by preconditioning (0.48+/-0.1 vs. ischemia, P<0.01). To determine whether reduced p38 activation was the cause or an effect of protection, we used SB203580, a p38 inhibitor. SB203580 reduced ischemic injury (CK release 38.0+/-3.1%, LDH release 77.3+/-4.0%, and MTT bioreduction 127.1+/-4.8% of control, n=20, P<0.05). To determine whether p38 activation was isoform selective, myocytes were infected with adenoviruses encoding wild-type p38alpha or p38beta. Transfected p38alpha and beta show differential activation (P<0.001) during sustained simulated ischemia, with p38alpha remaining activated (1.48+/-0.36 vs. basal) but p38beta deactivated (0.36+/-0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38alpha (0.65+/-0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38alpha, which prevented ischemic p38 activation, were resistant to lethal simulated ischemia (CK release 82.9+/-3.9% and MTT bioreduction 130.2+/-6.5% of control, n=8, P<0.05). Thus, inhibition of p38alpha activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.
 ...
PMID:The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. 1105 45


1 2 3 4 5 Next >>