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

Interleukin (IL)-3-induced Bcl2 phosphorylation at Ser(70) may be required for its full and potent antiapoptotic activity. However, in the absence of IL-3, increased expression of Bcl2 can also prolong cell survival. To determine how Bcl2 may be functionally phosphorylated following IL-3 withdrawal, a stress-activated Bcl2 kinase (SAK) was sought. Results indicate that anisomycin, a potent activator of the stress kinase JNK/SAPK, can induce Bcl2 phosphorylation at Ser(70) and that JNK1 can be latently activated following IL-3 withdrawal to mediate Bcl2 phosphorylation. JNK1 directly phosphorylates Bcl2 in vitro, co-localizes with Bcl2, and collaborates with Bcl-2 to mediate prolonged cell survival in the absence of IL-3 or following various stress applications. Dominant-negative (DN)-JNK1 can block both anisomycin and latent IL-3 withdrawal-induced Bcl2 phosphorylation (>90%) and potently enhances cell death. Furthermore, low dose okadaic acid (OA), a potent protein phosphatase 1 and 2A inhibitor, can activate the mitogen-activated protein kinases JNK1 and ERK1/2, but not p38 kinase, to induce Bcl2 phosphorylation and prolong cell survival in factor-deprived cells. Since PD98059, a specific MEK inhibitor, can only partially inhibit OA-induced Bcl2 phosphorylation but completely blocks OA-induced Bcl2 phosphorylation in cells expressing DN-JNK1, this supports the conclusion that OA may stimulate Bcl2 phosphorylation via a mechanism involving both JNK1 and ERK1/2. Collectively, these findings indicate a novel role for JNK1 as a SAK and may explain, at least in part, how functional phosphorylation of Bc12 can occur in the absence of growth factor.
...
PMID:Novel role for JNK as a stress-activated Bcl2 kinase. 1132 15

A mitogen-activated protein kinase kinase (MAPKK) gene, tMEK2, was isolated from tomato cv. Bonny Best. By mutagenesis, a permanently active variant, tMEK2MUT, was created. Both wild-type tMEK2 and mutant tMEK2MUT were driven by a newly described strong plant constitutive promoter, tCUP, in a tomato protoplast transient gene expression system. Pathogenesis-related genes, PRlb1, PR3 and Twi1, and a wound-inducible gene, ER5, were activated by tMEK2MUT. Specific inhibitors of p38 class MAPK inhibited tMEK2MUT-induced activation of PR3 and ER5 genes but not that of the PRlb1 or Twi1 gene. Arabidopsis dual-specificity protein tyrosine phosphatase 1 (DsPTP1) and maize protein phosphatase 1 (PP1) inhibited tMEK2MUT-induced activation of the ER5 gene and the Twi1 gene, respectively, whereas PRlb1 and PR3 were not affected by either AtDsPTP1, or maize PP1, or Arabidopsis protein phosphatase 2A (PP2A). We have demonstrated for the first time that a single MAPKK activates an array of PR and wound-related genes. Our observation indicates that the activation of the genes downstream of tMEK2 occurs through divergent pathways and that tMEK2 may play an important role in the interaction of signal transduction pathways that mediate responses to both biotic (e.g. disease) and abiotic stresses (e.g. wound responsiveness).
...
PMID:Activation of tomato PR and wound-related genes by a mutagenized tomato MAP kinase kinase through divergent pathways. 1143 46

The current studies were designed to examine the mechanisms of acute effects of ethanol on cerebellar granule neurons (CGNs) during neurodevelopment, with specific reference to activator protein-1 (AP-1). CGNs, isolated from 3-day-old Sprague-Dawley rats and cultured for 3 days, were exposed to 0, 22.5, and 100 mM ethanol for 1 h. Gel shift assays performed on the nuclear protein extracts showed increased AP-1 and heat shock factor-1 (HSF-1) transcriptional activation in response to ethanol. Western blots and RT-PCR showed increased c-JUN and phosphorylated c-JUN (serine 73) protein, as well as c-jun mRNA. Ethanol paradoxically decreased the activity of stress-activated protein kinase-1 (SAPK-1) while increasing p44 and p42 mitogen-activated protein kinase (MAPK) activity. The protein synthesis-inhibiting and SAPK-1 activity-inducing antibiotic, anisomycin (30 and 500 microM) decreased AP-1 transcriptional activation to 47 and 23% of control values, respectively. The anisomycin effect was enhanced in the presence of 100 mM ethanol. Similarly, cycloheximide decreased ethanol-induced AP-1 transcriptional activation. Pretreatment with the MAPK kinase (MEK) pathway inhibitor PD98059 resulted in decreases in both ethanol-induced and control AP-1 DNA binding. Thus this acute ethanol-induced increased AP-1 transcriptional activation requires protein synthesis and involves MEK-independent increased MAPK phosphorylation, on the one hand, and decreased SAPK-1 activity on the other. The ethanol effect is thus ascribed to the activities of alternate kinase pathways and/or the inhibition of (a) protein phosphatase(s). Exposure of CGNs to ethanol for 24 h resulted in decreased AP-1 DNA binding, an observation that could have consequences for overall neuronal function under chronic exposure conditions.
...
PMID:Acute exposure of cerebellar granule neurons to ethanol suppresses stress-activated protein kinase-1 and concomitantly induces AP-1. 1150 22

The transcription factor GATA-4 plays a central role in the regulation of cardiac-muscle gene transcription. The present study demonstrates that endothelin-1 (ET-1) induces GATA-4 activation and phosphorylation. The treatment of HL-1 adult mouse atrial-muscle cells with ET-1 (30 nM) caused a rapid increase in the DNA binding activity of GATA-4 within 3 min. The activation was associated with an upward mobility shift of the GATA-4 band on native PAGE in an electrophoretic- mobility-shift assay. The upward shift of the GATA-4 band also occurred on SDS/PAGE as monitored by immunoblotting. The in vitro treatment of nuclear extracts with lambda-protein phosphatase abolished the upward shift, indicating that GATA-4 was phosphorylated. ET-1 activated the p44/42 mitogen-activated protein kinase (MAPK) and the MAPK kinase (MEK) within 3 min, and PD98059 (a specific inhibitor of MEK) abolished the ET-1-induced GATA-4 phosphorylation. PMA also caused the rapid activation of MAPK and the phosphorylation of GATA-4. In contrast, the activation of MAPK by phenylephrine or H(2)O(2) was weak and did not lead to GATA-4 phosphorylation. Thus ET-1 induces a GATA-4 phosphorylation by activating a MEK-MAPK pathway.
...
PMID:Endothelin-1 induces phosphorylation of GATA-4 transcription factor in the HL-1 atrial-muscle cell line. 1158 84

Among plant defense responses to pathogen attack, the release of active oxygen species (AOS), termed the oxidative burst, may affect the attacking pathogen and the host plant cells at the infection site, thereby limiting the spread of the pathogen. Plasma membrane-associated NADPH oxidase represents a key enzyme in mediating the oxidative burst. The mechanisms of NADPH oxidase activation, however, remains unclear. Ectopic expression of AK1-6H, an Arabidopsis calmodulin-like domain protein kinase (CDPK) in tomato protoplasts enhanced plasma membrane-associated NADPH oxidase activity. Arabidopsis protein phosphatase 2A abolished this enhancement, whereas Arabidopsis dual-specificity protein tyrosine phosphatase 1 or maize protein phosphatase 1 had no effect tMEK2MUT, a constitutively activated, mitogen-activated protein kinase kinase from tomato, did not enhance NADPH oxidase activity when overexpressed. In a cell-free system, AK1-6H moderately stimulated the NADPH oxidase activity on plasma membrane. AK1-6H, but not tMEK2MUT, also enhanced production of AOS in intact protoplasts. Our results show that ectopic expression of a heterologous CDPK can enhance NADPH oxidase activity and stimulate an oxidative burst in tomato protoplasts.
...
PMID:Ectopic expression of an Arabidopsis calmodulin-like domain protein kinase-enhanced NADPH oxidase activity and oxidative burst in tomato protoplasts. 1160 66

Previous studies have shown that the Bacillus anthracis lethal toxin can induce both necrosis and apoptosis in mouse macrophage-like J774A.1 cells depending on both the toxin concentration and the phosphatase activity. In this study several protein kinase or phosphatase inhibitors were employed to evaluate the hypothesis that the lethal toxin induces cell death via protein phosphorylation processes. Pretreatment with a serine/threonine phosphatase inhibitor Calyculin A (300 nM) could inhibit about 78% of cell death induced by the lethal toxin, whereas inhibitors of kinases, such as H7, HA, Sphingosine, and Genestein, but other inhibitors of phosphatases, such as Okadaic acid, Tautomycin, and Cyclosporin A, did not. In addition, recent reports have demonstrated that the MEK1 protein may serve as a proteolytic target within its N-terminus for lethal factor cleavage. In this study, Calyculin A is shown to enhance the phosphorylation of the MEK1 protein. This prevents the cleavage of the MEK1 by lethal factor. These results suggest that a putative Calyculin A-sensitive protein phosphatase is involved in anthrax toxin induced cytotoxicity and that the blocking effect of Calyculin A on lethal factor cytotoxicity may be mediated through the MEK signaling pathway.
...
PMID:Calyculin A sensitive protein phosphatase is required for Bacillus anthracis lethal toxin induced cytotoxicity. 1181 54

The tumor suppressor PTEN possesses lipid and protein phosphatase activities. It has been well established that the lipid phosphatase activity is essential for its tumor-suppressive function via the phosphoinositide 3-kinase (PI3K) and Akt pathways. The precise role of the protein phosphatase activity is still unclear. In the current study, we demonstrate that overexpression of wild-type PTEN in the MCF-7 breast cancer line results in phosphatase activity-dependent decreases in the phosphorylation of ETS-2, which is a transcription factor whose DNA-binding ability is controlled by phosphorylation. Exposure of MCF-7 cells to insulin, insulin-like growth factor 1 (IGF-1) or epidermal growth factor (EGF) can lead to the phosphorylation of ETS-2, Akt and ERK1/2. The MEK inhibitor PD590089 abrogates insulin-stimulated phosphorylation of ETS-2. In contrast, the PI3K inhibitor LY492002 has no effect on insulin-stimulated phosphorylation of ETS-2, despite the fact that it diminishes insulin-stimulated phosphorylation of Akt. Interestingly, overexpression of PTEN in MCF-7 leads to blockade of insulin-stimulated, but not EGF-stimulated, phosphorylation of ERK, accompanied by dramatic decreases in ETS-2 phosphorylation. We further show that the relationship of PTEN and ETS-2 has functional significance by demonstrating that PTEN abrogates activation of the uPA Ras-responsive enhancer, a target of ETS-2 action, in a phosphatase-dependent manner, irrespective of the presence or absence of insulin. Our observations, therefore, suggest that PTEN blocks insulin-stimulated ETS-2 phosphorylation through inhibition of the ERK members of the MAP kinase family independently of PI3K, and that the PTEN effect on the phosphorylation status of ETS-2 may be mediated through PTEN's protein phosphatase activity.
...
PMID:PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. 1209 11

Protein phosphatase type 1 (PP1), together with protein phosphatase 2A (PP2A), is a major eukaryotic serine/threonine protein phosphatase involved in regulation of numerous cell functions. Although the roles of PP2A have been studied extensively using okadaic acid, a well known inhibitor of PP2A, biological analysis of PP1 has remained restricted because of lack of a specific inhibitor. Recently we reported that tautomycetin (TC) is a highly specific inhibitor of PP1. To elucidate the biological effects of TC, we demonstrated in preliminary experiments that treatment of COS-7 cells with 5 microm TC for 5 h inhibits endogenous PP1 by more than 90% without affecting PP2A activity. Therefore, using TC as a specific PP1 inhibitor, the biological effect of PP1 on MAPK signaling was examined. First, we found that inhibition of PP1 in COS-7 cells by TC specifically suppresses activation of ERK, among three MAPK kinases (ERK, JNK, and p38). TC-mediated inhibition of PP1 also suppressed activation of Raf-1, resulting in the inactivation of the MEK-ERK pathway. To examine the role of PP1 in regulation of Raf-1, we overexpressed the PP1 catalytic subunit (PP1C) in COS-7 cells and found that PP1C enhanced activation of Raf-1 activity, whereas phosphatase-dead PP1C blocked Raf-1 activation. Furthermore, a physical interaction between PP1C and Raf-1 was also observed. These data strongly suggest that PP1 positively regulates Raf-1 in vivo.
...
PMID:Usage of tautomycetin, a novel inhibitor of protein phosphatase 1 (PP1), reveals that PP1 is a positive regulator of Raf-1 in vivo. 1237 92

The Na(+)/Ca(2+) exchanger (NCX1) is regulated at the transcriptional level in cardiac hypertrophy, ischemia, and failure. Following pressure overload, activation of MAPKs coincides with the kinetics of NCX1 gene upregulation in adult cardiocytes. Using adenoviral gene delivery, we begin to identify the molecular pathways responsible for upregulation of the exchanger gene. Inhibition of ERK with the MEK inhibitor UO126, the ERK protein phosphatase MKP-3, inhibited ERK activation, but only inhibited alpha-adrenergic-induced NCX1 upregulation by 30%. Overexpression of DN-JNK lowered basal NCX1 expression. Overexpression of activated MKK-3 was sufficient for alpha-adrenergic-stimulated upregulation of the reporter gene. Together, this data indicates that (1) JNK mediates basal cardiac expression of the NCX1 gene, (2) ERK and p38 play a role in alpha-adrenergic-stimulated NCX1 upregulation, and (3) p38 activation alone is sufficient for NCX1 upregulation.
...
PMID:Pathways regulating Na+/Ca2+ exchanger expression in the heart. 1250 66

Chlamydiae are obligate intracellular bacterial parasites that infect eukaryotic cells and live their entire life cycle within a cytoplasmic vacuole or inclusion. We have employed cDNA microarray and conventional biological approaches to study the pathogen-host cell interaction during C. pneumoniae infection of eukaryotic cells. Two host cell signaling pathways, MEK/ERK and PI 3-kinase/Akt, were activated within 5 and 20 minutes, respectively, following infection with chlamydiae. Pharmacological inhibition of these pathways blocked invasion of HEp2 cells indicating that activation of these pathways was required for infection. Rho family GTPase activity was essential for invasion, since the pan-Rho GTPase inhibitor, compactin, blocked infection of HEp2 cells. cDNA microarrays and reverse transcriptase PCR were used to study host cell and chlamydial gene expression during the replication cycle. Analysis of host cell gene expression following infection with C. pneumoniae indicated that genes coding for cytokines, growth factors, and signaling molecules were upregulated, as early as 2 hours postinfection. Analysis of chlamydial gene expression indicated a temporal regulation of transcription with distinct early-, mid-, and late-cycle classes of RNA transcripts. Newly discovered genes encoding three Ser/Thr protein kinases and one protein phosphatase were upregulated 6-12 hours postinfection. One protein kinase, designated CpnPK1, was first detected at 12 hours postinfection, accumulated in the inclusion throughout the replication cycle, and may be a type III effector molecule. An increased understanding of chlamydial host cell interactions, in particular the role of various chlamydial proteins in infection and identification of essential virulence factors should provide novel targets for the development of new antimicrobials.
...
PMID:Chlamydiae host cell interactions revealed using DNA microarrays. 1253 65


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

---