Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolysis by the ubiquitin/proteasome pathway regulates the intracellular level of several proteins, some of which control cell proliferation and cell cycle progression. To determine what kinds of signaling cascades are activated or inhibited by proteasome inhibition, we treated PC12 cells with specific proteasome inhibitors and subsequently performed in-gel kinase assays. N-Acetyl-Leu-Leu-norleucinal and lactacystin, which inhibit the activity of the proteasome, induced the activation of p42/p44 mitogen-activated protein (MAP) kinases [extracellular signal-regulated kinases (ERKs) 1 and 2]. In contrast, N-acetyl-Leu-Leu-methional, which inhibits the activity of calpains, but not of the proteasome, failed to induce ERK activation. Uniquely, the kinetics of MAP kinase activation induced by proteasome inhibitors are very slow compared with those resulting from activation by nerve growth factor; ERK activation is detectable only after a 5-h treatment with the inhibitors, and its activity remained unchanged for at least until 27 h. Proteasome inhibitor-initiated ERK activation is inhibited by pretreatment with the ERK kinase inhibitor PD 98059, as well as by overexpression of a dominant-negative form of Ras. Thus, proteasome inhibitors induce sustained ERK activation in a Ras-dependent manner. Proteasome inhibitor-induced neurite outgrowth, however, is not inhibited by PD 98059, indicating that sustained activation of ERKs is not the factor responsible for proteasome inhibitor-induced morphological differentiation. Our data suggest the presence of a novel mechanism for activation of the MAP kinase cascade that involves proteasome activity.
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PMID:Delayed and sustained activation of p42/p44 mitogen-activated protein kinase induced by proteasome inhibitors through p21(ras) in PC12 cells. 1061 9

Insulin receptor substrate-1 (IRS-1) is a major substrate of the insulin receptor and acts as a docking protein for Src homology 2 domain containing signaling molecules that mediate many of the pleiotropic actions of insulin. Insulin stimulation elicits serine/threonine phosphorylation of IRS-1, which produces a mobility shift on SDS-PAGE, followed by degradation of IRS-1 after prolonged stimulation. We investigated the molecular mechanisms and the functional consequences of these phenomena in 3T3-L1 adipocytes. PI 3-kinase inhibitors or rapamycin, but not the MEK inhibitor, blocked both the insulin-induced electrophoretic mobility shift and degradation of IRS-1. Adenovirus-mediated expression of a membrane-targeted form of the p110 subunit of phosphatidylinositol (PI) 3-kinase (p110CAAX) induced a mobility shift and degradation of IRS-1, both of which were inhibited by rapamycin. Lactacystin, a specific proteasome inhibitor, inhibited insulin-induced degradation of IRS-1 without any effect on its electrophoretic mobility. Inhibition of the mobility shift did not significantly affect tyrosine phosphorylation of IRS-1 or downstream insulin signaling. In contrast, blockade of IRS-1 degradation resulted in sustained activation of Akt, p70 S6 kinase, and mitogen-activated protein (MAP) kinase during prolonged insulin treatment. These results indicate that insulin-induced serine/threonine phosphorylation and degradation of IRS-1 are mediated by a rapamycin-sensitive pathway, which is downstream of PI 3-kinase and independent of ras/MAP kinase. The pathway leads to degradation of IRS-1 by the proteasome, which plays a major role in down-regulation of certain insulin actions during prolonged stimulation.
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PMID:A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. 1084 81

Prolonged eosinophil survival is an essential step in the late and chronic phases of allergic inflammation and is regulated by the eosinophil survival cytokines. Our work has demonstrated that tumour necrosis factor (TNF)-alpha enhances survival (Trypan blue exclusion test) of human peripheral blood eosinophils from mildly allergic patients in a dose-dependent manner. The survival activity of TNF-alpha was inhibited by anti-TNF-RI, anti-TNF-RII antagonist antibodies and anti-granulocyte-monocyte colony-stimulating factor (GM-CSF) neutralizing antibodies but not by anti-interleukin (IL)-3 or anti-IL-5 antibodies. Furthermore, TNF-alpha-induced GM-CSF release from eosinophils. Anti-TNF-alpha antibodies also inhibited GM-CSF release from eosinophils induced by rat mast cell sonicate, which enhances eosinophil survival. To define the signal transduction pathway involved in GM-CSF production, eosinophils were incubated either with various mitogen-activated protein kinases (MAPK) inhibitors (MEK, JNK, P38), or Cyclosporin A (calcineurin inhibitor), or MG-132 (proteasome inhibitor). Only the proteasome inhibitor significantly decreased both TNF-alpha-enhanced eosinophil survival (from 38.1+/-4.1% to 13.3+/-1.4%) and GM-CSF release (from 6.2+/-0.7 pg/ml to 0.3+/-0.1 pg/ml). TNF-alpha also induced nuclear factor-kappaB (NF-kappaB) translocation to the nucleus, an essential step in GM-CSF mRNA production. All these findings provide evidence that NF-kappaB is involved in TNF-alpha-enhanced eosinophil survival through the regulation of GM-CSF production by eosinophils.
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PMID:Mechanism of tumour necrosis factor alpha mediated eosinophil survival. 1150 5

Enterohemorrhagic Escherichia coli (EHEC) infections are associated with hemorrhagic colitis and the hemolytic-uremic syndrome (HUS). In vivo, elevated plasma levels of the proinflammatory cytokine interleukin-8 (IL-8) in EHEC-infected children are correlated with a high risk of developing HUS. As IL-8 gene transcription is regulated by the transcription factors NF-kappaB and AP-1, we analyzed the role of these factors in the regulation of IL-8 production after infection of the epithelial intestinal T84 cell line by EHEC. By 6 h of infection, EHEC had induced significant secretion of IL-8 (35.84 +/- 6.76 ng/ml versus 0.44 +/- 0.04 ng/ml in control cells). EHEC induced AP-1 and NF-kappaB activation by 3 h of infection. Moreover, the three mitogen-activated protein kinases (MAPK) (ERK1/2, p38, and JNK) were phosphorylated in EHEC-infected T84 cells concomitant with induction of AP-1 DNA binding activity, and IkappaB-alpha was phosphorylated and then degraded concomitant with induction of NF-kappaB DNA binding activity. Pretreatment of cells with the highly specific MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and/or the proteasome inhibitor ALLN led to inhibition of the IL-8 secretion induced in EHEC-infected T84 cells. These findings demonstrate that (i) EHEC can induce in vitro a potent proinflammatory response by secretion of IL-8 and (ii) the secretion of IL-8 is due to the involvement of MAPK, AP-1, and NF-kappaB signaling pathways.
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PMID:Enterohemorrhagic Escherichia coli infection induces interleukin-8 production via activation of mitogen-activated protein kinases and the transcription factors NF-kappaB and AP-1 in T84 cells. 1195 64

The CC chemokine eotaxin is a potent eosinophil-specific chemoattractant that is crucial for allergic inflammation. Allergen-induced tumour necrosis factor (TNF) has been shown to induce eotaxin synthesis in eosinophils. Nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPK) have been found to play an essential role for the eotaxin-mediated eosinophilia. We investigated the modulation of NF-kappaB and MAPK activation in TNF-induced eotaxin release of human eosinophils. Human blood eosinophils were purified from fresh buffy coat using magnetic cell sorting. NF-kappaB pathway-related genes were evaluated by cDNA expression array system. Degradation of IkappaBalpha and phosphorylation of MAPK were detected by Western blot. Activation of NF-kappaB was determined by electrophoretic mobility shift assay. Eotaxin released into the eosinophil culture medium was measured by ELISA. TNF was found to up-regulate the gene expression of NF-kappaB and IkappaBalpha in eosinophils. TNF-induced IkappaBalpha degradation was inhibited by the proteasome inhibitor N-cbz-Leu-Leu-leucinal (MG-132) and a non-steroidal anti-inflammatory drug sodium salicylate (NaSal). Using EMSA, both MG-132 and NaSal were found to suppress the TNF-induced NF-kappaB activation in eosinophils. Furthermore, TNF was shown to induce phosphorylation of p38 MAPK time-dependently but not extracellular signal-regulated kinases (ERK). Inhibition of NF-kappaB activation and p38 MAPK activity decreased the TNF-induced release of eotaxin from eosinophils. These results indicate that NF-kappaB and p38 MAPK play an important role in TNF-activated signalling pathway regulating eotaxin release by eosinophils. They have also provided a biochemical basis for the potential of using specific inhibitors of NF-kappaB and p38 MAPK for treating allergic inflammation.
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PMID:Activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB in tumour necrosis factor-induced eotaxin release of human eosinophils. 1206 3

Mitogen-activated protein kinases/extracellular signal regulated kinases (MAPKs/ERKs) are typically thought to be soluble cytoplasmic enzymes that translocate to the nucleus subsequent to their phosphorylation by their activating kinases or mitogen-activated protein/extracellular signal regulated kinase kinase. We report here the first example of nuclear translocation of a MAPK that occurs via temporally regulated exit from a membranous organelle. Confocal microscopy examining the subcellular localization of ERK3 in several cell lines indicated that this enzyme was targeted to the Golgi/endoplasmic reticulum Golgi intermediate compartment. Deletion analysis of green fluorescent protein (GFP)-ERK3 uncovered a nuclear form that was carboxy-terminally truncated and established a Golgi targeting motif at the carboxy terminus. Immunoblot analysis of cells treated with the proteasome inhibitor MG132 further revealed two cleavage products, suggesting that in vivo, carboxy-terminal cleavage of the full-length protein controls its subcellular localization. In support of this hypothesis, we found that deletion of a small region rich in acidic residues within the carboxy terminus eliminated both the cleavage and nuclear translocation of GFP-ERK3. Finally, cell cycle synchronization studies revealed that the subcellular localization of ERK3 is temporally regulated. These data suggest a novel mechanism for the localization of an MAPK family member, ERK3, in which cell cycle-regulated, site-specific proteolysis generates the nuclear form of the protein.
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PMID:A novel mechanism for mitogen-activated protein kinase localization. 1526 85

Survivin is a member of the inhibitors of apoptosis protein (IAP) family and is highly expressed in various cancer cells. However, the molecular mechanisms regulating survivin expression remain unclear. In this study, we investigated the role of mitogen-activated protein kinases (MAPKs) in regulating survivin in the human lung adenocarcinoma cell line H1355 in response to arsenic trioxide (As(3+)). Our data indicated that As(3+) induced cytotoxicity accompanied by down-regulation of survivin, cleavage of Poly ADP-ribosyl polymerase (PARP) and activations of MAPKs, including ERK1/2, p38 and c-jun N-terminal kinase (JNK). We found that blockage of p38 or JNK activation attenuated the As(3+)-induced survivin down-regulation and PARP cleavage with significant reversal of cell viability, however, by only 5-8%. On the other hand, the MEK inhibitor PD098059 or the ubiquitin-proteasome inhibitor MG-132 exhibited little effect on survivin down-regulation and PARP cleavage induced by As(3+). In this study, we demonstrated that As(3+) could down-regulate survivin via activations of p38 and JNK in an ubiquitin-proteasome independent pathway and lead to cytotoxicity and apoptosis in the human lung adenocarcinoma cell line H1355.
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PMID:Mitogen-activated protein kinases mediate arsenic-induced down-regulation of survivin in human lung adenocarcinoma cells. 1632 41

Our previous work demonstrated that the proteasome is central to most of genes induced by lipopolysaccharide. In this study, we evaluated the role of the proteasome in response to two other microbial stimuli, CpG DNA (bacterial DNA) and peptidoglycan (PG), by measuring the effect of proteasome inhibition on cytokine secretion, induction of inflammatory gene expression, and activation of mitogen-activated protein kinases (MAPK) in murine macrophages. Pretreatment of macrophage cultures with lactacystin, a well-established proteasome inhibitor, significantly repressed tumor necrosis factor alpha secretion and tumor necrosis factor alpha and interleukin 1 beta gene expression, blocked the degradation of IkappaB, and dysregulated phosphorylation of MAPK induced by CpG DNA or PG. With respect to MAPK, lactacystin blocked expression of PG- or CpG-induced phosphorylated ERK1 and ERK2 and increased expression of phosphorylated c-Jun amino-terminal kinase but had no significant effect on phosphorylated p38. Increased expression of phoshorylated c-Jun amino-terminal kinase did not lead to an increase in AP-1 binding activity. Collectively, these data strongly support the conclusion that the proteasome is a key regulator of the CpG DNA- and PG-induced signaling pathways.
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PMID:Proteasome-mediated regulation of CpG DNA- and peptidoglycan-induced cytokines, inflammatory genes, and mitogen-activated protein kinase activation. 1672 Dec 67

This study was designed to test the hypothesis that inhibition of agonist-induced delta-receptor down-regulation would block the development of opioid tolerance in a cell-based model. A human embryonic kidney 293 cell line was established that expressed an epitope-tagged delta-opioid receptor (DOR). Treatment of DOR cells with Tyr-d-Ala-Gly-Phe-d-Leu-enkephalin (DADL) resulted in a time-dependent decrease in the B(max) of delta-opioid receptor binding sites and immunoreactive receptor protein. When cells were coincubated with the proteasome inhibitor N-benzyloxycarbonyl-l-leucyl-l-leucyl-l-leucinal (ZLLL) and DADL, the magnitude of the agonist-induced decrease in B(max) and immunoreactive receptor protein was reduced compared with DADL treatment alone. Acute treatment of DOR cells with DADL caused a 3-fold increase in the level of phosphorylated mitogen-activated protein (MAP) kinase. Prior exposure of DOR cells to DADL completely abrogated the agonist-induced activation of MAP kinase. When DOR cells were coincubated with DADL and ZLLL, the proteasome inhibitor prevented the loss of agonist activation of MAP kinase. Acute treatment of DOR cell membranes with DADL stimulated [(35)S]guanosine 5'-3-O-(thio-)triphosphate (GTPgammaS) binding. When DOR cells were preincubated with DADL, the agonist-induced increase in [(35)S]GTPgammaS binding was attenuated. Coincubation of ZLLL and agonist partially prevented the decreased responsiveness to agonist stimulation. The results of this study demonstrated that inhibition of agonist-induced down regulation with a proteasome inhibitor attenuated opioid tolerance in a cellular model, and suggest that coadministration of a proteasome inhibitor with chronic opioid agonist treatment may be useful for limiting opioid tolerance in vivo.
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PMID:Inhibition of agonist-induced down-regulation of the delta-opioid receptor with a proteasome inhibitor attenuates opioid tolerance in human embryonic kidney 293 cells. 1715 61

Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl(+) leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 microM, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cdelta (PKCdelta) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH(2)-terminal kinase and p38. The specific PKCdelta inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCdelta plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.
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PMID:Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cdelta. 1749 69


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