Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of more than one dental alloy in the oral cavity often causes pathological galvanic currents and voltage resulting in superficial erosions of the oral mucosa and eventually in the emergence of oral cancer. In the present study the mechanisms of apoptosis of oral mucosa cancer cells in response to electromagnetic fields was investigated. Direct current (DC) electrical fields with field strengths between 2 and 16 V/m, applied for 24 h to UM-SCC-14-C oral mucosa cancer cells, dose-dependently resulted in decreased cell proliferation as evaluated by Ki-67 immunohistochemistry and upregulation of the cyclin-dependent kinase (CDK) inhibitors p21(cip1/waf1) and p27(kip1), which are associated with cell cycle arrest. Electrical field treatment (4 V/m, 24 h) increased apoptosis as evaluated by immunohistochemical analysis of cleaved caspase-3 and poly-(ADP-ribose)-polymerase-1 (PARP-1). Furthermore, robust reactive oxygen species (ROS) generation, increased expression of NADPH oxidase subunits as well as Hsp70 was observed. Electrical field treatment (4 V/m, 24 h) resulted in increased expression of Cu/Zn superoxide dismutase and decreased intracellular concentration of reduced glutathione (GSH), whereas the expression of catalase remained unchanged. Pre-treatment with the free radical scavenger N-acetyl cysteine (NAC) and the superoxide dismutase mimetic EUK-8 abolished caspase-3 and PARP-1 induction, suggesting that apoptosis in oral mucosa cancer cells is initated by ROS generation in response to DC electrical field treatment.
 ...
PMID:Direct current electrical fields induce apoptosis in oral mucosa cancer cells by NADPH oxidase-derived reactive oxygen species. 1778 77

This study investigated the inhibitory effects of 2'-benzoyloxycinnamaldehyde (BCA) on cancer cells, including various drug-resistant cancer cell lines. To observe this activity, the anticancer drug-resistant cell lines were established by continuously exposing the parental cells to 5-fluorouracil (5-FU) and cyclophosphamide (CDDP), and examining the cells with the MTT assay and flow cytometric analysis. The BCA treatment produced similar growth inhibitory effects and apoptotic cell death on the drug-resistant cancer cells as their parental cells. The activation of the p38-mitogen activated protein kinase, an increased level of reactive oxygen species (ROS) generation and downregulation of Bcl-2 were observed in both the drug resistant and non-drug resistant cell lines. The GSH treatment effectively inhibited BCA-induced apoptosis by blocking ROS generation, suggesting that ROS is a major regulator in BCA-induced apoptotic cell death. These results suggest that BCA can be a useful drug candidate for treating drug-resistant cells.
 ...
PMID:The activity of 2'-benzoyloxycinnamaldehyde against drug-resistant cancer cell lines. 1785 88

Endothelial nitric oxide synthase (eNOS) is regulated by phosphorylation of Ser(1177) and Thr(495), which affects NO bioavailability. Cigarette smoke disturbs the eNOS-cGMP-NO pathway and causes decreased NO production. Here the authors investigated the acute effects of cigarette smoke on eNOS phosphorylation, focusing on protein kinases (PKs). Endothelial cell culture was concentration- and time-dependently treated first with cigarette smoke buffer (CSB), then with reduced glutathione (GSH) or various PK inhibitors (H-89, LY-294002, Ro-318425, and ruboxistaurin). eNOS, phospho-Ser(1177)-eNOS, phospho-Thr(495)-eNOS, Akt(PKB), and phospho-Akt protein levels were determined by Western blot. CSB increased the phosphorylation of eNOS at Ser(1177) and more at Thr(495) in a concentration- and time-dependent manner (p < .01, p < .05 versus control, respectively) and resulted in the dissociation of the active dimeric form of eNOS (p < .05). GSH decreased the phosphorylation of eNOS at both sites (p < .05 versus CSB without GSH) and prevented the decrease of dimer eNOS level. CSB treatment also decreased the level of phospho-Ser(473)-Akt (p < .05 versus control). Inhibition of PKA by H-89 did not affect CSB-induced phosphorylation, whereas the PKB inhibitor LY-294002 enhanced it at Ser(1117). The PKC blockers Ro-318425 and ruboxistaurin augmented the CSB-induced phosphorylation at Ser(1177) but decreased phosphorylation at Thr(495) (p < .05 versus CSB). Cigarette smoke causes a disruption of the enzymatically active eNOS dimers and shifts the eNOS phosphorylation to an inhibitory state. Both effects might lead to reduced NO bioavailability. The shift of the eNOS phosphorylation pattern to an inhibitory state seems to be independent of the PKA and phosphoinositol 3-kinase (PI3-K)/Akt pathways, whereas PKC appears to play a key role.
 ...
PMID:Cigarette smoke-induced alterations in endothelial nitric oxide synthase phosphorylation: role of protein kinase C. 1792 42

Peroxynitrite-mediated damage has been linked to numerous neurological and neurodegenerative diseases, including stroke, Alzheimer's and Parkinson's Diseases, amyotrophic lateral sclerosis and multiple sclerosis. Studies on the toxic effects of peroxynitrite in neurons have focused primarily on adverse effects resulting from the nitration of cellular proteins as the principal mode of toxicity while the consequences of the modulation of kinase pathways by peroxynitrite have received relatively less attention. Our results show that treatment of primary rat neurons with the peroxynitrite donor, SIN-1, leads to decreases in glutathione (GSH) levels and cell viability via a novel extracellular-signal-related kinase (ERK)/c-Myc phosphorylation pathway and a reduction in the nuclear expression of NF-E2-related factor-2 (Nrf2) that down-regulate the expression of glutamate cysteine ligase, the rate limiting enzyme for GSH synthesis. The flavonoid fisetin protects against the SIN-1-mediated alterations in ERK/c-Myc phosphorylation, nuclear Nrf2 levels, glutamate cysteine ligase levels, GSH concentration and cell viability. We also show that inhibition of mitogen-activated protein kinase kinase or Raf kinase can increase GSH levels in unstressed primary rat neurons through the same ERK/c-Myc phosphorylation pathway. Together, these results demonstrate that distinct signaling pathways modulate GSH metabolism in unstressed and stressed cortical neurons.
 ...
PMID:Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons. 1804 13

Lead (Pb2+) is a cytotoxic metal ion in plants, the mechanism of which is not yet established. The aim of this study is to investigate the signalling pathways that are activated by elevated concentrations of Pb2+ in rice roots. Root growth was stunted and cell death was accelerated when exposed to different dosages of Pb2+ during extended time periods. Using ROS-sensitive dye and Ca2+ indicator, we demonstrated that Pb2+ induced ROS production and Ca2+ accumulation, respectively. In addition, Pb2+ elicited a remarkable increase in myelin basic protein (MBP) kinase activities. By immunoblot and immunoprecipitation analysis, 40- and 42-kDa MBP kinases that were activated by Pb2+ were identified to be mitogen-activated protein (MAP) kinases. Pre-treatment of rice roots with an antioxidant and a NADPH oxidase inhibitor, glutathione (GSH) and diphenylene iodonium (DPI), effectively reduced Pb2+-induced cell death and MAP kinase activation. Moreover, calcium-dependent protein kinase (CDPK) antagonist, W7, attenuated Pb2+-induced cell death and MAP kinase activation. These results suggested that the ROS and CDPK may function in the Pb2+-triggered cell death and MAP kinase signalling pathway in rice roots.
 ...
PMID:ROS and CDPK-like kinase-mediated activation of MAP kinase in rice roots exposed to lead. 1816 45

The recognition of peptide antigens by T cells through their antigen receptors (T cell receptors, or TCR), together with the ligation of additional surface molecules called costimulatory receptors, rapidly induces interactive signaling pathways that lead to transcriptional initiation at genes such as that of the autocrine growth factor interleukin 2 (IL-2). Activation of the ERK and JNK subfamilies of MAPK mediates some of these signals. This unit presents procedures for a solid-phase kinase assay and immune-complex kinase assay to measure JNK and ERK activities, respectively, in T cells that have been appropriately stimulated. Also described is a procedure for preparing GSThyphen;cJun/GSH-Sepharose beads needed in the solid-phase JNK protein kinase activity assay.
 ...
PMID:Analyzing mitogen-activated protein kinase (MAPK) activities in T cells. 1843 22

Although there has been considerable interest in the regulation of NFkappaB activation by glutathionylation, the possibility of IkappaB as a target for glutathionylation has not been investigated. We now report that Cys(189) of IkappaB alpha is a target for S-glutathionylation. This modification is reversed by thiols such as dithiothreitol and GSH. The glutathionylated IkappaB alpha appears to be significantly less susceptible than is native protein to phosphorylation by IkappaB kinase and casein kinase II, as well as to in vitro ubiquitination. This finding suggests that glutathionylation plays a regulatory role, presumably through structural alterations. HeLa cells treated with oxidant inducing GSH oxidation such as diamide showed the accumulation of glutathionylated IkappaB alpha. This mechanism suggests an alternative modification to the redox regulation of cysteine in IkappaB alpha and a possible mechanism in the regulation of NFkappaB activation.
 ...
PMID:Glutathionylation regulates IkappaB. 1855 96

Estrogens are considered neurotrophic for dopamine neurons. Parkinson's disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild-type (WT) and parkin null mice (PK-/-). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl-2/Bax, chaperones, and GSH), but some of these inter-sex differences disappear in PK-/-. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK-/- mice. Neuronal cultures from midbrain of WT and PK-/- mice were treated with estradiol from 10 min to 48 h. Short-term treatments activated the mitogen-activated protein kinase pathway of WT and PK-/- neurons and the phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase-3 pathway of WT but not of PK-/- cultures. Long-term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK-/- cultures. The levels of estrogen receptor-alpha were elevated in midbrain cultures and in the striatum of adult PK-/- male mice, suggesting that suppression of parkin changes the estrogen receptor-alpha turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin-related Parkinson's disease patients.
 ...
PMID:Gender differences and estrogen effects in parkin null mice. 1864 94

Oxidative stress is known to be a common feature of cholestatic syndrome. We have described the internalization of multidrug resistance-associated protein 2 (Mrp2), a biliary transporter involved in bile salt-independent bile flow, under acute oxidative stress, and a series of signaling pathways finally leading to the activation of novel protein kinase C were involved in this mechanism; however, it has been unclear whether the internalized Mrp2 localization was relocalized to the canalicular membrane when the intracellular redox status was recovered from oxidative stress. In this study, we demonstrated that decreased canalicular expression of Mrp2 induced by tertiary-butyl hydroperoxide (t-BHP) was recovered to the canalicular membrane by the replenishment of GSH by GSH-ethyl ester, a cell-permeable form of GSH. Moreover, pretreatment of isolated rat hepatocytes with colchicine and PKA inhibitor did not affect the t-BHP-induced Mrp2 internalization process but did prevent the Mrp2 recycling process induced by GSH replenishment. Moreover, intracellular cAMP concentration similarly changed with the change of intracellular GSH content. Taken together, our data clearly indicate that the redox-sensitive balance of PKA/PKC activation regulates the reversible Mrp2 localization in two different pathways, the microtubule-independent internalization pathway and -dependent recycling pathway of Mrp2.
 ...
PMID:Canalicular Mrp2 localization is reversibly regulated by the intracellular redox status. 1933 16

Glyoxalase I (GLO1), together with glyoxalase II and the co-factor GSH, comprise the glyoxalase system, which is responsible for the detoxification of the cytotoxic glycolytic-derived metabolite methylglyoxal (MG). We, and others, have previously reported that GLO1 is subjected to several post-translational modifications, including a NO-mediated modification and phosphorylation. In this study, we demonstrate that GLO1 is a substrate for calcium, calmodulin-dependent protein kinase II (CaMKII). Site-directed mutagenesis of several serine and threonine residues revealed that CaMKII induced phosphorylation of GLO1 at a single site Thr-106. Mutagenesis of Thr-106 to Ala in GLO1 completely abolished the CaMKII-mediated phosphorylation. A phosphopeptide bracketing phosphothreonine-106 in GLO1 was used as an antigen to generate polyclonal antibodies against phosphothreonine-106. By using this phospho-specific antibody, we demonstrated that TNF induces phosphorylation of GLO1 on Thr-106. Furthermore, we investigated the role of NO-mediated modification and phosphorylation of GLO1 in the TNF-induced transcriptional activity of NF-kappaB. Overexpression of WT GLO1 suppressed TNF-induced NF-kappaB-dependent reporter gene expression. Suppression of the basal and TNF-induced NF-kappaB activity was significantly stronger upon expression of a GLO1 mutant that was either deficient for the NO-mediated modification or phosphorylation on Thr-106. However, upon overexpression of a GLO1 mutant that was deficient for both types of modification, the suppressive effect of GLO1 on TNF-induced NF-kappaB activity was completely abolished. These results suggest that NO-modification and phosphorylation of GLO1 contribute to the suppression of TNF-induced NF-kappaB-dependent reporter gene expression. In line with this, knock-down of GLO1 by siRNA significantly increased TNF-induced NF-kappaB-dependent reporter gene expression. These findings suggest that phosphorylation and NO-modification of glyoxalase I provides another control mechanism for modulating the basal and TNF-induced expression of NF-kappaB-responsive genes.
 ...
PMID:Phosphorylation on Thr-106 and NO-modification of glyoxalase I suppress the TNF-induced transcriptional activity of NF-kappaB. 1919 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>