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

Helicobacter pylori vacuolating cytotoxin, VacA, induces multiple effects on epithelial cells through different cellular events: one involves pore formation, leading to vacuolation, mitochondrial damage, and apoptosis, and the second involves cell signaling, resulting in stimulation of proinflammatory responses and cell detachment. Our recent data demonstrated that VacA uses receptor-like protein tyrosine phosphatase beta (RPTPbeta) as a receptor, of which five residues (QTTQP) at positions 747 to 751 are involved in binding. In AZ-521 cells, which mainly express RPTPbeta, VacA, after binding to RPTPbeta in non-lipid raft microdomains on the cell surface, is localized with RPTPbeta in lipid rafts in a temperature- and VacA concentration-dependent process. Methyl-beta-cyclodextrin (MCD) did not block binding to RPTPbeta but inhibited translocation of VacA with RPTPbeta to lipid rafts and all subsequent events. On the other hand, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), which disrupts anion channels, did not inhibit translocation of VacA to lipid rafts or VacA-induced activation of p38 mitogen-activated protein (MAP) kinase, but inhibited VacA internalization followed by vacuolation. Thus, p38 MAP kinase activation did not appear to be required for internalization. In contrast, phosphatidylinositol-specific phospholipase C (PI-PLC) inhibited translocation, as well as p38 MAP kinase/ATF-2 activation, internalization, and VacA-induced vacuolation. Neither NPPB nor PI-PLC affected VacA binding to cells and to its receptor, RPTPbeta. Thus, receptor-dependent translocation of VacA to lipid rafts is critical for signaling pathways leading to p38 MAP kinase/ATF-2 activation and vacuolation.
 ...
PMID:Clustering of Helicobacter pylori VacA in lipid rafts, mediated by its receptor, receptor-like protein tyrosine phosphatase beta, is required for intoxication in AZ-521 Cells. 1703 May 83

Studies on chemoprevention of cancer are generating increasing interest. The anti-neoplastic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) involves cyclooxygenase (COX)-dependent and COX-independent mechanisms. Evidence suggests that mitogen-activated protein kinases (MAPKs) may mediate apoptotic signaling induced by anti-neoplastic agents. While many reports have revealed the existence of MAPK activation in apoptosis induced by various stimuli, the signaling transduction pathways used by NSAIDs to trigger apoptosis in human renal cell carcinoma (RCC) remain largely unknown. Treatment of RCC 786-O cells with indomethacin resulted in growth regression and apoptosis. Caspase-dependent apoptosis was evidenced by the detection of enzymatic activities of caspase-3, caspase-6, and caspase-9 and suppression of toxicity using a caspase inhibitor. Indomethacin treatment was associated with increased expression of glucose-regulated protein 78 (GRP78) and C/EBP homologus protein (CHOP) and activation of ATF-6, characteristics of endoplasmic reticulum stress. In addition, the concomitant induction of peroxisome proliferator-activated receptor (PPAR), especially PPAR-beta, was apparent in treated cells. Western blotting revealed the activation of extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) with indomethacin treatment. Selective inhibitors of ERK, p38 MAPK, and JNK suppressed the induction of GRP78, CHOP, and PPAR-beta, attenuated indomethacin-induced cytotoxicity and reduced increased caspase activity. LY294002, a phosphoinositide-3 kinase (PI3K)/AKT inhibitor, and Trolox, an antioxidant, suppressed indomethacin-induced cytotoxicity and caspase activation. Furthermore, Trolox attenuated indomethacin-induced increased phosphorylation in ERK, p38 MAPK, JNK, and AKT. In conclusion, our findings establish a mechanistic link between the oxidative stress, PI3K/AKT pathway, MAPK pathway and indomethacin-induced cellular alterations and apoptosis in 786-O cells.
 ...
PMID:Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. 1734 18

HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-kappaB and CREB (cAMP-response element-binding protein)/ATF. Transforming growth factor-beta-activated kinase 1 (TAK1) has been shown to play a critical role in these transcription factors. Here, we found that TAK1 was constitutively activated in Tax-positive HTLV-1-transformed T cells. Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. Surprisingly, TAK1 was not involved in the activation of NF-kappaB. On the other hand, JNK and p38 mitogen-activated protein kinases were activated by TAK1. In addition, ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-kappaB.
 ...
PMID:Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB. 1762 13

Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-kappaB activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.
 ...
PMID:Herpes simplex virus remodels T-cell receptor signaling, resulting in p38-dependent selective synthesis of interleukin-10. 1780 1

Because mitogen-activated protein kinases (MAPK) are downstream effectors of antioxidant responses, changes in GSH levels in an organism might induce organ-specific responses. To test our hypothesis, mice were treated intraperitoneally with L-buthionine-S-R-sulfoximine (BSO) to inhibit GSH synthesis. A time-related GSH depletion in the liver and kidney correlated with p38(MAPK) phosphorylation and induction of thioredoxin 1 (Tx-1) transcription. This positive regulation was associated with nuclear translocation of NF-kappaB and ATF-2 and c-Jun phosphorylation in the liver, but only c-Jun phosphorylation in the kidney. Increased levels of GSH were observed in the brain together with extracellular regulated kinase 2 (ERK2) activation, Nrf2 nuclear accumulation, and increases in transcription of Nrf2, xCT, gamma-glutamylcysteine synthetase (gammaGCSr), and Tx-1. Pretreatment with MAPK inhibitors SB203580 and U0126, or addition of the exogenous thiol N-acetylcysteine, abrogated both p38(MAPK) and ERK2 activation as well as downstream effects on gene expression. No effect on gammaGCSr was observed. These results indicate that in mice, GSH depletion is associated with p38(MAPK) phosphorylation in the liver and kidney and with ERK2 activation in the brain, in what could be considered part of the brain's protective response to thiol depletion.
 ...
PMID:Glutathione depletion activates mitogen-activated protein kinase (MAPK) pathways that display organ-specific responses and brain protection in mice. 1789 47

Taxol (paclitaxel) is a new antineoplastic drug that has shown promise in the treatment of different tumor types. However, the molecular mechanisms governing taxol-induced apoptosis are poorly understood. Activation of mitogen-activated protein (MAP) kinases is induced by a wide variety of external stress signals and may lead to apoptosis. Therefore, we challenged the human melanoma cell lines A375 and BLM with taxol and characterized the molecular mechanisms regulating taxol-induced apoptosis. Taxol resulted in the activation of apoptosis signal regulated kinase (ASK)1, c-jun NH(2)-terminal kinase (JNK), p38(MAPK) and extracellular-regulated kinase (ERK) together with the downregulation of uncoupling protein 2 (UCP2). In addition, reactive oxygen species (ROS) were induced and DNA-binding activity of the transcription factors AP-1, ATF-2 and ELK-1 was enhanced. Ultimately, cytochrome c was released, and caspases-9 and -3 as well as PARP were cleaved. Pretreatment of melanoma cells with the JNK inhibitor (SP600125) or the p38 inhibitor (SB203580) blocked taxol-induced UCP2 downregulation, ROS generation and apoptosis, whereas the ERK inhibitor (PD98059) had no such effect. Our data provide evidence that taxol-induced mitochondrial stress occurs through the activation of both JNK and p38 pathways, and suggest a novel role for UCP2 in the modulation of taxol-induced apoptosis of melanoma cells.
 ...
PMID:Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2. 1806 34

Neonatal encephalopathy with seizures (NEWS) is a previously undescribed autosomal recessive disease of standard poodle puppies. Affected puppies are small and weak at birth. Many die in their first week of life. Those surviving past 1 week develop ataxia, a whole-body tremor, and, by 4 to 6 weeks of age, severe generalized clonic-tonic seizures. None have survived to 7 weeks of age. Cerebella from affected puppies were reduced in size and often contained dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons. We used deoxyribonucleic acid samples from related standard poodles to map the NEWS locus to a 2.87-Mb segment of CFA36, which contains the canine ortholog of ATF2. This gene encodes activating transcription factor 2 (ATF-2), which participates in the cellular responses to a wide variety of stimuli. We amplified and sequenced all coding regions of canine ATF2 from a NEWS-affected puppy and identified a T > G transversion that predicts a methionine-to-arginine missense mutation at amino acid position 51. Methionine-51 lies within a hydrophobic docking site for mitogen-activated protein kinases that activate ATF-2 so the arginine substitution is likely to interfere with ATF-2 activation. All 20 NEWS-affected puppies in the standard poodle family were homozygous for the mutant G allele. The 58 clinically normal family members were either G/T heterozygotes or homozygous for the ancestral T allele. There are no previous reports of spontaneous ATF2 mutations in people or animals; however, atf2-knockout mice have cerebellar lesions that are similar to those in puppies with NEWS.
 ...
PMID:A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. 1807 59

LPS stimulation of monocytes/macrophages induces the expression of genes encoding proinflammatory cytokines and the procoagulant protein, tissue factor. Induction of these genes is mediated by various signaling pathways, including mitogen-activated protein kinases, and several transcription factors, including Egr-1, AP-1, ATF-2, and NF-kappaB. We used a genetic approach to determine the role of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway in the regulation of LPS signaling and gene expression in isolated macrophages and in mice. The PI3K-Akt pathway is negatively regulated by the phosphatase and tensin homologue (PTEN). We used peritoneal exudate cells from Pik3r1-deficient mice, which lack the p85alpha regulatory subunit of PI3K and have reduced PI3K activity, and peritoneal macrophages from PTEN(flox/flox)/LysMCre mice (PTEN(-/-)), which have increased Akt activity. Analysis of LPS signaling in Pik3r1(-/-) and PTEN(-/-) cells indicated that the PI3K-Akt pathway inhibited activation of the ERK1/2, JNK1/2, and p38 mitogen-activated protein kinases and reduced the levels of nuclear Egr-1 protein and phosphorylated ATF-2. Modulating the PI3K-Akt pathway did not affect LPS-induced degradation of IkappaBalpha or NF-kappaB nuclear translocation. LPS induction of TNF-alpha, IL-6, and tissue factor gene expression was increased in Pik3r1(-/-) peritoneal exudate cells and decreased in PTEN(-/-) peritoneal macrophages compared with wild-type (WT) cells. Furthermore, LPS-induced inflammation and coagulation were enhanced in WT mice containing Pik3r1(-/-) bone marrow compared with WT mice containing WT bone marrow and in mice lacking the p85alpha subunit in all cells. Taken together, our results indicate that the PI3K-Akt pathway negatively regulates LPS signaling and gene expression in monocytes/macrophages.
 ...
PMID:Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages. 1832 34

The work presented here intends to address the question of whether the immediate/early promoter of cytomegalovirus (CMV), which is widely used for expressing transgenes in eukaryotic cells, yields a constitutive expression of the transgenes under stress conditions in Saccharomyces cerevisiae cells. This information would also be relevant because in the tetracycline-regulated expression (tetO) system, which is one of the first choices for studying gene function from yeast to human cells, the CMV promoter controls the expression of the tetO transactivator. We found that the CMV promoter in yeast cells is bidirectionally induced by osmotic stress and in glycerol media. The mitogen-activated protein (MAP) kinase Hog1 controls CMV activation by osmotic stress through the ATF/CRE-related transcription factor Sko1 and the yeast osmostress factor Hot1. Our results indicate that the CMV and tetO expression systems respond to external signals and this should be considered before using these systems in yeast. Moreover, our results also suggest that CMV could be regulated by the intracellular glucose concentration in human cells.
 ...
PMID:The bidirectional cytomegalovirus immediate/early promoter is regulated by Hog1 and the stress transcription factors Sko1 and Hot1 in yeast. 2036 87

Triethylene glycol dimethacrylate (TEGDMA) is a resin monomer available for short exposure scenarios of oral tissues due to incomplete polymerization processes of dental composite materials. The generation of reactive oxygen species (ROS) in the presence of resin monomers is discussed as a common mechanism underlying cellular reactions as diverse as disturbed responses of the innate immune system, inhibition of dentin mineralization processes, genotoxicity and a delayed cell cycle. Yet, the signaling pathway through a network of proteins that finally initiates the execution of monomer-induced specific cell responses is unknown so far. The aim of the present study was to extend the knowledge of molecular mechanisms of monomer-induced cell death as a basis for reasonable therapy strategies. Thus, the monomer-induced expression and phosphorylation of stress-related transcription factors was analyzed in various cell lines. The time-related induction of apoptosis was investigated as well. The expression of p53 increased in HeLa cell cultures treated with camptothecin (positive control) for 24h, and the formation of p53Ser15 and p53Ser46 was detected in cell nuclei by Western blotting. TEGDMA (3 mm) appeared to stimulate p53 expression only slightly, but increased p21 expression was found in cell nuclei and cytoplasm. Both camptothecin and TEGDMA increased p53 expression to some extent in the nuclear fraction in human transformed pulp-derived cells (tHPC), and similar effects were detected in RAW264.7 macrophages. No clear induction of c-Jun and phospho-c-Jun by TEGDMA was detected in HeLa cell nuclei, and the expression of ATF-2 and phospho-ATF-2 was inhibited in the presence of the monomer. ATF-3 expression was found only in the nuclear fraction of camptothecin-treated HeLa cultures. TEGDMA seemed to inhibit the formation of phospho-c-Jun and phospho-ATF-2 in tHPC, and the monomer acted negatively on the expression of c-Jun, ATF-2 and ATF-3 in RAW264.7 macrophages. These changes in the expression and activation of stress-related transcription factors were time-related to the induction of apoptosis by TEGDMA in all cell lines. The present study provides experimental evidence that TEGDMA interferes with the regulation of cellular pathways through transcription factors activated as a consequence of DNA damage like p53 or initiated downstream of MAPK (mitogen-activated protein kinases) like c-Jun, ATF-2 and ATF-3. The direct causal correlation between DNA damage, activation or inhibition of MAPKs and transcription factors, and apoptosis is under current investigation. However, the induction of apoptosis in different cell lines in the presence of monomers like TEGDMA may be subject to a higher level of complexity than currently suggested by simple linear models.
 ...
PMID:Activation of stress-regulated transcription factors by triethylene glycol dimethacrylate monomer. 2114 83


<< Previous 1 2 3 4 5 Next >>