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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of mitogen-activated protein kinase (MAPK, also known as extracellular signal regulated kinase; ERK) stimulation in gonadotropin-releasing hormone (GnRH) signaling was investigated in cultured pituitary cells of tilapia hybrids (Oreochromis niloticus x O. aureus). Exposure of the cells to salmon GnRH (sGnRH) resulted in a dose- and time-dependent elevation in ERK levels. The PKC activator, 1-O-tetradecanoyl phorbol-13-acetate (TPA) increased kinase levels, while addition of GnRH had no further effect. However, chronic exposure to TPA resulted in reduction of basal and GnRH-induced ERK elevation. When PKC was inhibited by GF109203X, the GnRH-elevated ERK levels were totally abolished. The role of MAPK activation on GPalpha, FSHbeta and LHbeta gene expression was determined by administration of MAPK-kinase (MEK) inhibitor (PD98059; PD). This inhibitor completely blocked GnRH-induced increases in ERK activity. Furthermore, it suppressed GPalpha and LHbeta mRNA responses to GnRH, but had no effect on FSHbeta transcript levels. PD also decreased basal LHbeta mRNA levels. These results indicate that in tilapia pituitary cells, GnRH activates MAPK cascade in a PKC-dependent manner. ERK is involved in GnRH elevation of GPalpha and LHbeta, but not in FSHbeta genes transcription.
...
PMID:GnRH receptor signaling in tilapia pituitary cells: role of mitogen-activated protein kinase (MAPK). 1139 87

The abundance and activity of three subgroups of mitogen-activated protein (MAP) kinases, the extracellular signal regulated kinase 1 (ERK1), stress-activated protein kinase 1/ Jun N-terminal kinase (SAPK1), and stress-activated protein kinase 2/ p38 (SAPK2), were measured in gill epithelium of the euryhaline teleost Fundulus heteroclitus exposed for 1 h to 4 weeks to hyper- and hyposmotic stress. The abundance of ERK1, SAPK1 and SAPK2 was analyzed by standard Western immunodetection. MAP kinase activity is a function of phosphorylation and was measured using phospho-specific and MAP kinase subgroup-specific antibodies. The abundance of the 63 kDa fish isoform of SAPK2 increases significantly during hyper- but not hyposmotic stress while ERK1 and SAPK1 protein levels remain unchanged during both types of osmotic stress. In contrast to this small effect of osmotic stress on MAP kinase abundance, the activity of all MAP kinases decreases significantly in response to hyperosmotic stress and increases significantly during hyposmotic stress. These results demonstrate for the first time that the activity of all major MAP kinases is osmoregulated in gill epithelium of euryhaline fish. Based on these results we conclude that MAP kinases are important components of salinity adaptation and participate in osmosensory signaling pathways in gill epithelium of euryhaline fishes.
...
PMID:Mitogen-activated protein kinases are in vivo transducers of osmosensory signals in fish gill cells. 1143 36

1. We tested the hypothesis that long-distance running activates parallel mitogen-activated protein kinase (MAPK) cascades that involve extracellular signal regulated kinase 1 and 2 (ERK1/2) and p38 MAPK and their downstream substrates. 2. Eleven men completed a 42.2 km marathon (mean race time 4 h 1 min; range 2 h 56 min to 4 h 33 min). Vastus lateralis muscle biopsies were obtained before and after the race. Glycogen content was measured spectrophotometrically. ERK1/2 and p38 MAPK phosphorylation was determined by immunoblot analysis using phosphospecific antibodies. Activation of the downstream targets of ERK1/2 and p38 MAPK, MAPK-activated protein kinase-1 (MAPKAP-K1; also called p90 ribosomal S6 kinase, p90rsk), MAPK-activated protein kinase-2 (MAPKAP-K2), mitogen- and stress-activated kinase 1 (MSK1) and mitogen- and stress-activated kinase 2 (MSK2) was determined using immune complex assays. 3. Muscle glycogen content was reduced by 40 +/- 6 % after the marathon. ERK1/2 phosphorylation increased 7.8-fold and p38 MAPK phosphorylation increased 4.4-fold post-exercise. Prolonged running did not alter ERK1/2 and p38 MAPK protein expression. The activity of p90rsk, a downstream target of ERK1/2, increased 2.8-fold after the marathon. The activity of MAPKAPK-K2, a downstream target of p38 MAPK, increased 3.1-fold post-exercise. MSK1 and MSK2 are downstream of both ERK1/2 and p38 MAPK. MSK1 activity increased 2.4-fold post-exercise. MSK2 activity was low, relative to MSK1, with little activation post-exercise. 4. In conclusion, prolonged distance running activates MAPK signalling cascades in skeletal muscle, including increased activity of downstream targets: p90rsk, MAPKAP-K2 and MSK. Activation of these downstream targets provides a potential mechanism by which exercise induces gene transcription in skeletal muscle.
...
PMID:Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle. 1157 75

Inhibiting the mitogenic response of vascular endothelial cells may in part mediate the antiangiogenic and anticancer activity of supranutritional selenium supplements. Our previous work had shown that methylseleninic acid (MSeA), a precursor of the critical anticancer methylselenol metabolite pool, was a potent inhibitor of the growth and survival of human umbilical vein endothelial cells (HUVECs). Here we investigated the effects of MSeA on selected protein kinase signaling transduction pathways to characterize their role in methylselenium induction of HUVEC cell cycle arrest and apoptosis. Exposure of asynchronous HUVECs for 30 h to 3-5 microM MSeA led to a profound G(1) arrest, and exposure to higher levels of MSeA not only led to G(1) arrest but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose)polymerase, both biochemical hallmarks of apoptosis. Immunoblot analyses indicated that G(1) arrest induced by the sublethal doses of MSeA was associated with dose-dependent reductions of the levels of phospho-protein kinase B (also known as AKT or PKB), phospho-extracellular signal regulated kinase (ERK) 1/2, and phospho-Jun NH(2)-terminal kinases 1/2 in the absence of any change in p38 mitogen-activated protein kinase (MAPK) phosphorylation. Apoptosis induced by MSeA was associated with an increased phosphorylation of p38 MAPK in addition to the dephosphorylation of the above kinases. In HUVECs deprived of endothelial cell growth supplement (ECGS) for 48 h, resumption of ECGS stimulation resulted in an approximately 10-fold increase in mitogenic response, as indicated by [(3)H]thymidine incorporation into DNA. The ECGS-stimulated mitogenic response was inhibited in a dose-dependent manner by MSeA exposure with a IC(50) approximately 1 microM and a complete blockage at 3 microM. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) upstream of AKT, potently inhibited the ECGS-stimulated DNA synthesis (IC(50), approximately 40 nM). Combining MSeA with Wortmannin showed an additive antimitogenic effect. An inhibitor of MAPK/ERK kinase 1, PD98059, also inhibited ECGS-stimulated DNA synthesis (IC(50), approximately 55 microM), but combining PD98059 with MSeA had an effect similar to that when PD98059 was used alone. A time-course experiment indicated that PI3K (AKT and ribosomal protein S6 kinase) activation occurred between 6 and 12 h of ECGS stimulation, and 3 microM MSeA exposure decreased AKT phosphorylation after 12 h of exposure, whereas no inhibitory effect was observed for ERK1/2 phosphorylation throughout the 30-h exposure duration. Additional experiments indicated that MSeA, Wortmannin, or a more specific PI3K inhibitor, LY294002, seemed to target, in the mid- to late-G(1) phase, a common mechanism(s) controlling G(1) progression to S while having no inhibitory effect on DNA synthesis once S-phase had initiated. Taken together, the results support a potent inhibitory activity at achievable serum levels of MSeA on ECGS-stimulated mitogenesis in the mid- to late-G(1) phase, and the target(s) of this inhibitory activity seems to be PI3K or components of this signal pathway. At pharmacological levels of exposure, modulation of ERK1/2 and other protein kinases may be relevant for the proapoptotic action of MSeA.
...
PMID:Antimitogenic and proapoptotic activities of methylseleninic acid in vascular endothelial cells and associated effects on PI3K-AKT, ERK, JNK and p38 MAPK signaling. 1158 51

The contribution of the angiotensin (Ang) II type 2 receptor (AT2R) to cardiac hypertrophy is still controversial. Here we examined the effect of overexpressing the human AT2R in cultured porcine cardiac fibroblasts (pFib) on proliferation, procollagen I mRNA expression, and - as putatively underlying signal-transduction pathways - on mitogen-activated protein kinase ERK1/ERK2 and phosphotyrosine phosphatase activities. As quantitated by 125I-(Sar1,Ile8)-Ang II binding, transduction of cardiac fibroblasts with the adenoviral AT2R expression vector led to a six- to tenfold higher AT2 than endogenous Ang II type 1 receptor (AT1R) expression. The overexpressed AT2R had the same apparent molecular mass as the endogenous AT2R in rat PC12W cells. Proliferation was not significantly lower in AT2R expressing pFib than in antisense-transduced controls (TA2) upon stimulation with Ang II (AT2R 110.5+/-4.8% vs. TA2 110.2+/-5.5%), Ang II plus the AT1R blocker Irbesartan (97.1+/-1.4% vs. 108.0+/-5.0; P=0.052) and the partial AT2R antagonist CGP42112 at the agonistic concentration of 50 nM (92.1+/-2.7% vs. 99.8+/-3.1%; P=0.053). Procollagen Ialpha2 (COL1A2) mRNA levels were quantitated by (a) northern blot analysis and (b) reverse transcriptase polymerase chain reaction. COL1A2/GAPDH (a) and COL1A2/beta-actin (b) ratios revealed no differences between AT2R-transduced fibroblasts and antisense controls when stimulated with Ang II (1 microM, 24 h) plus Irbesartan and 10 ng/ml transforming growth factor beta1. Ang II stimulation of the endogenous AT1R increased extracellular signal regulated kinase 1/2 activities. This response was reduced by Irbesartan, but PD123319 had no effect. Time course and magnitude of Ang II stimulated ERK1/ERK2 activation was identical in AT2R-transduced and control cells. Also, neither simultaneous nor Ang II pre-stimulation, suggested to induce gene expression of the MAP kinase phosphatase 1, modulated phorbol myristate acetate-stimulated ERK1/ERK2 activation in AT2R-transduced pFib, in AT2R-transduced human umbilical vein endothelial cells, and in PC12W cells. By the use of a tyrosine phosphatase assay we observed an inhibition of phosphotyrosine phosphatase activity by 30.8% (P=0.009, n=5) after 5 min Ang II stimulation of AT2R-expressing pFib. Immunoprecipitation-tyrosine phosphatase assays revealed that inhibition of phosphotyrosine phosphatase 1B, which regulates insulin signaling, contributed to this effect. In conclusion, stimulation of the overexpressed human AT2R in porcine cardiac fibroblasts inhibited tyrosine phosphatase activity but had no significant effect on fibroblast functions related to cardiac fibrosis. It is conceivable that possible antifibrotic AT2R effects are species specific and/or require the interaction between fibroblasts and cardiomyocytes, probably via paracrine factors, or mechanical load.
...
PMID:Adenovirus-mediated overexpression and stimulation of the human angiotensin II type 2 receptor in porcine cardiac fibroblasts does not modulate proliferation, collagen I mRNA expression and ERK1/ERK2 activity, but inhibits protein tyrosine phosphatases. 1169 64

Sphingosine-1-phosphate (SPP), formed by sphingosine kinase, is the ligand for EDG-1, a GPCR important for cell migration and vascular maturation. Here we show that cytoskeletal rearrangements, lamellipodia extensions, and cell motility induced by platelet-derived growth factor (PDGF) are abrogated in EDG-1 null fibroblasts. However, EDG-1 appears to be dispensable for mitogenicity and survival effects, even those induced by its ligand SPP and by PDGF. Furthermore, PDGF induced focal adhesion formation and activation of FAK, Src, and stress-activated protein kinase 2, p38, were dysregulated in the absence of EDG-1. In contrast, tyrosine phosphorylation of the PDGFR and activation of extracellular signal regulated kinase (ERK1/2), important for growth and survival, were unaltered. Our results suggest that EDG-1 functions as an integrator linking the PDGFR to lamellipodia extension and cell migration. PDGF, which stimulates sphingosine kinase, leading to increased SPP levels in many cell types, also induces translocation of sphingosine kinase to membrane ruffles. Hence, recruitment of sphingosine kinase to the cell's leading edge and localized formation of SPP may spatially and temporally stimulate EDG-1, resulting in activation and integration of downstream signals important for directional movement toward chemoattractants, such as PDGF. These results may also shed light on the vital role of EDG-1 in vascular maturation.
...
PMID:EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration. 1172 41

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.
...
PMID:Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2. 1174 68

The effect of quercetin on lipopolysaccharide (LPS)-induced nitric oxide (NO) production was studied. Quercetin pretreatment significantly inhibited NO production in an LPS-stimulated RAW 264.7 murine macrophage cell line. Post-treatment with quercetin partially inhibited NO production. The inhibitory action of quercetin was due to neither the cytotoxic action nor altered LPS binding. The expression of inducible-type NO synthase (iNOS) was markedly down-regulated by quercetin. Quercetin suppressed the release of free nuclear factor (NF)-kappaB by preventing degradation of IkappaB-alpha and IkappaB-beta. Moreover, quercetin blocked the phosphorylation of extracellular signal regulated kinase 1/2 (Erk 1/2), p38, and c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and, further, the activity of tyrosine kinases in LPS-stimulated RAW cells. Quercetin also inhibited interferon (IFN)-gamma-induced NO production. Taken together, these results indicate that the inhibitory action of quercetin on NO production in LPS- and/or IFN-gamma-stimulated macrophages might be due to abrogation of iNOS protein induction by impairment of a series of intracellular signal pathways.
...
PMID:The inhibitory action of quercetin on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells. 1175 12

The fruit hull of mangosteen, Garcinia mangostana L., has been used for many years as a medicine for treatment of skin infection, wounds, and diarrhea in Southeast Asia. In the present study, we examined the effect of gamma-mangostin, a tetraoxygenated diprenylated xanthone contained in mangosteen, on arachidonic acid (AA) cascade in C6 rat glioma cells. gamma-Mangostin had a potent inhibitory activity of prostaglandin E2 (PGE2) release induced by A23187, a Ca2+ ionophore. The inhibition was concentration-dependent, with the IC50 value of about 5 microM. gamma-Mangostin had no inhibitory effect on A23187-induced phosphorylation of p42/p44 extracellular signal regulated kinase/mitogen-activated protein kinase or on the liberation of [14C]-AA from the cells labeled with [14C]-AA. However, gamma-mangostin concentration-dependently inhibited the conversion of AA to PGE2 in microsomal preparations, showing its possible inhibition of cyclooxygenase (COX). In enzyme assay in vitro, gamma-mangostin inhibited the activities of both constitutive COX (COX-1) and inducible COX (COX-2) in a concentration-dependent manner, with the IC50 values of about 0.8 and 2 microM, respectively. Lineweaver-Burk plot analysis indicated that gamma-mangostin competitively inhibited the activities of both COX-1 and -2. This study is a first demonstration that gamma-mangostin, a xanthone derivative, directly inhibits COX activity.
...
PMID:Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells. 1175 76

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF-mediated EC activation. EC apoptosis is likely important in the process termed "plaque erosion" that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide-dependent protective pathways that involve enzymes PI3-kinase and Akt. Conversely, our laboratory has identified nitric oxide-independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen-activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF-mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre-exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen-activated protein kinase kinase inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Flow-mediated inhibition of JNK was unaffected by 0.1 mM L-nitroarginine, 100 pM 8-bromo-cyclic GMP, or 100 microM 8-bromo-cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow-mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.
...
PMID:Endothelial atheroprotective and anti-inflammatory mechanisms. 1179 13


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

---