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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As part of an ongoing project to understand the molecular mechanisms of fruit body development in Lentinula edodes (Shiitake mushroom), RNA fingerprinting by arbitrarily primed PCR (RAP-PCR) was used to identify differentially expressed genes in RNA populations from four stages of L. edodes development vegetative mycelium, primordium, young fruit body and mature fruit body. From 30 RNA fingerprints, we cloned and sequenced 33 RAP fragments after their differential expression patterns had been verified by reverse Northern dot-blot hybridization. Thirteen RAP fragments show high sequence similarity to known gene products which are involved in (1) transport across the plasma membrane (drug efflux pump and sugar transporter); (2) cell cycle control (cyclin B); (3) signal transduction and transcriptional regulation (mitogen-activated protein kinase, Cdc39/Not1, PriA, Jun-D); (4) intracellular molecule trafficking (ubiquitin, plasma membrane proton ATPase, and alpha-adaptin); (5) mitochondrial biogenesis (mitochondrial processing peptidase beta-subunit, mitochondrial glycerol-3-phosphate dehydrogenase); and (6) intermediary metabolism (fructose 1,6 bisphosphatase). The transcript levels for plasma membrane proton ATPase and alpha-adaptin remained constant, whereas the other eleven genes were differentially expressed during L. edodes. development. The expression profiles of the genes suggest that transport across the plasma membrane is important in the mycelial stage. Specific signal transduction and transcriptional controls may play important roles during the initiation of primordia and the formation of young fruiting bodies. When the mushroom matures, expression of genes involved in metabolic pathways becomes prominent. The isolation of these genes indicates their involvement in homobasidiomycete development and suggests new directions for molecular studies on mechanisms of mushroom development.
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PMID:Identification by RNA fingerprinting of genes differentially expressed during the development of the basidiomycete Lentinula edodes. 1066 59

p38 is a member of the mitogen-activated protein (MAP) kinase family. Activation (phosphorylation) of p38 acts as a switch for the transcriptional and translational regulation of a number of proteins, including the proinflammatory cytokines. Investigation of a set of small peptides revealed that, as with protein substrates, p38-alpha behaves as a proline-directed Ser/Thr MAP kinase for a peptide substrate, peptide 4 (IPTSPITTTYFFFKKK). We investigated the steady-state kinetic mechanism of the p38-alpha-catalyzed kinase reaction with EGF receptor peptide, peptide 1, as a substrate. Lineweaver-Burk analysis of the substrate kinetics yielded a family of lines intersecting to the left of the ordinate, with either ATP or peptide 1 as the varied substrate. Kinetic analysis in the presence of ADP yielded a competitive inhibition pattern when ATP was the varied substrate and a noncompetitive pattern if peptide 1 was the varied substrate. At saturating peptide substrate concentrations, inhibition by phosphopeptide product yielded an uncompetitive pattern when ATP was the varied substrate. These data are consistent with ordered binding with ATP as the initial substrate. We provide further evidence of the existence of a productive p38.ATP binary complex in that (a) activated p38-alpha has intrinsic ATPase activity, (b) ATPase and kinase activities are coupled, and (c) inhibitors of ATPase activity also inhibit the kinase activity with a similar inhibition constant. The k(cat) for the kinase reaction was lowered by 1.8-fold when ATP-gamma-S was used. Microviscosity linearly affected the k(cat) values of both the ATP and ATP-gamma-S reactions with a slope of about 0.8. These observations were interpreted to mean that the phosphoryl transfer step is not rate-limiting and that the release of product and/or enzyme isomerization is a possible rate-limiting step(s).
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PMID:Kinetic mechanism of the p38-alpha MAP kinase: phosphoryl transfer to synthetic peptides. 1068 58

The effect of two Ca(2+) ATPase inhibitors, cyclopiazonic acid (CPA) and 2,5-di-(tert-butyl)-1,4-hydroquinone (DTBHQ), on the release of MCP-1 from bone marrow-derived mast cells (BMMCs) were investigated. CPA and DTBHQ increased the intracellular free Ca(2+) concentration ([Ca(2+)](i)) and induced MCP-1 release in a dose-dependent manner. These Ca(2+) ATPase inhibitors induced MCP-1 release in the absence of phorbol ester, in contrast to their induction of TNF-alpha. MCP-1 release reached a maximum at 6-9 h. It was inhibited by treatment with actinomycin D, the immunosuppressant cyclosporin A, and the cytosolic Ca(2+) chelator BAPTA-AM. Furthermore, RT-PCR showed a time-dependent increase of MCP-1 mRNA. Thus MCP-1 release seems to depend on Ca(2+)-dependent transcriptional activation. MCP-1 release was dose-dependently inhibited by the p38 MAP kinase inhibitor SB202190, but not by the p44/42 MAP kinase inhibitor PD98059. Therefore, transcriptional activation of MCP-1 production and its release seem to be dependent on the nuclear factor of activated T cells and p38 MAP kinase activation. This is the first report to show the regulation of MCP-1 production in BMMCs.
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PMID:Effect of Ca(2+) ATPase inhibitors on MCP-1 release from bone marrow-derived mast cells and the involvement of p38 MAP kinase activation. 1068 7

1. Stimulation of the murine macrophage cell line RAW 264.7 with thapsigargin, an endomembrane Ca(2+)-ATPase inhibitor, induced histamine production in a time- and concentration-dependent manner. 2. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), also enhanced histamine production. 3. alpha-Fluoromethylhistidine, a suicide substrate of L-histidine decarboxylase (HDC), suppressed the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production. 4. Both thapsigargin (30 nM) and TPA (30 nM) induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. 5. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially. 6. The other MEK-1 inhibitor, U-0126, also inhibited both the thapsigargin- and TPA-induced histamine production in a concentration-dependent manner. 7. Thapsigargin (30 nM) and TPA (30 nM) increased the levels of HDC mRNA at 4 h, but PD98059 suppressed both the thapsigargin- and TPA-induced increases in the HDC mRNA level. 8. These findings indicate that thapsigargin and TPA induce histamine production in RAW 264.7 cells by increasing the level of HDC mRNA, and that both the thapsigargin- and TPA-induced histamine production are regulated largely by p44/p42 MAP kinase and partially by p38 MAP kinase.
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PMID:Participation of mitogen-activated protein kinase in thapsigargin- and TPA-induced histamine production in murine macrophage RAW 264.7 cells. 1071 50

Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of Na(+)-K(+)-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1 beta gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the Na(+)/Ca(2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta. These findings suggest that Na(+)-K(+)-ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1 beta and TNF-alpha expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations.
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PMID:ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. 1071 38

Thapsigargin, which elevates cytosolic calcium levels by inhibiting the sarcoplasmic/endoplasmic reticulum calcium-dependent ATPase, was tested for its ability to degranulate bone marrow-derived mast cells (BMMCs) from src homology 2-containing inositol phosphatase +/+ (SHIP+/+) and SHIP-/- mice. As was found previously with steel factor, thapsigargin stimulated far more degranulation in SHIP-/- than in SHIP+/+ BMMCs, and this was blocked with the phosphatidylinositol-3 (PI-3) kinase inhibitors, LY294002 and wortmannin. In contrast to steel factor, however, this heightened degranulation of SHIP-/- BMMCs was not due to a greater calcium influx into these cells, nor was the thapsigargin-induced calcium influx inhibited by LY294002, suggesting that the heightened thapsigargin-induced degranulation of SHIP-/- BMMCs was due to a PI-3 kinase-regulated step distinct from that regulating calcium entry. An investigation of thapsigargin-stimulated pathways in both cell types revealed that MAPK was heavily but equally phosphorylated. Interestingly, the protein kinase C inhibitor, bisindolylmaleimide (compound 3), totally blocked thapsigargin-induced degranulation in both SHIP+/+ and SHIP-/- BMMCs. As well, thapsigargin stimulated a PI-3 kinase-dependent, transient activation of protein kinase B, and this activation was far greater in SHIP-/- than in SHIP+/+ BMMCs. Consistent with this, thapsigargin was found to be a potent survival factor, following cytokine withdrawal, for both cell types and was more potent with SHIP-/- cells. These studies have both identified an additional PI-3 kinase-dependent step within the mast cell degranulation process, possibly involving 3-phosphoinositide-dependent protein kinase-1 and a diacylglycerol-independent protein kinase C isoform, and shown that the tumor-promoting activity of thapsigargin may be due to its activation of protein kinase B and subsequent promotion of cell survival.
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PMID:Thapsigargin-induced degranulation of mast cells is dependent on transient activation of phosphatidylinositol-3 kinase. 1086 Oct 44

Previous work from this laboratory demonstrated that arachidonic acid activates c-jun NH(2)-terminal kinase (JNK) through oxidative intermediates in a Ca(2+)-independent manner (Cui X and Douglas JG. Arachidonic acid activates c-jun N-terminal kinase through NADPH oxidase in rabbit proximal tubular epithelial cells. Proc Natl Acad Sci USA 94: 3771-3776, 1997.). We now report that JNK can also be activated via a Ca(2+)-dependent mechanism by agents that increase the cytosolic Ca(2+) concentration (Ca(2+) ionophore A(23187), Ca(2+)-ATPase inhibitor thapsigargin) or deplete intracellular Ca(2+) stores [intracellular Ca(2+) chelator 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM]. The activation of JNK by BAPTA-AM occurs despite a decrease in cytosolic Ca(2+) concentration as detected by the indicator dye fura 2, but appears to be related to Ca(2+) metabolism, because modification of BAPTA with two methyl groups increases not only the chelation affinity for Ca(2+), but also the potency for JNK activation. BAPTA-AM stimulates Ca(2+) influx across the plasma membrane, and the resulting local Ca(2+) increases are probably involved in activation of JNK because Ca(2+) influx inhibitors (SKF-96365, nifedipine) and lowering of the free extracellular Ca(2+) concentration with EGTA reduce the BAPTA-induced JNK activation.
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PMID:Ca(2+)-dependent activation of c-jun NH(2)-terminal kinase in primary rabbit proximal tubule epithelial cells. 1091 7

Cellular stress can trigger a process of self-destruction known as apoptosis. Cells can also respond to stress by adaptive changes that increase their ability to tolerate normally lethal conditions. Expression of the major heat-inducible protein hsp70 protects cells from heat-induced apoptosis. hsp70 has been reported to act in some situations upstream or downstream of caspase activation, and its protective effects have been said to be either dependent on or independent of its ability to inhibit JNK activation. Purified hsp70 has been shown to block procaspase processing in vitro but is unable to inhibit the activity of active caspase 3. Since some aspects of hsp70 function can occur in the absence of its chaperone activity, we examined whether hsp70 lacking its ATPase domain or the C-terminal EEVD sequence that is essential for peptide binding was required for the prevention of apoptosis. We generated stable cell lines with tetracycline-regulated expression of hsp70, hsc70, and chaperone-defective hsp70 mutants lacking the ATPase domain or the C-terminal EEVD sequence or containing AAAA in place of EEVD. Overexpression of hsp70 or hsc70 protected cells from heat shock-induced cell death by preventing the processing of procaspases 9 and 3. This required the chaperone function of hsp70 since hsp70 mutant proteins did not prevent procaspase processing or provide protection from apoptosis. JNK activation was inhibited by both hsp70 and hsc70 and by each of the hsp70 domain mutant proteins. The chaperoning activity of hsp70 is therefore not required for inhibition of JNK activation, and JNK inhibition was not sufficient for the prevention of apoptosis. Release of cytochrome c from mitochondria was inhibited in cells expressing full-length hsp70 but not in cells expressing the protein with ATPase deleted. Together with the recently identified ability of hsp70 to inhibit cytochrome c-mediated procaspase 9 processing in vitro, these data demonstrate that hsp70 can affect the apoptotic pathway at the levels of both cytochrome c release and initiator caspase activation and that the chaperone function of hsp70 is required for these effects.
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PMID:The chaperone function of hsp70 is required for protection against stress-induced apoptosis. 1098 31

The mitogen-activated protein (MAP) kinases are characterized by their requirement for dual phosphorylation at a conserved threonine and tyrosine residue for catalytic activation. The structural consequences of dual-phosphorylation in the MAP kinase ERK2 (extracellular signal-regulated kinase 2) include active site closure, alignment of key catalytic residues that interact with ATP, and remodeling of the activation loop. In this study, we report the specific effects of dual phosphorylation on the individual catalytic reaction steps in ERK2. Dual phosphorylation leads to an increase in overall catalytic efficiency and turnover rate of approximately 600,000- and 50,000-fold, respectively. Solvent viscosometric studies reveal moderate decreases in the equilibrium dissociation constants (K(d)) for both ATP and myelin basic protein. However, the majority of the overall rate enhancement is due to an increase in the rate of the phosphoryl group transfer step by approximately 60,000-fold. By comparison, the rate of the same step in the ATPase reaction is enhanced only 2000-fold. This suggests that optimizing the position of the invariant residues Lys(52) and Glu(69), which stabilize the phosphates of ATP, accounts for only part of the enhanced rate of phosphoryl group transfer in the kinase reaction. Thus, significant stabilization of the protein phosphoacceptor group must also occur. Our results demonstrate similarities between the activation mechanisms of ERK2 and the cell cycle control enzyme, Cdk2 (cyclin-dependent kinase 2). Rather than dual phosphorylation, however, activation of the latter is controlled by cyclin binding followed by phosphorylation at Thr(160).
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PMID:Mechanism of activation of ERK2 by dual phosphorylation. 1101 42

Glucose triggers transcriptional and post-transcriptional mechanisms that increase the amount and the activity of Saccharomyces cerevisiae plasma membrane H(+)-ATPase. In a previous study, we found that a mutation in the Rsp5 ubiquitin-protein ligase enzyme affected the post-transcriptional activation of the enzyme by glucose. Mutations at the RSP5 locus alter the glucose-triggered K(m) decrease. In a genetic screening for multicopy suppressors of the rsp5 mutation, we identified the WSC2/YNL283c gene. Deletion of the WSC2 gene disturbs ATPase activation by glucose, abolishing the K(m) decrease that occurs during this process. Wsc2 is a component of the PKC1-MPK1 mitogen-activated protein kinase (MAPK) signaling pathway that controls the cell wall integrity. Deletion of the MPK1/SLT2 gene disturbs the glucose-triggered K(m) decrease in ATPase.
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PMID:The cell wall integrity/remodeling MAPK cascade is involved in glucose activation of the yeast plasma membrane H(+)-ATPase. 1111 30


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