Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increase in dopamine (DA) availability in rat brain has been suggested to participate in certain neurodegenerative processes. However, the regulatory effects of DA on glial cells have not been extensively studied. Using a rat C6 glioma cell line stably expressing recombinant D2L receptors, we have found that micromolar levels of DA stimulate mitogenesis and glial fibrillary acidic protein (GFAP) expression, both serving as parameters of reactive gliosis. This mitogenesis occurs about 29 h after exposure to DA and requires D2-receptor-mediated intracellular redox-tyrosine kinase activation. Either DA or quinpirole, a D2 receptor agonist, stimulates protein tyrosine phosphorylation. Application of either DPI, a potent inhibitor of NADPH-dependent oxidase, or NAC, an anti-oxidant, effectively prevented DA-induced tyrosine phosphorylation and DNA synthesis. Preincubation of (+)-butaclamol, a D2 receptor antagonist, inhibits both DA-stimulated tyrosine phosphorylation and mitogenesis. DA at micromolar levels also stimulates GFAP expression. This DA-regulated GFAP expression can be completely inhibited by SB203580, a selective p38 MAPK inhibitor, but not influenced by (+)-butaclamol and genistein, a protein tyrosine kinase inhibitor. Thus, our data suggest that regulation of DNA synthesis and GFAP expression induced by DA is mediated by independent signaling pathways. The mitogenesis requires a D2-receptor-mediated protein tyrosine kinase cascade, while GFAP expression needs a D2-receptor-independent p38 MAPK activation. This observation may help to understand the processes of reactive gliosis in some dopaminergic-related neurodegenerative diseases.
 ...
PMID:Dopamine stimulates redox-tyrosine kinase signaling and p38 MAPK in activation of astrocytic C6-D2L cells. 1062 45

Heme oxygenase-1 (HO), the heat shock/stress cognate of the heat shock protein 32 (HSP32) family of proteins, is postulated to be a component of cellular defense mechanisms against oxidative stress-mediated injury. Nitric oxide (NO) is among the extensive array of stimuli that induce HO-1. The cellular signaling mechanisms that regulate the induction of HO-1 by NO are not understood. In the present study, we have demonstrated that exposure of HeLa cells to the NO donor, sodium nitroprusside (SNP), results in concentration and time-dependent increase in HO-1 mRNA and activation of MAPKs: ERK (ERK1 and ERK2) and p38 pathways, but not SAPK/JNK pathway. Pre-treatment of the cells with PD98059, a selective ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, blocked the induction of HO-1 by the NO donor in a dose-dependent manner. In addition, an increase in HO-1 mRNA level that was detected as early as 2 hrs.following SNP treatment preceded c-jun and c-fos induction. These transcription factors are downstream of SAPK/JNK pathway, and their increased expression was detected at 3hr. and 6hr. after SNP treatment. Similarly, AP-1 DNA binding activity was not increased when measured 6 hrs. after SNP treatment. ERK and p38 inhibitors also suppressed induction of HO-1 by SNAP and GSNO. The increase in HO-1 mRNA was inhibited by actinomycin D and cycloheximide, but not by NAC, and was not mimicked by the lipophilic cGMP analogue, 8-bromo-cGMP, suggesting that NO-mediated induction required de novo RNA and protein synthesis and was unrelated to cGMP and redox signaling. Collectively, the findings suggest that MAP kinase ERK and p38 pathways are involved in the NO-mediated induction of HO-1 and that SAPK/JNK pathway and increased DNA binding of AP-1 transcription factor are not involved in HO-1 gene activation by NO. A plausible mechanism by which the NO donors cause HO-1 induction may involve HO-1 gene regulation by its substrate, heme.
 ...
PMID:Nitric oxide induces heme oxygenase-1 via mitogen-activated protein kinases ERK and p38. 1087 47

The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu(2+) alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC(50) of 300 microM and 180 microM, respectively. However, PDTC and Cu(2+) in the complex form markedly potentiated with each other by about 1,000-fold with IC(50) of 0.3 microM PDTC plus 10 microM Cu(2+). Other metals at concentrations of 3-10 microM (VO(4)(5+), Cr(6+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Pb(2+), Bi(2+), Ba(2+), UO(2+), Cs(+), SeO(4)(2-), La(3+)) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu(2+) complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu(2+) complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu(2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu(2+) chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu(2+)-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu(2+) complex. We concluded that the death signaling pathway of PDTC-Cu(2+) complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction.
 ...
PMID:Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu(2+) complex in the cultured rat cortical astrocytes. 1094 Nov 51

Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in several cardiovascular diseases. Ang II-induced cellular events have been mediated, in part, by reactive oxygen species (ROS) which also involve activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that the therapeutic administration of antioxidants is useful for vascular diseases, the precise mechanisms which regulate ROS-sensitive signaling events have not been well characterized. Thus, we hypothesized that antioxidants may affect ROS-mediated MAP kinases activation induced by Ang II. The present findings showed that Ang II stimulated rapid and significant activation of ERK 1/2, JNK and p38 MAPK in cultured rat aortic smooth muscle cells (RASMC). Ang II-induced ERK 1/2 activation was not affected by all antioxidants examined, whereas JNK was sensitive to all antioxidants. In contrast, p38 MAPK activation was inhibited by DPI and ascorbic acid concentration-dependently, but by NAC only at high concentration. DETC and Trolox C had no effects on p38 MAPK activation by Ang II. We further examined the effects of antioxidants on Ang II-induced increases in oxygen consumption as an index of ROS generation in RASMC. DPI strongly inhibited Ang II-induced increases in oxygen consumption. DETC also inhibited Ang II-induced oxygen consumption, whereas ascorbic acid markedly augmented it. These findings suggest that the inhibitory effects of antioxidants on MAP kinases activation in VSMC are attributable, in part, to their modulating effects on ROS generation by Ang II in VSMC. Thus, inhibition of MAP kinases by antioxidants may imply their usefulness for relief of cardiovascular diseases.
 ...
PMID:Antioxidants inhibit JNK and p38 MAPK activation but not ERK 1/2 activation by angiotensin II in rat aortic smooth muscle cells. 1140 48

Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.
 ...
PMID:Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process. 1149 80

The aim of this study was to elucidate the redox regulation of cytokine-induced NF-kappaB activation and NF-kappaB mediated gene induction in A549 cells and primary cultures of human airway epithelial cells. In A549 cells, Western blot analysis showed transient depletion of IkappaBalpha after 15 min IL-1beta treatment followed by its reappearance after 60 min, indicating efficient NF-kappaB-driven gene induction. A similar pattern was observed in primary epithelial cells however, the kinetics were slower and depletion was less. In primary airway epithelial cells IkappaBalpha levels were 59.8+/-8.5% of control following 30 min treatment with IL-1beta and in A549 cells 29.1+/-8.5% of control following 15 min IL-1beta treatment. Cytokine-induced IkappaBalpha depletion was associated with NF-kappaB nuclear accumulation and subsequent resynthesis of IkappaBalpha and upregulation of ICAM-1 in both cell types. The antioxidant, NAC (20 mM) had no effect on the kinetics of cytokine-induced IkappaBalpha depletion or NF-kappaB p65 nuclear translocation in either cell type and failed to influence kappaB dependent IkappaBalpha resynthesis. H2O2 treatment alone or in combination with cytokines had no significant effects on IkappaBalpha depletion, NF-kappaB p65 nuclear translocation or ICAM-1 expression in either cell type but did cause significant activation of p38 MAPK. These results suggest that cytokine-induced NF-kappaB activation in cultured human airway epithelial cells does not involve an NAC-sensitive oxidant stress and that H2O2-induced oxidant stress does not result in effective NF-kappaB activation and NF-kappaB mediated gene induction.
 ...
PMID:Regulation of NF-kappaB and ICAM-1 expression in human airway epithelial cells. 1174 93

Synucleins are small, highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched in presynaptic terminals. alpha-Synuclein protein and a fragment of it, called NAC, have been found in association with pathological lesions of neurodegenerative diseases. Recently, mutations in a alpha-synuclein gene have been reported in families susceptible to an inherited form of Parkinson's diseases. In addition, alpha-synuclein has been implicated in the pathophysiology of other neurodegenerative diseases, including Alzheimer's disease and multiple system atrophy. Far less is known about other members of the synuclein family, beta- and gamma-synucleins. gamma-synuclein is up-regulated in several types of cancer and may affect the integrity of the neurofilament network, while its bovine ortholog, synoretin, activates the Elk-1 signal transduction pathway. In this paper, we present data about the localization and properties of human and bovine gamma-synuclein in several neuronal and non-neuronal cell cultures derived from ocular tissues. We show that gamma-synuclein is present in the perinuclear area and is localized to centrosomes in several types of human interphase cells and in bovine retinal pigment epithelium. In mitotic cells, gamma-synuclein staining is localized to the poles of the spindle. Further, overexpression of synoretin in retinoblastoma cells up-regulates MAPK and Elk-1. These results support the view that gamma-synuclein is a centrosome protein that may be involved in signal transduction pathways.
 ...
PMID:Gamma synuclein: subcellular localization in neuronal and non-neuronal cells and effect on signal transduction. 1174 66

Redox regulation of mitogen-activated protein kinase (MAPK(p38))-mediated pro-inflammatory cytokine production is not well characterized in the alveolar epithelium. It was hypothesized that the involvement of the MAPK(p38) pathway in regulating lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha and interleukin-6 secretion is redox-sensitive and affected by NAC, an antioxidant and a precursor of glutathione, and L-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis. Exposure of fetal alveolar type II epithelial cells to Escherichia coli-derived LPS induced, in a time-dependent manner, the phosphorylation/activation of MAPK(p38) (peak at 15min). In addition, LPS up-regulated the phosphorylation of MAPK(p38) in a dose-dependent manner. The effect of LPS on the MAPK(p38) pathway was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small 27kDa heat-shock protein (Hsp27). LPS induced the phosphorylation of Hsp27 in a time- and dose-dependent manner. Selective blockage of the MAPK(p38) pathway by a pyridinyl-imidazole (SB-203580) abrogated LPS-induced release of TNF-alpha and IL-6. Pre-treatment with NAC reduced LPS-mediated secretion of TNF-alpha and IL-6. Incubation of cells with NAC induced intracellular accumulation of GSH, but reduced the concentration of GSSG. On the other hand, pre-treatment with BSO augmented LPS-mediated secretion of TNF-alpha and IL-6. In addition, BSO induced intracellular accumulation of GSSG, but reduced the concentration of GSH. Whereas NAC blocked the phosphorylation/activation of MAPK(p38), BSO amplified the LPS-mediated effect on MAPK(p38). These results indicated that intracellular redox signaling plays an important role in regulating LPS-induced activation of the MAPK(p38) pathway and MAPK(p38)-mediated regulation of LPS-dependent inflammatory cytokine production in the alveolar epithelium.
 ...
PMID:The involvement of L-gamma-glutamyl-L-cysteinyl-glycine (glutathione/GSH) in the mechanism of redox signaling mediating MAPK(p38)-dependent regulation of pro-inflammatory cytokine production. 1184 6

Presence of increased reactive oxygen species (ROS) has been observed in most high risk factors for brain tumor development. Our past study demonstrated that ROS could induce increased brain tumor cell proliferation. Growth effects of ROS may involve modifications of cellular proteins such as mitogen-activated protein kinases (MAPKs), which regulate cell proliferation. Here, we report effects of a ROS (hydrogen peroxide, H2O2) and an antioxidant (N-acetylcysteine, NAC) on MAPK activation in astrocytoma (U373-MG) cells. MAPKs are activated by phosphorylation that can be detected by Western blot analysis. The unphosphorylated/inactivated form of MAPK exhibits slower mobility on SDS-PAGE compared to the phosphorylated/activated form. Densitometric analysis was used to measure MAPK activation. Results indicate that H2O2 caused a dose and time-dependent increase in MAPK activation in astrocytoma cells. Furthermore, ROS-induced activation was almost completely suppressed by NAC. NAC also inhibited serum-induced MAPK activation indicating there may be an oxidant-sensitive component to serum-induced growth signaling. Modifications of MAPKs by H2O2 demonstrate that ROS-induced proliferation is via biochemical pathways similar to other known growth stimuli. Understanding of processes that link a proliferation signal (ROS) to cell proliferation can aid in the selection of therapy used to suppress brain tumor growth.
 ...
PMID:Mitogen activated protein kinase activation and oxidant signaling in astrocytoma cells. 1199 11

Lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells (VSMCs) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we examined the importance of reactive oxygen species (ROS) in lysoPC-stimulated ERK1/2 activation in cultured rat VSMCs. Treatment with lysoPC for 3 minutes caused a 2-fold increase in intracellular ROS that was blocked by the NADH/NADPH oxidase inhibitor, diphenylene iodonium (DPI). Antioxidants, N-acetyl-L-cysteine, glutathione monoester, or alpha -tocopherol, inhibited ERK1/2 activation by lysoPC. Almost identical results were obtained in the VSMC line A10. Pretreatment of VSMCs with DPI but not allopurinol or potassium cyanide (KCN) abrogated the activation of ERK1/2. The Flag-tagged p47phox expressed in A10 cells was translocated from the cytosol to the membrane after 2 minutes of stimulation with lysoPC. The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation. The ROS-dependent ERK activation by lysoPC seems to involve protein kinase C- and Ras-dependent raf-1 activation. Induction of c-fos expression and enhanced AP-1 binding activity by lysoPC were also inhibited by DPI and NAC. Taken together, these data suggest that ROS generated by NADH/NADPH oxidase contribute to lysoPC-induced activation of ERK1/2 and subsequent growth promotion in VSMCs.
 ...
PMID:Lysophosphatidylcholine activates extracellular signal-regulated kinases 1/2 through reactive oxygen species in rat vascular smooth muscle cells. 1200 86


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