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)

Since both endothelin-1 (ET-1) and aldosterone have been shown to induce expression of several pro-inflammatory genes, including cyclooxygenase-2 (COX-2), in the vasculature as a cardiovascular risk hormone, the present study was undertaken to examine the effects of ET-1 and aldosterone on COX-2 gene expression as measured by a real-time reverse transcriptase-polymerase chain reaction in aortic endothelial cells. Treatment with ET-1(10 M) markedly upregulated COX-2 mRNA levels in rat endothelial cells, whereas aldosterone (10 M) did not show any effect. The ET-1-induced COX-2 upregulation was inhibited by pretreatment with a non-selective endothelin receptor antagonist (TAK044), a protein kinase C inhibitor (GF109203X), and a MEK inhibitor (PD98059). Furthermore, ET-1 increased intracellular reactive oxygen species generation as estimated by the measurement of dichlorofluorescein fluorescence, whose effect was blocked by a COX-2 inhibitor (NS398). Our data show that ET-1 induces COX-2 upregulation in rat endothelial cells via a protein kinase C-dependent and extracellular signal-regulated kinase-dependent pathway, which may largely contribute to the generation of intracellular reactive oxygen species.
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PMID:Endothelin-1 induces cyclooxygenase-2 expression and generation of reactive oxygen species in endothelial cells. 1583 13

Telomerase is a specialized reverse transcriptase that extends telomeres of eukaryotic chromosomes. The functional telomerase complex contains a telomerase reverse transcriptase catalytic subunit and a telomerase template RNA. We have previously demonstrated that human telomerase reverse transcriptase (hTERT) catalytic subunit is functionally compatible with a telomerase template RNA from rabbit. In this study, we show that hTERT is also functionally compatible with a telomerase template RNA from bovine. Introduction of hTERT into bovine lens epithelial cells (BLECs) provides the transfected cells telomerase activity. The expressed hTERT in BLECs supports normal growth of the transfected cells for 108 population doublings so far, and these cells are still extremely healthy in both morphology and growth. In contrast, the vector-transfected cells display growth crisis after 20 population doublings. These cells run into cellular senescence due to shortening of the telomeres and also commit differentiation as indicated by the accumulation of the differentiation markers, beta-crystallin and filensin. hTERT prevents the occurrence of both events. By synthesizing new telomere, hTERT prevents replicative senescence, and through regulation of MEK/ERK, protein kinase C, and protein kinase A and eventual suppression of the MEK/ERK signaling pathway, hTERT inhibits differentiation of BLECs. Our finding that hTERT can suppress RAS/RAF/MEK/ERK signaling pathway to prevent differentiation provides a novel mechanism to explain how hTERT regulates cell differentiation.
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PMID:Human telomerase reverse transcriptase immortalizes bovine lens epithelial cells and suppresses differentiation through regulation of the ERK signaling pathway. 1584 92

We have previously shown that, in bovine retina pericytes, amyloid beta(1-42) and its truncated form containing amino acids 25-35, after 24 h treatment, stimulate arachidonic acid (AA) release and phosphatidylcholine hydrolysis, by activation of both cytosolic (cPLA(2)) and Ca(2+)-independent (iPLA(2)) phospholipase A(2). A putative role for MAP kinases in this process emerged. Here we studied the role of the MAP-kinase family as well as both cPLA(2) and iPLA(2) mRNA expression by a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the same sublethal model of amyloid-beta (Abeta) damage to pericytes in vitro. Abeta(25-35) peptide evoked AA release as well as stimulated phosphorylation of ERK1/2, p38 MAPKs and cPLA(2), but not c-Jun N-terminal kinase (JNK/SAPK). PD98059, an inhibitor of ERK-activating kinase MEK-1, and SB203580, an inhibitor of p38 protein kinase, abolished the stimulation of AA release and MAPK activities. In cells stimulated by Abeta(25-35) peptide, Western blotting and confocal microscopy analyses confirmed either an increase in the phosphorylated form of ERKs and p38 or their nuclear translocation. A complete inhibition of MAPK activation and AA release was also observed when pericytes were treated with GF109203X, a general PKC inhibitor, indicating the important role of both PKC and the two MAPKs in mediating the Abeta peptide response. Compared with samples untreated or treated with reverse Abeta(35-25) peptide, pretreatment with 50 microM Abeta(25-35) for 24 h significantly increased the level of constitutively expressed iPLA(2) mRNA by 25%, which seems to depend on the activation of kinases. By contrast, the level of cPLA(2) mRNA remained unchanged. Together, these data link either the stimulation of PKC-ERK-p38 cascades or PLA(2) activity by Abeta peptide to prooxidant mechanism induced by amyloid, which may initially stimulate the cell reaction as well as metabolic repair, such as during inflammation.
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PMID:MAPKs mediate the activation of cytosolic phospholipase A2 by amyloid beta(25-35) peptide in bovine retina pericytes. 1586 64

Kaposi's sarcoma-associated herpesvirus (KSHV) in vitro target cell infection is characterized by the expression of the latency-associated genes ORF 73 (LANA-1), ORF 72, and K13 and by the transient expression of a very limited number of lytic genes such as lytic cycle switch gene ORF 50 (RTA) and the immediate early (IE) lytic K5, K8, and v-IRF2 genes. During the early stages of infection, several overlapping multistep complex events precede the initiation of viral gene expression. KSHV envelope glycoprotein gB induces the FAK-Src-PI3K-RhoGTPase (where FAK is focal adhesion kinase) signaling pathway. As early as 5 min postinfection (p.i.), KSHV induced the extracellular signal-regulated kinase 1 and 2 (ERK1/2) via the PI3K-PKCzeta-MEK pathway. In addition, KSHV modulated the transcription of several host genes of primary human dermal microvascular endothelial cells (HMVEC-d) and fibroblast (HFF) cells by 2 h and 4 h p.i. Neutralization of virus entry and infection by PI-3K and other cellular tyrosine kinase inhibitors suggested a critical role for signaling molecules in KSHV infection of target cells. Here we investigated the induction of ERK1/2 by KSHV and KSHV envelope glycoproteins gB and gpK8.1A and the role of induced ERK in viral and host gene expression. Early during infection, significant ERK1/2 induction was observed even with low multiplicity of infection of live and UV-inactivated KSHV in serum-starved cells as well as in the presence of serum. Entry of UV-inactivated virus and the absence of viral gene expression suggested that ERK1/2 induction is mediated by the initial signal cascade induced by KSHV binding and entry. Purified soluble gpK8.1A induced the MEK1/2 dependent ERK1/2 but not ERK5 and p38 mitogen-activated protein kinase (MAPK) in HMVEC-d and HFF. Moderate ERK induction with soluble gB was seen only in HMVEC-d. Preincubation of gpK8.1A with heparin or anti-gpK8.1A antibodies inhibited the ERK induction. U0126, a selective inhibitor for MEK/ERK blocked the gpK8.1A- and KSHV-induced ERK activation. ERK1/2 inhibition did not block viral DNA internalization and had no significant effect on nuclear delivery of KSHV DNA during de novo infection. Analyses of viral gene expression by quantitative real-time reverse transcriptase PCR revealed that pretreatment of cells with U0126 for 1 h and during the 2-h infection with KSHV significantly inhibited the expression of ORF 73, ORF 50 (RTA), and the IE-K8 and v-IRF2 genes. However, the expression of lytic IE-K5 gene was not affected significantly. Expression of ORF 73 in BCBL-1 cells was also significantly inhibited by preincubation with U0126. Inhibition of ERK1/2 also inhibited the transcription of some of the vital host genes such as DUSP5 (dual specificity phosphatase 5), ICAM-1 (intercellular adhesion molecule 1), heparin binding epidermal growth factor, and vascular endothelial growth factor that were up-regulated early during KSHV infection. Several MAPK-regulated host transcription factors such as c-Jun, STAT1alpha, MEF2, c-Myc, ATF-2 and c-Fos were induced early during infection, and ERK inhibition significantly blocked the c-Fos, c-Jun, c-Myc, and STAT1alpha activation in the infected cells. AP1 transcription factors binding to the RTA promoter in electrophoretic mobility shift assays were readily detected in the infected cell nuclear extracts which were significantly reduced by ERK inhibition. Together, these results suggest that very early during de novo infection, KSHV induces the ERK1/2 to modulate the initiation of viral gene expression and host cell genes, which further supports our hypothesis that beside the conduit for viral DNA delivery into the cytoplasm, KSHV interactions with host cell receptor(s) create an appropriate intracellular environment facilitating infection.
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PMID:ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. 1605 24

Hedgehog (HH)/GLI signaling plays a critical role in epidermal development and basal cell carcinoma. Here, we provide evidence that epidermal growth factor receptor (EGFR) signaling modulates the target gene expression profile of GLI transcription factors in epidermal cells. Using expression profiling and quantitative reverse transcriptase PCR, we identified a set of 19 genes whose transcription is synergistically induced by GLI1 and parallel EGF treatment. Promoter studies of a subset of GLI/EGF-regulated genes, including the genes encoding interleukin-1 antagonist IL1R2, Jagged 2, cyclin D1, S100A7, and S100A9, suggest convergence of EGFR and HH/GLI signaling at the level of promoters of selected direct GLI target genes. Inhibition of EGFR and MEK/ERK but not of phosphatidylinositol 3-kinase/AKT abrogated synergistic activation of GLI/EGF target genes, showing that EGFR can signal via RAF/MEK/ERK to cooperate with GLI proteins in selective target gene regulation. Coexpression of the GLI/EGF target IL1R2, EGFR, and activated ERK1/2 in human anagen hair follicles argues for a cooperative role of EGFR and HH/GLI signaling in specifying the fate of outer root sheath (ORS) cells. We also show that EGF treatment neutralizes GLI-mediated induction of epidermal stem cell marker expression and provide evidence that EGFR signaling is essential for GLI-induced cell cycle progression in epidermal cells. The results suggest that EGFR signaling modulates GLI target gene profiles which may play an important regulatory role in ORS specification, hair growth, and possibly cancer.
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PMID:Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. 1688 May 36

We have established a stroma-dependent myelomonocytic cell line, NAMO-2, with FLT3 internal tandem duplication (FLT3/ITD). Leukemia cells from a patient with acute myelomonocytic leukemia were administered to form subcutaneous tumors in nude mice, which were maintained successively, although we failed to establish continuously growing cells from the original leukemia cell culture. In the cultures of cells from subcutaneous tumors, there were stroma cells that had originated from the nude mice and showed continuous growth. The leukemia cells showed continuous growth dependent on this stroma, and this cell line was named NAMO-2. Detection of FLT3/ITD by the reverse transcriptase polymerase chain reaction (PCR) and genomic PCR showed that NAMO-2 was homozygous for FLT3/ITD. Constitutive activation of FLT3 was detected by Western blotting, and the phosphorylation of Akt, MEK, and STAT5 was also observed. FLT3 kinase inhibitor AG1296 specifically inhibited cell growth. NAMO-2 provides a useful tool to analyze adherence-dependent survival signaling of leukemia with FLT3/ITD and a model for the screening of FLT3 kinase inhibitors.
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PMID:Establishment of a stroma-dependent human acute myelomonocytic leukemia cell line, NAMO-2, with FLT3 tandem duplication. 1711 59

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.
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PMID:RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells. 1763 24

Antimicrobial peptides (AMPs) are important components of our first line of defense. Induction of AMPs such as LL-37 of the cathelicidin family might provide a novel approach in treating bacterial infections. In this study we identified 4-phenylbutyrate (PBA) as a novel inducer of AMP expression and investigated affected regulatory pathways. We treated various cell lines with PBA and assessed mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Cathelicidin AMP (CAMP) gene expression was found to be upregulated in all four cell lines tested. Additionally, we found that the beta-defensin 1 gene was upregulated in the lung epithelial cell line VA10 while being downregulated in the monocytic cell line U937. Further we found that PBA induced CAMP gene expression synergistically with 1,25-dihydroxyvitamin D(3) at both protein and mRNA levels. The general mechanism of induction of CAMP gene expression by PBA was found to be dependent on protein synthesis. Results from quantitative chromatin immunoprecipitation experiments challenge the common view that histone deacetylase inhibitors directly increase CAMP gene expression. Furthermore, we have demonstrated that inhibition of the mitogen-activated protein kinases MEK1/2 and c-Jun N-terminal kinase attenuate PBA-induced CAMP gene expression. Similarly, alpha-methylhydrocinnamate (ST7), an analogue of PBA, increases CAMP gene expression. Our findings contribute to understanding of the regulation of AMP expression and suggest that PBA and/or ST7 is a promising drug candidate for treatment of microbial infections by strengthening the epithelial antimicrobial barriers.
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PMID:Phenylbutyrate induces antimicrobial peptide expression. 1977 Feb 73

Mitogen-activated protein kinase kinases (MAPKKs) are essential components of evolutionary conserved signalling modules that regulate a variety of fundamental cellular processes in response to environmental stimuli. To date, no MAPKK ortholog has been characterised in free-living or parasitic flatworm species. Here, we report the identification and molecular characterisation of two such molecules in the human parasitic cestode Echinococcus multilocularis, the causative agent of alveolar echinococcosis. Using degenerative PCR approaches as well as 3'- and 5'-rapid amplification of cDNA ends (RACE), the cDNAs encoding two different E. multilocularis MAPKKs, EmMKK1 and EmMKK2, have been identified and fully cloned. Structurally, EmMKK1 and EmMKK2 closely resemble members of the MKK3/6- and the MEK1/2-MAPKK sub-families, respectively, from a variety of vertebrate and invertebrate organisms, and contain all catalytically important residues of MAPKKs at the corresponding positions. By reverse transcriptase-PCR analyses, expression of the EmMKK2-encoding gene, emmkk2, was observed in the larval stages, metacestode and protoscolex while emmkk1 displayed a protoscolex-specific expression pattern. In yeast two-hybrid analyses, EmMKK1 strongly interacted with the previously identified Echinococcus MAPKK kinase EmRaf but not with the Erk-like MAP kinase EmMPK1 or the p38-like MAP kinase EmMPK2. EmMKK2, on the other hand, not only interacted with EmRaf and a member of the parasite's 14-3-3 protein family, but also with EmMPK1, which was confirmed by co-immunoprecipitation assays. Incubation of in vitro cultivated metacestode vesicles with small-molecule inhibitors of Raf- and MEK-kinases resulted in a marked de-phosphorylation of EmMPK1 and negatively affected parasite growth, but was ineffective in vesicle killing. Taken together, our results define EmRaf, EmMKK2 and EmMPK1 as the three components of the Erk-like E. multilocularis MAPK cascade module and provide a solid basis for further investigations into the role of Erk-like MAPK signalling in parasite development and stem cell function.
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PMID:Molecular characterisation of MEK1/2- and MKK3/6-like mitogen-activated protein kinase kinases (MAPKK) from the fox tapeworm Echinococcus multilocularis. 1988 70

This study investigated the signaling pathways involved in the different biological effects of brain-derived neurotrophic factor (BDNF) in multiple myeloma (MM). The effects of BDNF on proliferation of MM cell lines and primary myeloma cells were examined by [(3)H]thymidine incorporation assay. The effects of BDNF on MM cells migration were studied by transwell migration assay. Stimulation by BDNF of vascular endothelial growth factor (VEGF) production was analyzed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The signal-transduction pathways that are activated in response to BDNF were determined by Western blots. VEGF is induced by BDNF in a dose-dependent manner in MM cells. Stimulation of MM cells with BDNF led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the MEK-extracellular signal-regulated protein kinase pathways. Using specific signal-transduction inhibitors, we demonstrated that MEK is required for BDNF-induced proliferation, whereas activation of PI3K is required for BDNF-stimulated migration and VEGF production. BDNF affects different cell signaling pathways mediating growth, migration, and VEGF secretion in MM cells. Our observations provided the framework for novel therapeutic strategies targeting BDNF signaling cascades in MM.
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PMID:Brain-derived neurotrophic factor induces proliferation, migration, and VEGF secretion in human multiple myeloma cells via activation of MEK-ERK and PI3K/AKT signaling. 2035 25


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