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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemokine stromal-derived factor-1alpha (SDF-1alpha/CXCL-12) and its receptor, CXCR4, play a crucial role in adhesion and transendothelium migration (TEM) of prostate cancer cells. We tested the hypothesis that enhanced expression of CXCR4 in prostate cancer cells is dependent upon SDF-1alpha-mediated activation of nuclear factor-kappaB (NF-kappaB). SDF-1alpha increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1alpha enhanced the NF-kappaB-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1alpha increased PC-3 cell adhesion to the human umbilical vein endothelial cell monolayer and enhanced TEM, which was abrogated with anti-CXCR4 monoclonal antibody (mAb). Suppression of NF-kappaB activity in PC-3 cells by a mutant IkappaBalpha super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited adhesion and TEM. Transient overexpression of p65 subunit of NF-kappaB in PC-3 cells up-regulated CXCR4 receptor expression and increased the adhesion and TEM of these cells in response to SDF-1alpha gradient. Treatment of PC-3 cells with SDF-1alpha leads to nuclear translocation of NF-kappaB protein within 15 to 30 minutes, which correlated with IkappaBalpha phosphorylation. A p42/44 mitogen-activated protein kinase [MAPK, extracellular signal regulated kinase-1/2 (ERK-1/2)] biphasic activation pattern was observed in these cells at 15 minutes and 3 hours after SDF-1alpha treatment. Phosphorylation of IkappaB kinase alpha was observed within 30 minutes, which was blocked by PD98059 [MAPK kinase (MEK) inhibitor]. PD98059 cotreatment significantly inhibited SDF-1alpha-induced NF-kappaB reporter activity and CXCR4 receptor expression as shown by flow cytometry. These data suggest that SDF-1alpha-induced expression of CXCR4 in PC-3 cells is dependent on MEK/ERK signaling cascade and NF-kappaB activation.
...
PMID:Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. 1626 13

Human pulmonary artery smooth muscle cells (hPASM cells) express PDE4A10, PDE4A11, PDE4B2, PDE4C and PDE4D5 isoforms. Hypoxia causes a transient up-regulation of PDE4B2 that reaches a maximum after 7 days and sustained up-regulation of PDE4A10/11 and PDE4D5 over 14 days in hypoxia. Seven days in hypoxia increases both intracellular cAMP levels, protein kinase A (PKA) activity and activated, phosphorylated extracellular signal regulated kinase (pERK) but does not alter either PKA isoform expression or total cAMP phosphodiesterase-4 (PDE4) activity or cAMP phosphodiesterase-3 (PDE3) activity. Both the cyclooxygenase inhibitor, indomethacin and the ERK inhibitors, UO126 and PD980589 reverse the hypoxia-induced increase in intracellular cAMP levels back to those seen in normoxic hPASM cells. Challenge of normoxic hPASM cells with prostaglandin E(2) (PGE(2)) elevates cAMP to levels comparable to those seen in hypoxic cells but fails to increase intracellular cAMP levels in hypoxic hPASM cells. The adenylyl cyclase activator, forskolin increases cAMP levels in both normoxic and hypoxic hPASM cells to comparable elevated levels. Challenge of hypoxic hPASM cells with indomethacin attenuates total PDE4 activity whilst challenge with UO126 increases total PDE4 activity. We propose that the hypoxia-induced activation of ERK initiates a phospholipase A(2)/COX-driven autocrine effect whereupon PGE(2) is generated, causing the activation of adenylyl cyclase and increase in intracellular cAMP. Despite the hypoxia-induced increases in the expression of PDE4A10/11, PDE4B2 and PDE4D5 and activation of certain of these long PDE4 isoforms through PKA phosphorylation, we suggest that the failure to see any overall increase in PDE4 activity is due to ERK-mediated phosphorylation and inhibition of particular PDE4 long isoforms. Such hypoxia-induced increase in expression of PDE4 isoforms known to interact with certain signalling scaffold proteins may result in alterations in compartmentalised cAMP signalling. The hypoxia-induced increase in cAMP may represent a compensatory protective mechanism against hypoxia-induced mitogens such as endothelin-1 and serotonin.
...
PMID:Hypoxia-induced remodelling of PDE4 isoform expression and cAMP handling in human pulmonary artery smooth muscle cells. 1645 97

The objective was to reveal whether a protein kinase C (PKC [all isozymes])-mediated self-sustaining MAPK3/1 (3/1 extracellular signal regulated kinase 2/1, also known as ERK2/1) activation loop was necessary for FSH- or epidermal growth factor (EGF)-induced DNA synthesis in the granulosa cells of intact preantral follicles. For this purpose, hamster preantral follicles were cultured with FSH or EGF in the presence of selective kinase inhibitors FSH or EGF phosphorylated RAF1, MAP2K1, and MAPK3/1. However, a relatively higher dose of EGF was necessary to sustain the MAPK3/1 activity, which was essential for cyclin-dependent kinase 4 (CDK4) activation and DNA synthesis. In intact preantral follicles, FSH or EGF stimulated DNA synthesis only in the granulosa cells. Sustained activation of MAPK3/1 beyond 3 h was independent of EGFR kinase activity but dependent on PKC activity, which appeared to form a self-sustaining MAPK3/1 activation loop by activating RAF1, MAP2K1, and PLA2G4 (phospholipase A2 [all cytosolic isozymes]). Inhibition of PKC activity as late as 4 h after the administration of FSH or EGF arrested DNA synthesis, which corresponded with attenuated phosphorylation of RAF1 and MAPK3/1, thus suggesting an essential role of PKC in MAPK3/1 activation. Collectively, these data present a novel self-sustaining mechanism comprised of MAPK3/1, PLA2G4, PKC, and RAF1 for CDK4 activation leading to DNA synthesis in granulosa cells. Either FSH or EGF can activate the loop to activate CDK4 and initiate DNA synthesis; however, consistent with our previous findings, FSH effect seems to be mediated by EGF, which initiates the event by stimulating EGFR kinase.
...
PMID:A novel mechanism of FSH regulation of DNA synthesis in the granulosa cells of hamster preantral follicles: involvement of a protein kinase C-mediated MAP kinase 3/1 self-activation loop. 1652 34

Linoleic acid (18:2n-6), is a major unsaturated fatty acid in the American diet. Linoleic acid is considered to be atherogenic because of its pro-oxidative and proinflammatory properties. There is substantial evidence that linoleic acid (LA) can activate vascular endothelial cells and contribute to an inflammatory response. To explore the mechanisms of LA-induced proinflammatory signaling pathways, the present study addresses the role of the phosphatidylinositol 3-kinase/amino kinase terminal (PI3K/Akt), extracellular signal regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathways during vascular endothelial cell activation. After a 3- to 6-h exposure, LA significantly activated both Akt and ERK in endothelial cells, as assessed by western blot and immunofluorescence. In contrast, LA activated p38 MAPK already at 10 min, suggesting that p38 MAPK signaling occurred upstream of the ERK1/2 pathway. Furthermore, inhibition of ERK activity by PD98059 and PI3K/Akt activity by LY294002 or wortmannin significantly reduced the LA-induced activation of nuclear factor kappa B (NF-kappaB). These results suggest a contribution of both the ERK1/2 and PI3K/Akt pathways to the effect of LA on NF-kappaB-dependent transcription. Indeed, LA-mediated gene expression of the vascular cell adhesion molecule 1 was suppressed by PD98059, wortmannin and LY294002. These data indicate that both PI3K/Akt- and ERK1/2-mediated proinflammatory signaling events are critical in LA-induced endothelial cell activation and vascular inflammation.
...
PMID:Linoleic acid induces proinflammatory events in vascular endothelial cells via activation of PI3K/Akt and ERK1/2 signaling. 1656 18

Activation of cAMP response element binding protein (CREB) is implicated in neuronal survival. The mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activates a transcription factor CREB. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) protects neurons from ischemia via enhancing ERK dependent CREB phosphorylation. To investigate whether NAMDA induces endogenous survival pathways in apoptotic conditions and whether the neuroprotectant enhances a preexisting survival pathway, we determined the degree of ERK-CREB activation and resistance to apoptosis in staurosporine-treated SK-N-BE(2)C neurons. Compared to forskolin-treated apoptotic cultures, NAMDA-treated cultures induced a minimum activation on ERK (pERK) or CREB (pCREB). However, NAMDA enhanced the activation of ERK and CREB in the presence of forskolin (1.7-fold increase for pCREB, 2.1-fold increase for pERK2, p<0.05 from forskolin). The effect was completely blocked by a specific MEK inhibitor U0126, suggesting the involvement of ERK dependent CREB signaling. Cleavage of caspase-3 and poly-(ADP-ribose)-polymerase was additively reduced in cultures treated with NAMDA and forskolin simultaneously, but not in the presence of U0126. The data showed that NAMDA enhances forskolin-induced ERK-CREB activation and potentiates forskolin-induced resistance to apoptosis. The study indicates that enhancing endogenous survival pathways by NAMDA combined with other neuroprotective measure(s) might be a useful strategy to reduce apoptosis.
...
PMID:Enhanced ERK dependent CREB activation reduces apoptosis in staurosporine-treated human neuroblastoma SK-N-BE(2)C cells. 1667 46

MUC5AC is a secretory mucin normally expressed by the surface mucous cells of the human stomach and in the bronchial tract. It is absent from normal pancreas, but de novo expression of this mucin occurs in early-stage pancreatic intraepithelial neoplasias and in the invasive ductal adenocarcinoma of the pancreas, prompting this study of MUC5AC gene regulation in pancreatic cancer cells. Promoter deletion constructs and EMSA studies revealed that transcription factors Sp1 and AP-1 are both involved in basal transcription of the MUC5AC gene. Phorbol 12-myrisate 13-acetate (PMA) increased MUC5AC mRNA expression and transcriptional activities of MUC5AC promoter-reporter deletion constructs containing AP-1 consensus sites. EMSA studies showed that Fos/Jun binding to putative AP-1 sites is increased by PMA treatment. Western blot analysis showed that ERK, JNK and p38 are all activated by PMA treatment in SW1990 cells. Inhibitors of mitogen-activated protein/extracellular signal regulated kinase (MEK), such as ERK inhibitor PD98059 and JNK inhibitors dicumarol and SP60015, but not p38 inhibitor SB203580, inhibited PMA-induced MUC5AC reporter activity. Our studies indicate that Sp1 is involved in basal MUC5AC promoter activity while AP-1 is involved in basal and PMA-induced MUC5AC promoter activation in pancreatic cancer cells. Furthermore, PMA-induced MUC5AC gene transcription appears to be mediated by activating Sp1, PKC/ERK/AP-1 and PKC/JNK/AP-1 pathways.
...
PMID:MUC5AC mucin gene regulation in pancreatic cancer cells. 1677 82

Ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA) are two contagious neoplastic diseases of secretory epithelial cells in the respiratory system of sheep and goats. Jaagsiekte sheep retrovirus (JSRV) is the aetiological agent of OPA, and enzootic nasal tumour virus (ENTV) is associated with ENA. The genomes of these retroviruses do not contain known oncogenes but products of the env gene are important in the generation of transforming stimuli. However, the cell signalling pathways activated in vivo are not completely understood. This study was based on the use of activation stage antibodies specifically detecting proteins of the extracellular signal regulated kinase Erk 1/2 cell signalling pathway and transcription factors. Tissue sections were collected from four natural cases of OPA, four experimentally induced OPA tumours, four ENA tumours in sheep, four ENA tumours in goats, two normal sheep lungs and two lungs with chronic inflammation. Routine immunohistochemical procedures with phosphorylation stage-specific antibodies were carried out. Representative proteins of the Erk1/2 pathway (Raf-1, Mek1/2 and p44/42MAPK) were activated in natural cases of OPA and ENA in sheep and goats and also in experimentally induced OPA. Transcription factors 90Rsk and Elk-1 were activated in OPA and ENA tumours. However, c-Myc was activated only in OPA tumours. In contagious respiratory neoplasms of sheep and goats the Erk1/2 pathway appears to be important for the in-vivo generation of the transforming stimuli.
...
PMID:In-situ demonstration of mitogen-activated protein kinase Erk 1/2 signalling pathway in contagious respiratory tumours of sheep and goats. 1681 1

The TLR agonists, flagellin (FLG) and lipopolysaccharide (LPS) stimulate functional activation and cytokine gene expression via the extracellular signal regulated kinase 1/2 (ERK1/2) MAP kinase cascade. However, the upstream mechanisms of these signaling events remain unknown. In mammals, the small GTP-binding protein Ras mediates ERK1/2 activation through activation of downstream effectors Raf-1-MEK1/2-ERK1/2 in response to a variety of stimuli. It is not clear whether this classic Ras cascade plays a role in TLR signaling in avian cells. In the present study, we investigated the role of Ras in FLG- and LPS-mediated signaling in ERK activation in chicken heterophils. Treatment of heterophils with LPS caused a rapid (within 5min) activation of Ras-GTP. The role of Ras activation in LPS-induced stimulation of ERK1/2 was corroborated when the specific Ras inhibitor, FTI-277, inhibited ERK1/2 activation. The classic Ras-mediated pathway of ERK1/2 activation by LPS was confirmed when the specific Raf-1 inhibitor, GW 5074, and the MEK1/2 inhibitor, U0126, both reduced ERK activation by 51-60%. Of more interest was that treatment of the heterophils with FLG did not activate Ras-GTP. Likewise, neither FTI-277 nor GW 5074 had any effect on FLG-mediated activation of ERK1/2. Another small GTPase, Rap1, has been shown to play a role in mammalian neutrophil function. Using a Rap1-GTP pull-down assay, we found that FLG stimulation, but not LPS, of avian heterophils induced a rapid and transient Rap1 activation. Rap1 has been shown to activate the ERK1/2 via a different Raf family member B-Raf whose downstream effector is MEK1/2. We show here that FLG stimulation of heterophils induces the phosphorylation of Rap1. The FLG induction of the Rap1-->B-Raf-->MEK1/2-->ERK1/2 cascade was confirmed by the reduction of ERK1/2 activation by the specific Rap1 inhibitor (GGTI-298) and U0126. The results demonstrate that for the first time that the small GTPase Ras family is involved in TLR signaling of avian heterophils with the TLR agonists LPS (Ras) and FLG (Rap1) inducing differential signaling cascades to activate the downstream ERK MAP kinase.
...
PMID:Flagellin and lipopolysaccharide stimulate the MEK-ERK signaling pathway in chicken heterophils through differential activation of the small GTPases, Ras and Rap1. 1704 53

The aim of the present study was to investigate the contribution of extracellular signal regulated kinase-1/2 (ERK1/2) to pulmonary artery contraction in response to 4-aminopyridione (4-AP), an inhibitor of a voltage-gated K(+) channels that regulate pulmonary vascular tone. Pulmonary artery rings 1-1.5 mm in diameter from male adult Wistar rat were isolated and cut into 3-mm in length. ERK1/2 up-stream kinase (MEK) inhibitors 2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio)-butadiene (U0126), which block the activation of ERK1/2, were used to test the role of ERK1/2 in 4-AP induced pulmonary arterial vasoconstriction and the influences of 4-AP on expressions of phosphorylated ERK1/2 (p-ERK1/2) in cultured rat pulmonary arterial smooth muscle cells (PASMCs) and whole tissues. Our results show that 4-AP elicited concentration-dependent increases in tension of rat pulmonary artery rings, effects that were reduced by pretreatment of the rings with ERK inhibitors, PD98059 (20 microM) and U0126 (10 microM). Moreover, 4-AP increased the expressions of p-ERK1/2 in cultured PASMCs s and whole tissues, which were prevented by pretreatment of the cells or tissues with U0126. These results indicate that ERK1/2 signaling pathway contributes to pulmonary vasoconstriction induced by 4-AP.
...
PMID:Role of ERK1/2 signaling pathways in 4-aminopyridine-induced rat pulmonary vasoconstriction. 1753 30

R,S(+/-)-3,4-methylenedioxymethamphetamine (R,S(+/-)-MDMA, 'Ecstasy') is known to stimulate dopamine (DA) transmission in the nucleus accumbens (NAc). In order to investigate the post-synaptic correlates of pre-synaptic changes in DA transmission and their relationship with MDMA enantiomers, we studied the effects of R,S(+/-)-MDMA, S(+)-MDMA, and R(-)-MDMA on extracellular DA and phosphorylated extracellular signal regulated kinase (pERK) in the NAc shell and core. Male Sprague-Dawley rats, implanted with a catheter in the femoral vein and vertical concentric dialysis probes in the NAc shell and core, were administered i.v. saline, R,S(+/-)-MDMA, S(+)-MDMA, or R(-)-MDMA. Extracellular DA was monitored by in vivo microdialysis with HPLC. Intravenous R,S(+/-)-MDMA (0.64, 1, and 2 mg/kg) increased dialysate DA, preferentially in the shell, in a dose-related manner. S(+)-MDMA exerted similar effects but at lower doses than R,S(+/-)-MDMA, while R(-)-MDMA (1 and 2 mg/kg) failed to affect dialysate DA. R,S(+/-)- and S(+)-MDMA but not R(-)-MDMA increased ERK phosphorylation (expressed as density/neuron and number of pERK-positive neurons/area) in both subdivisions of the NAc. The administration of the D1 receptor antagonist, SCH 39166, prevented the increase in pERK elicited by R,S(+/-)-MDMA and S(+)-MDMA, while the D2/3 receptor antagonist, raclopride, increased pERK in the NAc core per se but failed to affect the R,S(+/-)-MDMA-elicited stimulation of pERK. The present results provide evidence that the DA stimulant effects of racemic MDMA are accounted for by the S(+)-enantiomer and that pERK may represent a post-synaptic correlate of the stimulant effect of R,S(+/-)-MDMA on D1-dependent DA transmission.
...
PMID:Differential effects of intravenous R,S-(+/-)-3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and its S(+)- and R(-)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core. 1756 78


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

---