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

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of lead on the signal transduction pathways that may be involved in the release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus have not been well defined. Using the GT1-7 cell line, an in vitro model for GnRH-secreting neurons, we examined signal transduction pathways directly affected by lead. We found that lead-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2), as well as p90RSK and cAMP response element-binding protein (CREB), but did not induce IkappaB degradation. MEK1/2 inhibitor (PD98059) suppressed lead-induced ERK and p90RSK activation. Neither PKC inhibitors (Go6983, Go6976) nor CaMKII inhibitor (KN-62) had a pronounced effect on lead-induced ERK1 and ERK2 phosphorylation. However, MEK1/2 inhibitor, CaMKII inhibitor, and PKC inhibitor significantly suppressed lead-induced CREB phosphorylation. These results indicate that lead-activated PKC, CaMKII and MEK/ERK/p90RSK pathways simultaneously, all of which contributed to CREB phosphorylation. Our results also indicate that lead-induced p90RSK and CREB activation does not alter expression of early response genes like c-fos. We conclude that lead activates PKC, CaMKII or MEK-ERK-p90RSK pathways in GT1-7 cells, leading to CREB phosphorylation and modulation of gene expression.
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PMID:Lead-induced cell signaling cascades in GT1-7 cells. 1283 8

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.
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PMID:The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. 1291 64

Suramin is a well known antitrypanosomal drug and a novel experimental agent for the treatment of several cancers, yet the molecular mechanisms through which suramin exerts its effects on cell functions are not completely clear. In this study, we investigated the potential of suramin to activate the mitogen-activated protein kinase cascade in cultured Chinese hamster ovary (CHO) cells. The treatment of CHO cells with suramin increased the enzyme activity of extracellular signal-regulated kinases (ERK1/2) approximately 10-fold dose and time dependently. The EC(50) value was approximately 2.4 microM. This activation is inhibited by PD98059 and wortmannin/LY294002, indicating a crucial role for mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K), respectively. Suramin-mediated stimulation of PI3K was confirmed by the observation that suramin stimulates the phosphorylation of protein kinase B (Akt) in a wortmannin-sensitive manner. Furthermore, cAMP response element-binding protein, a transcription factor, was also activated by suramin in a MEK-dependent manner. The suramin-induced phosphorylation of cGMP-dependent protein kinase was also suggested by a solid-phase kinase assay. The suramin effects on CHO cells were shown to have a concomitant increase in DNA synthesis, which was attenuated by PD98059. Similar activation of ERK1/2 activity by suramin was observed in other cell lines such as Chinese hamster lung or PC12 cells, but not in RBL2H3, ECV304, and OVK18 cells, indicating a cell-type specific mechanism for suramin. These results indicate that suramin induces mitogenic activity in several cell lines through the pathway from PI3K to MEK and ERK.
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PMID:Stimulation of extracellular signal-regulated kinase pathway by suramin with concomitant activation of DNA synthesis in cultured cells. 1459 92

Extracellular signals may regulate mitogen-activated protein kinase (MAPK) cascades through a receptor-mediated mechanism. As a signaling superhighway to the nucleus, active Ras-MAPK cascades phosphorylate transcription factors and facilitate gene expression. In cultured rat striatal neurons, the present work systemically examined the linkage between glutamate receptors and the extracellular signal-regulated kinase 1/2 (ERK1/2) subclass of MAPK. We found that glutamate induced a rapid and transient phosphorylation of ERK1/2. Similar responses of ERK1/2 phosphorylation were also induced by the ligands selective for each of three subtypes of ionotropic receptors (NMDA, AMPA and kainate), although not by the subgroup-selective agonists for three subgroups of metabotropic glutamate receptors after 8-9 days in culture. The ERK1/2 phosphorylation induced by all ionotropic receptor agents was dose-, time- and Ca(2+) influx-dependent and occurred in neurons, but not glia. The NMDA-, AMPA- and kainate-induced ERK1/2 phosphorylation was blocked only by the antagonists selective for respective subtypes. The ERK1/2 phosphorylation induced by these agents was also sensitive to the MAPK kinase 1 (MEK1) inhibitor PD98059 and the MEK1/2 inhibitor U0126. In a further attempt to evaluate the role of active ERK1/2 in activating a downstream transcription factor cAMP response element-binding protein (CREB), NMDA, AMPA, and kainate were found to increase CREB phosphorylation. The NMDA- and AMPA/kainate-induced CREB phosphorylation was completely and partially blocked by U0126, respectively. These results revealed a positive linkage between ionotropic glutamate receptors and MEK-sensitive ERK1/2 phosphorylation in striatal neurons. The active ERK1/2 cascade activates the downstream transcription factor CREB to participate in the regulation of gene expression.
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PMID:Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in cultured rat striatal neurons. 1501 79

Radiation-induced endothelial cell apoptosis is involved in the development of many radiation injuries, including radiation-induced skin ulcers. The proangiogenic growth factor basic fibroblast growth factor (bFGF, NUDT6) enhances endothelial cell survival. In the present study, we set up a model of apoptosis in which primary cultured human umbilical vein endothelial cells (HUVECs) were irradiated with (60)Co gamma rays to explore the effects of bFGF on radiation-induced apoptosis of HUVECs and the signaling pathways involved. We found that bFGF inhibited radiation-induced apoptosis of HUVECs, and that the effect was mediated in part by the RAS/MEK/ MAPK/RSK (p90 ribosomal S6 kinase)/BAD pathway. This pathway was activated by exposure of irradiated HUVECs to bFGF, involving phosphorylation of FGFR, MEK and p44/42 MAPK. The survival-enhancing effect of bFGF was partly inhibited by U0126 and PD98059. The fact that the anti-apoptosis effect of bFGF on irradiated HUVECs was not completely abrogated by U0126 and PD98059 suggests that other survival signaling pathways may exist. Transfection of a dominant-negative form of RSK2 (DN RSK2) partly blocked the anti-apoptosis effect of bFGF in irradiated HUVECs. Moreover, we provide evidence for the first time that bFGF induced BAD phosphorylation (at serine 112) and CREB (cAMP response element-binding protein) activation (phosphorylation at serine 133) in gamma-irradiated HUVECs. In our model, inhibition of MAPK signaling-dependent phosphorylation of BAD at serine 112 promoted increased association with BCL-X(L), suggesting that MAPK pathway-dependent serine 112 phosphorylation of BAD is critical for the effect of bFGF on cell survival. These results showed that RAS/MAPK/BAD pathway participated in the bFGF-induced effect on survival of HUVECs exposed to radiation. It is suggested that RAS/ MAPK pathway in tumor vascular endothelium could be a potential therapeutic target to enhance the efficacy of ionizing radiation.
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PMID:Basic fibroblast growth factor inhibits radiation-induced apoptosis of HUVECs. II. The RAS/MAPK pathway and phosphorylation of BAD at serine 112. 1516 49

VIP exerts a spectrum of effects as a potent anti-inflammatory factor. In addition, VIP increases expression of MUC2, a major intestinal secretory mucin. We therefore investigated the effects of VIP on the promoter activity of the 5'-flanking region of the MUC2 gene. VIP activated MUC2 transcription in human colonic epithelial cells via cAMP signaling to ERK and p38. cAMP/Epac/Rap1/B-Raf signaling was not involved in MUC2 reporter activation. Furthermore, activation of MUC2 transcription was independent of many of the reported downstream effectors of G protein-coupled receptors, such as PKC, Ras, Raf, Src, calcium, and phosphoinositide 3-kinase. VIP induced cAMP response element-binding protein (CREB)/ATF1 phosphorylation, and this was prevented by treatment with inhibitors of either MEK or p38 and by PKA and MSK1 inhibitor H89. CREB/ATF1 and c-Jun were shown to bind to an oligonucleotide encompassing a distal, conserved CREB/AP1 site in the 5'-flanking region of the MUC2 gene, and this cis element was shown to mediate promoter reporter activation by VIP. This study has identified a new, functional cis element within the MUC2 promoter and also a new pathway regulating MUC2 expression, thus providing further insight into the molecular mechanism of VIP action in the colon. These findings are relevant to the normal biology of the colonic mucosa as well as to the development of VIP as a therapeutic agent for treatment of inflammatory bowel disease.
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PMID:Vasoactive intestinal peptide upregulates MUC2 intestinal mucin via CREB/ATF1. 1622 28

Glucagon-like peptide-1 and its potent agonist exendin-4 induce several immediate early response genes (IEGs) that code for transcription factors implicated in cell proliferation, differentiation, and apoptosis. We recently observed that early growth response factor-1 (EGR-1), an IEG product, was required for transcriptional activation of Ccnd1 (cyclin D1) gene by exendin-4. Herein, the regulatory mechanism whereby exendin-4 activates the transcription of EGR-1 gene was investigated in the pancreatic beta-cell line INS-1. Deletion analysis of rat EGR-1 promoter identified a critical region between -73 and -46 for the activation of EGR-1 in response to exendin-4. Mutation of the proximal putative cAMP response element (CRE, 5'-GTACGTCA-3') located at -69 resulted in a significant decrease in the EGR-1 transcription, whereas the mutation of the distal putative CRE at -139 was without such an effect. In immune supershift assays using exendin-4-treated cells, binding of cAMP response element-binding protein (CREB) phosphorylated on Ser(133) to the proximal CRE was increased. Employment of a CREB mutant containing Ala substitution at Ser(133) or a dominant negative CREB mutant that inhibits the binding of endogenous CREB to DNA significantly decreased the exendin-4-induced EGR-1 transcription. In experiments using specific protein kinase inhibitors, the effect of H-89 was more prominent than PD-98059, indicating the predominance of the PKA signaling over the MEK/ERK in induction of EGR-1. Therefore, it appears that the proximal CRE site is critical and the binding with CREB phosphorylated on Ser(133) is necessary for induction of the EGR-1 transcription by exendin-4.
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PMID:Proximal cyclic AMP response element is essential for exendin-4 induction of rat EGR-1 gene. 1692 76

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.
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PMID:Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. 1713 41

Hippocalcin (Hpca) is a member of the neuronal calcium sensor protein family and is highly expressed in hippocampal neurons. Hpca-deficient (Hpca(-/-)) mice display a defect in cAMP response element-binding protein (CREB) activation associated with impaired spatial and associative memory. Here we examine the involvement of Hpca in the extracellular signal-regulated kinase (ERK) cascade leading to CREB activation, because application of PD98059, a broad ERK cascade inhibitor, has resulted in similar levels of CREB activation in Hpca(-/-) hippocampus. N-methyl-D-aspartate (NMDA)- and KCl-induced phosphorylation of ERK was significantly attenuated in Hpca(-/-) hippocampal slices, as was ionomycin-induced phosphorylation of ERK, whereas forskolin and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulation yielded indistinguishable levels of ERK phosphorylation in both wild-type and Hpca(-/-) slices. In an in vitro reconstitution assay system, recombinant Hpca affected neither Raf-1 protein kinase activity with recombinant MEK-1 as a substrate nor MEK-1 kinase activity with ERK2 as a substrate. Activation of Ras by NMDA and KCl stimulation of hippocampal slices showed no obvious changes between the two genotypes; however, phosphorylation of Raf-1 was significantly lower in Hpca(-/-) slices. These results suggest that Hpca plays an important role in the activation of Raf conducted by Ras.
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PMID:Lack of hippocalcin causes impairment in Ras/extracellular signal-regulated kinase cascade via a Raf-mediated activation process. 1727 41

The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.
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PMID:Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. 1789 29


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