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 steroid hormone aldosterone is important for salt and water homeostasis as well as for pathological tissue modifications in the cardiovascular system and the kidney. The mechanisms of action include a classical genomic pathway, but physiological relevant nongenotropic effects have also been described. Unlike for estrogens or progesterone, the mechanisms for these nongenotropic effects are not well understood, although pharmacological studies suggest a role for the mineralocorticoid receptor (MR). Here we investigated whether the MR contributes to nongenotropic effects. After transfection with human MR, aldosterone induced a rapid and dose-dependent phosphorylation of ERK1/2 and c-Jun NH2-terminal kinase (JNK) 1/2 kinases in Chinese hamster ovary or human embryonic kidney cells, which was reduced by the MR-antagonist spironolactone and involved cSrc kinase as well as the epidermal growth factor receptor. In primary human aortic endothelial cells, similar results were obtained for ERK1/2 and JNK1/2. Inhibition of MAPK kinase (MEK) kinase but not of protein kinase C prevented the rapid action of aldosterone and also reduced aldosterone-induced transactivation, most probably due to impaired nuclear-cytoplasmic shuttling of MR. Cytosolic Ca2+ was increased by aldosterone in mock- and in human MR-transfected cells to the same extend due to Ca2+ influx, whereas dexamethasone had virtually no effect. Spironolactone did not prevent the Ca2+ response. We conclude that some nongenotropic effects of aldosterone are MR dependent and others are MR independent (e.g. Ca2+), indicating a higher degree of complexity of rapid aldosterone signaling. According to this model, we have to distinguish three aldosterone signaling pathways: 1) genomic via MR, 2) nongenotropic via MR, and 3) nongenotropic MR independent.
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PMID:Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. 1576 Oct 31

Genetic manipulation of diphosphoinositol polyphosphate synthesis impacts many biological processes (reviewed in S.B. Shears, Biochem. J. 377, 2004, 265-280). These observations lacked a cell-signalling context, until the recent discovery that bis-diphosphoinositol tetrakisphosphate ([PP]2-InsP4 or "InsP8") accumulates rapidly in mammalian cells in response to hyperosmotic stress (X. Pesesse, K. Choi, T. Zhang, and S. B. Shears J. Biol. Chem. 279, 2004, 43378-43381). We now investigate how widely applicable is this new stress-response. [PP]2-InsP4 did not respond to mechanical strain or oxidative stress in mammalian cells. Furthermore, despite tight conservation of many molecular stress responses across the phylogenetic spectrum, we show that cellular [PP]2-InsP4 levels do not respond significantly to osmotic imbalance, heat stress and salt toxicity in Saccharomyces cerevisiae. In contrast, we show that [PP]2-InsP4 is a novel sensor of mild thermal stress in mammalian cells: [PP]2-InsP4 levels increased 3-4 fold when cells were cooled from 37 to 33 degrees C, or heated to 42 degrees C. Increases in [PP]2-InsP4 levels following heat-shock were evident <5 min, and reversible (t(1/2)=7 min) once cells were returned to 37 degrees C. These responses were blocked by pharmacological inhibition of the ERK/MEK pathway. Additional control processes may lie upstream of [PP]2-InsP4 synthesis, which was synergistically activated when heat stress and osmotic stress were combined. Our data add to the repertoire of signaling responses following thermal challenges, a topic of current interest for its possible therapeutic value.
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PMID:Signal transduction during environmental stress: InsP8 operates within highly restricted contexts. 1593 74

Sulforaphane (SFN) is a major isothiocyanate compound in cruciferous vegetables such as broccoli, cauliflower, and Brussels sprouts. Preclinical animal models have recently shown that SFN and other isothiocyanates may be useful for prostrate cancer (PCa) chemoprevention. In this study we used a DU145 human PCa cell culture model to investigate the role of protein kinase signaling pathway(s) in SFN-induced cell cycle arrest and apoptosis and whether another chemopreventive agent selenium enhances the apoptosis potency of SFN. The results showed that SFN exposure for 24 h or longer significantly decreased the number of viable DU145 cells in a dose-dependent manner with an IC50 of asymptotically equal to 10 microM. The decreased cell number was associated with G2/M phase arrest and apoptotic cell death, with the latter being evidenced by caspase-mediated cleavage of poly(ADP-ribose) polymerase and increased release of histone-associated DNA fragments. A peptide inhibitor of caspase-8 completely blocked SFN-induced apoptosis and that for caspase-9 exerted a major protection; however, neither inhibitor attenuated SFN-induced G2/M arrest. Regarding potential mediators, SFN treatment induced a transient rise of reactive oxygen species (ROS) peaking within (1/2) h and the activation of JNK within 1 h but did not have any detectable effect on the phosphorylation of p38MAPK or ERK1/2 from 6 h to 24 h. Pretreatment of cells with N-acetylcysteine to enrich intracellular glutathione blocked SFN-induced ROS and apoptotic cell death. Inhibiting the JNK activity with a pharmacologic inhibitor SP600125 abolished the induction of G2/M arrest and apoptosis by SFN, whereas chemical inhibitors for p38MAPK and MEK1/2 did not have any modulating effect on SFN-induced apoptosis. Taken together, the data indicate that SFN decreased viable DU145 cell number in large part through the generation of ROS and JNK-mediated signaling to G2/M arrest and caspase-dependent apoptosis. Selenium in the form of inorganic sodium selenite salt or methylseleninic acid did not enhance SFN-induced apoptosis in this cell culture model.
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PMID:Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells. 1620 52

In eukaryotes, mitogen-activated protein kinase (MAPK) pathways are very important signal transduction modules that regulate various cellular processes. Although eukaryotic cells possess a number of MAP kinase pathways, normally the MAPKKs selectively activate their cognate MAPK. Recent studies suggest that the MAPK-docking site in MAPKK facilitates this specific recognition and activation. However, the role of the docking site under in vivo conditions has not been demonstrated. In yeast external high osmolarity activates HOG (high osmolarity glycerol) MAPK pathway that consists of MAPKKK (Ste11p or Ssk2p/Ssk22p), MAPKK (Pbs2p), and MAPK (Hog1p). Previously, we have isolated a Pbs2p homologue (Dpbs2p) from osmo-tolerant and salt-tolerant yeast Debaryomyces hansenii that complemented pbs2 mutation in Saccharomyces cerevisiae. Here we show, for the first time, the presence of a MAPK-docking domain in Dpbs2p that is essential for its function in vivo. Mutation in this motif completely abolished its binding to Hog1p in vitro.
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PMID:Evidence that the MAPK-docking site in MAPKK Dpbs2p is essential for its function. 1676 17

The purpose of this study was to investigate whether latanoprost, a prostaglandin F2alpha analogue, has a direct anti-apoptotic effect both in retinal neuro-glial cells in culture and in diabetic retina. R28 cells, immortalized retinal neuroglial progenitor cells, were induced apoptosis by 24h serum deprivation. Serum withdrawal made up to 15% of R28 cells pyknotic and activated caspase-3 immunoreactive, and latanoprost acid suppressed apoptosis with dose dependency at an optimum concentration of 1.0 microM (P<0.001). UO126, a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) 1 and 2 inhibitor reversed this effect. Streptozotocin induced one- or three-month diabetic rats received balanced-salt-solution (BSS) in the left eye and latanoprost eye drops in the right for 5 days. Retinal wholemount was subjected to terminal dUTP nick end labeling (TUNEL) staining, whereas eyeballs were enucleated for cleaved caspase-3 immunofluorescence. Retinal homogenates were probed for phospho- or total p44/p42 MAPK and Akt. One- and three-month diabetic retina had 30.2+/-15.3 and 23.6+/-9.0 TUNEL positive cells per 0.5 cm(2), respectively, whereas control retina had few TUNEL positive cells. Latanoprost instillation significantly reduced these cells (10.0+/-3.1 and 11.3+/-3.1 cells per 0.5 cm(2) for 1M and 3M, respectively, P<0.01), whereas BSS did not. Latanoprost also significantly reduced cleaved caspase-3 immunoreactive cells in ganglion cell and inner nuclear layers (P<0.05). Latanoprost increased phosphorylated to total protein ratio of p44/p42 MAPK (P<0.05), but not of Akt. Taken together, the present findings suggest that latanoprost rescues retinal neurons and/or glial cells from apoptosis, which is probably mediated by p44/p42 MAPK through caspase-3 inhibition.
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PMID:Latanoprost rescues retinal neuro-glial cells from apoptosis by inhibiting caspase-3, which is mediated by p44/p42 mitogen-activated protein kinase. 1683 45

In plants, mitogen-activated protein kinases (MAPKs) are involved in signalling to hormones, cell cycle regulation, stresses, and plant defence responses. In this work, several MAPKs were detected by immunobloting in roots and nodules of Lupinus albus produced by inoculation with Bradyrhizobium sp. (Lupinus). In vitro kinase assays showed that inoculation of seedling roots with B. sp. (Lupinus) activates salt stress-inducible and stress-activated MAPKs after 5 min of incubation. By contrast, inoculation with dead B. sp. (Lupinus) or the heterologous bacteria Sinorhizobium meliloti did not induce salt stress-inducible and stress-activated MAPK activities. In vivo experiments showed that inoculation with B. sp. (Lupinus) induced the activation of MAPKs in roots. The maximal activation was in the region of the root tip with emerging hairs, which corresponds to the infection zone. The p38 MAPK inhibitors SB 202190 and SB 203580 blocked these kinase activities. Experiments with SB 202190 and the MAPKK inhibitor UO 126 altered the pattern of nodulation in the main root, decreasing the number and weight of nodules produced in the upper sites while increasing the nodule number in the younger lower root zone. These data suggest that MAPK inhibition blocks early events in the susceptible root zone to rhizobial infection, delaying nodulation, and support a role for MAPKs in the infection and nodulation of L. albus by B. sp. (Lupinus).
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PMID:Involvement of mitogen-activated protein kinases in the symbiosis Bradyrhizobium-Lupinus. 1686 44

We investigated the effect of beta-estradiol (E2) on synaptogenesis in the hippocampus using organotypic hippocampal slice cultures and subregional hippocampal neuron cultures. E2 increased the expression of PSD95, a postsynaptic marker, specifically in stratum lucidum of Cornu Ammonis 3 (CA3SL) in cultured hippocampal slices. E2 also increased the spine density at the proximal site of CA3 apical dendrites in CA3SL and PSD95 was clustered on these spine heads. The effects of E2 on the expression of PSD95 and the spine density disappeared when the dentate gyrus (DG) had been excised at 1 day in vitro (DIV). FM1-43 analysis of subregional hippocampal neuron cultures which were comprised of Ammon's horn neurons, DG neurons, or a mixture of these neurons, revealed that E2 increased the number of presynaptic sites in the cultures that contained DG neurons. K252a, a potent inhibitor of the high affinity receptor of brain-derived neurotrophic factor (BDNF), and function-blocking antibody to BDNF (BDNFAB) completely inhibited the effects of E2 in hippocampal slice cultures and subregional neuron cultures, whereas ICI182,780 (ICI), a strong antagonist of nuclear estrogen receptors (nERs), did not. Expression of BDNF in DG neurons was markedly higher than that in Ammon's horn neurons and E2 did not affect these expression levels. E2 significantly increased the BDNF release from DG neurons. KT5720, a specific inhibitor of 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA), and Rp-adenosine 3', 5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMP), a non-hydrolyzable diastereoisomer and a potent inhibitor of PKA, completely suppressed the E2-induced increase in BDNF release, whereas ICI and U0126, a potent inhibitor of MAP kinase kinase (MEK), did not. These results suggest that E2 induces synaptogenesis between mossy fibers and CA3 neurons by enhancing BDNF release from DG granule cells in a nER-independent and PKA-dependent manner.
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PMID:beta-Estradiol induces synaptogenesis in the hippocampus by enhancing brain-derived neurotrophic factor release from dentate gyrus granule cells. 1743 70

The Arabidopsis mitogen-activated protein kinase (MAPK) kinase 2 (MKK2) was shown to mediate cold and salt stress responses through activation of the two MAP kinases MPK4 and MPK6. Transcriptome analysis of plants expressing constitutively active MKK2 (MKK2-EE plants) showed altered expression of genes induced by abiotic stresses but also a significant number of genes involved in defense responses. Both MPK4 and MPK6 became rapidly activated upon Pseudomonas syringae pv. tomato DC3000 infection and MKK2-EE plants showed enhanced levels of MPK4 activation. Although MKK2-EE plants shared enhanced expression of genes encoding enzymes of ethylene (ET) and jasmonic acid (JA) synthesis, ET, JA, and salicylic acid (SA) levels did not differ dramatically from those of wild-type or mkk2-null plants under ambient growth conditions. Upon P. syringae pv. tomato DC3000 infection, however, MKK2-EE plants showed reduced increases of JA and SA levels. These results indicate that MKK2 is involved in regulating hormone levels in response to pathogens. MKK2-EE plants were more resistant to infection by P. syringae pv. tomato DC3000 and Erwinia carotovora subsp. carotovora, but showed enhanced sensitivity to the fungal necrotroph Alternaria brassicicola. Our data indicate that MKK2 plays a role in abiotic stress tolerance and plant disease resistance.
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PMID:The MAP kinase kinase MKK2 affects disease resistance in Arabidopsis. 1750 36

Pancreatic and lung inflammation during acute pancreatitis is a poorly understood, but clinically important, phenomenon. The proto-oncogene Tpl2 (tumor progression locus-2) has recently been shown to have important immunomodulatory effects on some inflammatory processes, but its importance to pancreatitis has not been previously examined. Our studies were designed to (a) define the effects of Tpl2 on pancreatic and lung inflammation during pancreatitis and (b) identify mechanisms and cell types responsible for those effects. We examined pancreatitis-associated Tpl2 effects in wild type and Tpl2(-/-) mice subjected to either secretagogue-induced or bile salt-induced pancreatitis. To determine the myeloid or non-myeloid lineage of cells responsible for the Tpl2 effects, we used Tpl2(-/-) chimeric mice generated by lethal irradiation followed by bone marrow transplantation. Mechanisms responsible for the effects of Tpl2 ablation on caerulein-induced proinflammatory events were evaluated under in vivo and in vitro conditions using the techniques of electrophoretic mobility shift assay, immunoblot analysis, and quantitative reverse transcription-PCR. We found that Tpl2 ablation markedly reduced pancreatic and lung inflammation in these two dissimilar models of pancreatitis, but it did not alter pancreatic injury/necrosis in either model. The reduction in caerulein-induced pancreatic inflammation is dependent upon Tpl2 ablation in non-myeloid cells and is associated with both in vivo and in vitro inhibition of MEK, JNK, and AP-1 activation and the expression of MCP-1, MIP-2, and interleukin-6. Non-myeloid cell expression of Tpl2 regulates pancreatic inflammation during pancreatitis by mediating proinflammatory signals and the generation of neutrophil chemoattracting factors.
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PMID:Tumor progression locus-2 is a critical regulator of pancreatic and lung inflammation during acute pancreatitis. 1753 24

Proteins containing the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants, participate in diverse biological processes. The PB1 domains adopt a ubiquitin-like beta-grasp fold, containing two alpha helices and a mixed five-stranded beta sheet, and are classified into groups harboring an acidic OPCA motif (type I), the invariant lysine residue on the first beta strand (type II), or both (type I/II). The OPCA motif of a type I PB1 domain forms salt bridges with basic residues, especially the conserved lysine, of a type II PB1 domain, thereby mediating a specific PB1-PB1 heterodimerization, whereas additional contacts contribute to high affinity and specificity of the modular interaction. The canonical PB1 dimerization is required for the formation of complexes between p40(phox) and p67(phox) (for activation of the NADPH oxidase crucial for mammalian host defense), between the scaffold Bem1 and the guanine nucleotide exchange factor Cdc24 (for polarity establishment in yeasts), and between the polarity protein Par6 and atypical protein kinase C (for cell polarization in animal cells), as well as for the interaction between the mitogen-activated protein kinase kinase kinases MEKK2 or MEKK3 and the downstream target mitogen-activated protein kinase kinase MEK5 (for early cardiovascular development in mammals). PB1 domains can also mediate interactions with other protein domains. For example, an intramolecular interaction between the PB1 and PX domains of p40(phox) regulates phagosomal targeting of the microbicidal NADPH oxidase; the PB1 domain of MEK5 is likely responsible for binding to the downstream kinase ERK5, which lacks a PB1 domain; and the scaffold protein Nbr1 associates through a PB1-containing region with titin, a sarcomere protein without a PB1 domain. This Review describes various aspects of PB1 domains at the molecular and cellular levels.
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PMID:Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants. 1772 78


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