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)

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in several human tumors including gastric, lung, colon, prostate and breast. However, the role of PPARgamma signals in leukemia is still unclear. The aim of this study is to evaluate the ability of 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2), that is a ligand for PPARgamma, on proliferation of human leukemia cell line U937. 15dPGJ2 at 5 micromol/l stimulated the proliferation. In contrast, 15dPGJ2 at concentrations of >10 micromol/l inhibited the proliferation through the induction of apoptosis. PGD2, PGJ2 and Delta12-PGJ2 (DeltaPGJ2), those are precursors of 15dPGJ2, had similarly proliferative effects, whereas they showed antiproliferative effects at high concentrations. FACScan analysis revealed that PGD2 at 5 micromol/l, PGJ2 at 1 micromol/l, DeltaPGJ2 at 1 micromol/l and 15dPGJ2 at 5 micromol/l, all accelerated cell cycle progression. Immunoblotting analysis revealed that PGD2 at 5 micromol/l and 15dPGJ2 at 5 micromol/l inhibited the expression of phospho-p38, phospho-MKK3/MKK6 and phospho-ATF-2, and the expression of Cdk inhibitors including p18, p27. In contrast, PGJ2 at 1 micromol/l and DeltaPGJ2 at 1 micromol/l did not affect the expression of them. These results suggest that 15dPGJ2 and PGD2 may, through inactivation of the p38 MAPK pathway, inhibit the expression of Cdk inhibitors, leading to acceleration of proliferation.
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PMID:Induction of proliferation by 15-deoxy-delta12,14-prostaglandin J2 and the precursors in monocytic leukemia U937. 1524 Sep 94

The systemic administration of trimethyltin (TMT, 2.8 mg/kg, i.p.) induced granule cell death in the mouse dentate gyrus selectively 2 days later. The administration of TMT not only enhanced activator protein-1 DNA binding, along with an increase in expression of c-Jun and Fra-2, in the hippocampus 1 day later, but also facilitated phosphorylation of c-Jun N-terminal kinase (JNK) within the cytosol and nucleus. There was also a concomitant increase in the level of phosphorylated JNK kinase (MKK4/SEK1) in the cytosol 16-24 h after the administration. Moreover, TMT markedly elevated endogenous levels of both phosphorylated c-Jun and phosphorylated activating transcription factor-2 (ATF-2), in addition to activating JNK activity in the nuclear extracts obtained 16-24 h post-administration. Immunohistochemical analysis revealed that whereas Fra-2 and phosphorylated ATF-2 were expressed in the CA1 pyramidal cell layer predominantly, phosphorylated c-Jun was observed in both the CA1 pyramidal and dentate granule cell layers after TMT administration. Taken together, our data indicate that TMT activates the JNK pathway in the hippocampus prior to neuronal cell death. The prior activation of this pathway could be at least in part involved in the TMT-induced neural damage seen in the dentate granule cells of mice.
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PMID:In vivo activation of c-Jun N-terminal kinase signaling cascade prior to granule cell death induced by trimethyltin in the dentate gyrus of mice. 1538 Mar 79

Growth differentiation factor-8 (GDF-8), a member of the TGF-beta superfamily, is a negative regulator of skeletal muscle growth, which functions through activation of the Smad proteins. We found that GDF-8 can activate the p38 mitogen-activated protein kinase (MAPK) through the TGF-beta-activated kinase 1 (TAK1), and this appeared to be independent of Smad signaling. GDF-8-induced transcriptional activation was inhibited by expression of dominant negative MKK6 or treatment with the p38 inhibitor SB203580, while overexpression of wild-type forms of either MKK6 or p38 augmented GDF-8-induced transcriptional activity. In addition, ATF-2, a known transcription factor target of p38, was found to be phosphorylated on GDF-8 stimulation and was detected in a complex with Smad3/Smad4 upon GDF-8 treatment. Furthermore, we found that the p38 MAPK played an important role in GDF-8-induced inhibition of proliferation and upregulation of the cyclin kinase inhibitor p21. Together, these results highlight a functional link between the p38 MAPK and GDF-8-activated Smad pathways, and identify a critical role for the p38 MAPK in GDF-8's function as a negative regulator of muscle growth.
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PMID:Regulation of GDF-8 signaling by the p38 MAPK. 1556 67

Dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways by various viruses has been shown to be responsible for viral pathogenicity. The molecular mechanism by which hepatitis C virus (HCV) infection caused human liver diseases has been investigated on the basis of abnormal intracellular signal events. Current data are very limited involved in transmembrane signal transduction triggered by HCV E2 protein. Here we explored regulation of the MAPK/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway by E2 expressed in Chinese hamster oval cells. In human hepatoma Huh-7 cells, E2 specifically activated the MAPK/ERK pathway including downstream transcription factor ATF-2 and greatly promoted cell proliferation. CD81 and low density lipoprotein receptor (LDLR) on the cell surface mediated binding of E2 to Huh-7 cells. The MAPK/ERK activation and cell proliferation driven by E2 were suppressed by blockage of CD81 as well as LDLR. Furthermore, pretreatment with an upstream kinase MEK1/2 inhibitor U0126 also impaired the MAPK/ERK activation and cell proliferation induced by E2. Our results suggest that the MAPK/ERK signaling pathway triggered by HCV E2 via its receptors maintains survival and growth of target cells.
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PMID:Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. 1577 84

The nucleotide excision repair (NER) system consists of two sub-pathways, global genome repair (GGR) and transcription-coupled repair (TCR), which exhibit distinct functions in the cellular response to genotoxic stress. Defects in TCR result in prolonged UV light-induced stalling of RNA polymerase II and hypersensitivity to apoptosis induced by UV and certain chemotherapeutic drugs. Here, we show that low doses of UV trigger delayed activation of the stress-induced MAPkinase JNK and its proapoptotic targets c-Jun and ATF-3 in TCR-deficient primary human fibroblasts from Xeroderma Pigmentosum (XP) and Cockayne syndrome (CS) patients. This delayed activation of the JNK pathway is not observed in GGR-deficient TCR-proficient XP cells, is independent of functional p53, and is established through repression of the JNK-phosphatase MKP-1 rather than by activation of the JNK kinases MKK4 and 7. Enzymatic reversal of UV-induced cyclobutane pyrimidine dimers (CPDs) by CPD photolyase abrogated JNK activation, MKP-1 repression, and apoptosis in TCR-deficient XPA cells. Ectopic expression of MKP-1 inhibited DNA-damage-induced JNK activity and apoptosis. These results identify both MKP-1 and JNK as sensors and downstream effectors of persistent DNA damage in transcribed genes and suggest a link between the JNK pathway and UV-induced stalling of RNApol II.
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PMID:DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. 1604 58

Estradiol (E2) and the naturally occurring polyamines (putrescine, spermidine, and spermine) play important roles in breast cancer cell growth and differentiation. We examined the effects of E2 and spermine on the phosphorylation and DNA binding of activating transcription factor-2 (ATF-2) in MCF-7 breast cancer cells. ATF-2 is a transcription factor involved in estrogenic regulation of cyclin D1 gene, and thereby cell cycle progression. DNA affinity immunoblot assays showed a six- to eightfold increase in the binding of ATF-2 to a 74-mer ATF/CRE oligonucleotide (ODN1) from cyclin D1 promoter in the presence of 4 nM E2 and 0.5 mM spermine, compared to untreated control. Individual treatments with E2 or spermine caused a twofold or lower increase in ATF-2 binding to ODN1. Immunoblotting with phospho-ATF-2 antibody showed that increased DNA binding of ATF-2 was associated with its phosphorylation. A p38 MAP kinase inhibitor, PD169316, inhibited ATF-2 phosphorylation. In contrast, the MEK-ERK1/2 inhibitor, PD98059, or the JNK inhibitor, SP600125, had no significant effect on DNA binding of ATF-2. Cyclin D1 promoter (-1745CD1) activity increased by approximately 12-fold (above control) in the presence of E2 and spermine, compared to a sixfold increase in the presence of E2 alone and a twofold increase with spermine. Cells transfected with a dominant negative mutant of ATF-2 showed decreased transactivation of cyclin D1 promoter in response to E2 and spermine. These results indicate that spermine can enhance E2-induced cell signaling and cyclin D1 transcription by activation of the p38 MAP kinase and phosphorylation of ATF-2, contributing to breast cancer cell proliferation.
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PMID:Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. 1605 Jan 33

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

It has been proposed that, among other cellular responses, TNF-alpha induces not only cell death, but also cell proliferation by activation of p38. It has also been reported that IL-1-alpha favours cell proliferation by p38 activation. The aim of the present study was to evaluate upstream (alpha-PAK, MEK-6) and downstream (Elk-1 and ATF-2) components of the p38 transduction pathway in normal prostate, benign prostatic hyperplasia (BPH), and prostate carcinoma (PC). Immunohistochemical and western blot analyses were performed in 20 samples of normal prostate, 47 samples of BPH, and 27 samples of PC. In all normal prostates, immunoreactivity for p-Elk-1 and p-ATF-2 was observed in epithelial cell nuclei, but no expression of alpha-PAK or MEK-6. In BPH, there was expression of alpha-PAK (cytoplasm) and MEK-6 (cytoplasm), while the proportions of lesions that were immunoreactive for p-Elk-1 (nucleus and cytoplasm) and p-ATF-2 (nucleus) decreased. In PC, the percentages of cells that were immunoreactive for alpha-PAK (cytoplasm) or MEK-6 (cytoplasm) rose slightly in comparison with BPH, while the percentages of cells that were immunoreactive for p-Elk-1 (nucleus and cytoplasm) or p-ATF-2 (nucleus and cytoplasm) were much higher than in BPH. It is concluded that overexpression of alpha-PAK, MEK-6, p38, p-Elk-1, and p-ATF-2 in BPH, and more intensely in PC, enhances cell proliferation. In BPH, such proliferation is triggered by IL-1 and in part counteracted by the TNF-alpha/AP-1 pathway, which promotes apoptosis. In PC, proliferation is triggered by IL-1 and TNF-alpha (the TNF-alpha/AP-1 pathway is diverted towards p38 activation). Since in a study of the same patients immunoexpression of IL-1alpha and IL-1RI was previously observed to be increased in PC, inhibition of p38 is a possible target for PC treatment, as this inhibition would both decrease IL-1-induced cell proliferation and increase TNF-alpha-induced cell death.
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PMID:The p38 transduction pathway in prostatic neoplasia. 1636 14

Phosphorylation (P-) of cAMP-response element-binding protein (CREB) by protein kinase A or mitogen-activated protein kinases was implicated in mediating the increased tyrosine hydroxylase (TH) gene expression after prolonged exposure to nicotine in vivo and in cell culture. We examined the time course and signaling pathways for phosphorylation of CREB and possible involvement of ATF-2. Treatment of PC12 cells with 200 microm nicotine triggered rapid but transient elevation of P-CREB followed by a second sustained rise after 2-5 h of continuous nicotine. In contrast, ERK1/2 was only phosphorylated with short term nicotine exposure. MEK inhibitor U0126 abolished nicotine-induced rise in P-ERK1/2, but not P-CREB, nor did it inhibit nicotine-evoked elevation in TH promoter activity, indicating that ERK1/2 was not needed for induction of TH gene expression by nicotine. In contrast, protein kinase A inhibitor H-89 or Ca(2+)/calmodulin-activated protein kinase inhibitor KN-93 reduced the nicotine-triggered rise in P-CREB and TH promoter activity. There was a delayed elevation of P-ATF-2 after 1 h of nicotine treatment, accompanied by increased ATF-2 protein. Upstream kinase JNK, but not p38, was phosphorylated especially after 5 min to 2 h of nicotine exposure. To examine the requirement for CREB and ATF-2, cells were transfected with dominant negative forms of ATF-2 or CREB. Both reduced the basal TH promoter activity and the response to nicotine. Knockdown of ATF-2 or CREB with siRNA did not alter basal TH promoter activity or mRNA but greatly attenuated the response to nicotine. The results suggest that both ATF-2 and CREB mediate activation of TH gene transcription by nicotine.
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PMID:Prolonged activation of cAMP-response element-binding protein and ATF-2 needed for nicotine-triggered elevation of tyrosine hydroxylase gene transcription in PC12 cells. 1645 70

Klebsiella pneumoniae (KP), an enterobacterium, usually causes urinary tract infection or pneumonia; however, it has caused severe liver abscess in diabetic patients in recent years. How this emerging virulent KP strain causes liver abscess is not known. This study investigates signalling pathways in HepG2 cells infected by virulent KP. Cells were infected with bacteria for various durations and harvested to screen for signalling molecules by Western blotting. Our results showed that phosphorylated mitogen-activated protein kinase (MAPK) kinase (MEK) 1/2, p44/p42 MAPK and p90 ribosomal S6 kinase (p90RSK) were observed and this pathway was inhibited by MEK1/2 inhibitors U0126 and PD98059. Phosphorylation of MEK3/6, p38 kinase and ATF-2 was also observed and this pathway was inhibited by p38 kinase inhibitors SB203850 and SB202190. Toll-like receptor (TLR) 2 and 4 expressions were increased and maximized 2-4 h post infection. The JNK pathway, Elk, MAPKAPK-2 and HSP27 were not activated. These results suggest that KP infections induce signal transduction through TLR2 and TLR4 and activate two downstream MAP kinase pathways, MEK1/2-p44/p42 MAPK-p90RSK and MEK3/6-p38 kinase-ATF-2, but not the JNK pathway in HepG2 cells. The infected HepG2 eventually showed apoptosis and died.
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PMID:Mitogen-activated protein kinase (MAPK) signalling pathways in HepG2 cells infected with a virulent strain of Klebsiella pneumoniae. 1692 65


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