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)

The regeneration of circulating red blood cells in response to anaemia associated with blood loss or haemolysis involves an increased rate of erythropoiesis and expansion of proerythroblasts, the bone marrow precursor cells that terminally differentiate into mature erythrocytes. This study investigated the mechanisms by which erythropoietin (Epo) and stem cell factor (Scf) modulate the expansion of proerythroblasts. Homogenous populations of primary human proerythroblasts were generated in liquid cultures of CD34(+) cells. In serum-free cultures, proerythroblasts failed to survive in the presence of Epo or Scf alone, but exhibited synergistic proliferation in response to combined Epo and Scf treatment, exhibiting one-log expansion in 5 d. Intracellular signal transduction in response to Epo and Scf revealed that tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5, a downstream target for the non-receptor tyrosine kinase, Janus kinase 2 (Jak2), was mediated by Epo but not Scf. The mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) 1-2 were phosphorylated in response to either Epo or Scf. Phosphorylation of Akt, a signalling molecule downstream of phosphatidylinositol 3-kinase (PI3K), was observed following Scf but not Epo treatment. To determine the contribution of specific signalling pathways to synergistic expansion of proerythroblasts in response to co-operative effects of Epo and Scf, cells were treated with kinase inhibitors targeting Jak2, PI3K and MAPK kinase. There was a significant, dose-dependent inhibition of proerythroblast expansion in response to all three kinase inhibitors. In conclusion, Epo- and Scf-mediated co-operative, synergistic expansion of primary erythroid precursors requires selective activation of multiple signalling pathways, including the Jak-Stat, PI3K and MAPK pathways.
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PMID:Co-operative signalling mechanisms required for erythroid precursor expansion in response to erythropoietin and stem cell factor. 1598 54

Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, ss2-adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium-activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti-myristoylated alanine-rich C kinase substrate (MARCKS), peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen-activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal-regulated kinase (MEK/ERK), inhibitors, human calcium-activated chloride (hCACL2), channel blockers and retinoic acid receptor-a antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.
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PMID:Treatment of airway mucus hypersecretion. 1658 97

The chemokine interleukin-8 (IL-8) has been implicated in inflammatory diseases including periodontitis. In this study the effect of epidermal growth factor (EGF) on the production and regulation of interleukin-8 (IL-8) in human gingival fibroblasts challenged with interleukin-1beta (IL-1beta) was investigated. EGF, in comparison to the effect of IL-1beta, weakly increased the mRNA and protein expression of IL-8 in gingival fibroblasts. When the cells were treated simultaneously with EGF and IL-1beta, however, EGF synergistically enhanced the mRNA expression and production of IL-8. The stimulatory effect of EGF on IL-1beta-induced IL-8 production was completely abolished by the broad range tyrosine kinase inhibitor Herbimycin A, and considerably reduced by the receptor tyrosine kinase specific inhibitor PD 153035. Herbimycin A abolished IL-8 production induced by IL-1beta, whereas PD 153035 had no effect on the cytokine-induced IL-8 production. Furthermore, the p38 mitogen-activated protein (MAP) kinase inhibitor SB 203580 reduced IL-8 production induced by IL-1beta as well as by the combination of EGF and IL-1beta but had no effect on EGF-induced IL-8 production. In conclusion, the study demonstrates that EGF synergistically stimulates IL-8 production in the presence of IL-1beta and that tyrosine kinase(s) seem to be involved in the signalling pathway of IL-1beta and EGF. The synergistic interactions between EGF and IL-1beta on IL-8 production may play an essential role in the pathogenesis of the inflammatory disease periodontitis.
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PMID:Epidermal growth factor synergistically enhances interleukin-8 production in human gingival fibroblasts stimulated with interleukin-1beta. 1667 83

RET/papillary thyroid carcinoma (PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC1 activates the Rap1 small GTPase. The activation of Rap1 was dependent on the phosphorylation of RET Tyr(1062). RET/PTC1 recruited a complex containing growth factor receptor binding protein 2-associated binding protein 1 (Gab1), CrkII (v-crk sarcoma virus CT10 oncogene homologue II), and C3G (Rap guanine nucleotide exchange factor 1). By using dominant-negative and small interfering duplex (small interfering RNA) oligonucleotides, we show that RET/PTC1-mediated Rap1 activation was dependent on CrkII, C3G, and Gab1. Activation of Rap1 was involved in the RET/PTC1-mediated stimulation of the BRAF kinase and the p42/p44 mitogen-activated protein kinases. Proliferation and stress fiber formation of RET/PTC1-expressing PC Cl 3 thyroid follicular cells were inhibited by the dominant-negative Rap1(N17) and by Rap1-specific GTPase-activating protein. Thus, Rap1 is a downstream effector of RET/PTC and may contribute to the transformed phenotype of RET/PTC-expressing thyrocytes.
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PMID:RET/papillary thyroid carcinoma oncogenic signaling through the Rap1 small GTPase. 1721 Jul 21

The small G-protein Ras is a tightly controlled regulator of cell fate. Prolonged or persistent arrest in the activated GTP-loaded state by mutation of Ras as in lung cancer or in a Ras-GTPase-activating protein as in neurofibromatosis type 1 promotes tumorigenesis. We now show that the tumor-suppressor protein merlin (mutated in neurofibromatosis type 2) also controls Ras activity. Systematic analysis of growth factor signaling located the step of merlin interference to the activation of Ras and Rac. Merlin independently uncouples both Ras and Rac from growth factor signals. In the case of Ras, merlin acts downstream of the receptor tyrosine kinase-growth factor receptor binding protein 2 (Grb2)-SOS complex. However, merlin does not bind either SOS or Ras, but it counteracts the ERM (ezrin, radixin, moesin)-dependent activation of Ras, which correlates with the formation of a complex comprising ERM proteins, Grb2, SOS, Ras, and filamentous actin. Because efficient signaling from Ras requires Rac-p21-activated kinase-dependent phosphorylations of Raf and mitogen-activated protein/extracellular signal-regulated kinase kinase, merlin can also inhibit signal transfer from dominantly active Ras mutants. We propose that the interference of merlin with Ras- and Rac-dependent signal transfer represents part of the tumor-suppressive action of merlin.
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PMID:Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. 1723 59

Infectious bursal disease virus (IBDV) induces apoptosis and immunosuppression. To understand the molecular mechanisms involved in the pathogenesis of infectious bursal disease (IBD) and the host-directed antiviral responses, cDNA microarrays were used to identify the differentially expressed transcripts in IBDV-infected chicken embryonic fibroblasts. The results suggest a general suppression of surface receptors, including CD40 ligand and SEMA4D. These are related to T- and B-cell activation and differentiation, which may contribute to the immunosuppression of IBD. In addition, activation of genes involved in Toll-like receptor- and interferon (IFN)-mediated antiviral responses was detected. In particular, upregulation of Toll-like receptor 3, a double-stranded (ds) RNA receptor, and MX1, an IFN-inducible antiviral GTPase, may represent the possible host-directed defence responses against the virus and its dsRNA genome. Interestingly, several lines of evidence suggest the modulation of G protein-coupled receptors and receptor tyrosine kinase signalling pathways, especially the possible transactivation of epidermal growth factor receptor by lysophosphatidic acid. Alteration of these may contribute to the previously reported activation of mitogen-activated protein kinases upon IBDV infection, resulting in macrophage activation and inflammatory responses. Additionally, numerous target genes and inducers of nuclear factor kappa B (NF-kappaB) were upregulated profoundly, implying that IBDV may modulate host-cell survival and apoptosis to support its replication and facilitate viral spread through NF-kappaB activation. In summary, this investigation of host-gene expression unravelled the candidate physiological pathways involved in host-virus interaction on a molecular level, providing a foundation for researchers to design experiments based on testable hypotheses targeting individual genes.
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PMID:Screening of differentially expressed transcripts in infectious bursal disease virus-induced apoptotic chicken embryonic fibroblasts by using cDNA microarrays. 1748 40

Agrin-deficient mice die at birth because of aberrant development of the neuromuscular junctions. Here, we examined the role of agrin at brain synapses. We show that agrin is associated with excitatory but not inhibitory synapses in the cerebral cortex. Most importantly, we examined the brains of agrin-deficient mice whose perinatal death was prevented by the selective expression of agrin in motor neurons. We find that the number of presynaptic and postsynaptic specializations is strongly reduced in the cortex of 5- to 7-week-old mice. Consistent with a reduction in the number of synapses, the frequency of miniature postsynaptic currents was greatly decreased. In accordance with the synaptic localization of agrin to excitatory synapses, changes in the frequency were only detected for excitatory but not inhibitory synapses. Moreover, we find that the muscle-specific receptor tyrosine kinase MuSK, which is known to be an essential component of agrin-induced signaling at the neuromuscular junction, is also localized to a subset of excitatory synapses. Finally, some components of the mitogen-activated protein (MAP) kinase pathway, which has been shown to be activated by agrin in cultured neurons, are deregulated in agrin-deficient mice. In summary, our results provide strong evidence that agrin plays an important role in the formation and/or the maintenance of excitatory synapses in the brain, and we provide evidence that this function involves MAP kinase signaling.
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PMID:Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. 1761 Dec 72

Neurons concentrate mitochondria at sites in the cell that have a high demand for ATP and/or calcium buffering. To accomplish this, mitochondrial transport and docking are thought to respond to intracellular signaling pathways. However, the cell might also concentrate mitochondrial function by locally modulating mitochondrial activity. We tested this hypothesis by measuring the membrane potential of individual mitochondria throughout the axons of chick sensory neurons using the dye tetramethylrhodamine methylester (TMRM). We found no difference in the TMRM mitochondrial-to-cytoplasmic fluorescence ratio (F(m)/F(c)) among three functionally distinct regions: axonal branch points, distal axons, and the remaining axon shaft. In addition, we found no difference in F(m)/F(c) among stationary, retrogradely moving, or anterogradely moving mitochondria. However, F(m)/F(c) was significantly higher in the lamellipodia of growth cones, and among a small fraction of mitochondria throughout the axon. To identify possible signals controlling membrane potential, we used beads covalently coupled to survival and guidance cues to provide a local stimulus along the axon shaft. NGF- or semaphorin 3A-coupled beads caused a significant increase in F(m)/F(c) in the immediately adjacent region of axon, and this was diminished in the presence of the PI3 (phosphatidylinositol-3) kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] or the MAP (mitogen-activated protein) kinase inhibitor U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-amino-phenylthio]butadiene), demonstrating that signaling pathways downstream of both ligands affect the DeltaPsi(m) of mitochondria. In addition, general inhibition of receptor tyrosine kinase activity produced a profound global decrease in F(m)/F(c). Thus, two guidance molecules that exert different effects on growth cone motility both elicit local, receptor-mediated increases in membrane potential.
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PMID:Mitochondrial membrane potential in axons increases with local nerve growth factor or semaphorin signaling. 1870 93

Three prominent hallmarks of triple-negative/basal-like breast carcinomas, a subtype of breast cancer gene phenotype associated with poor relapse-free and overall survival, are overexpression of the epidermal growth factor receptor (EGFR), hyperactivation of the MEK/ERK transduction pathway and high sensitivity to DNA-damaging agents. The cytotoxic interaction between EGFR inhibitors (monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors such as gefitinib) and DNA cross-linking agents (e.g. platinum derivatives) might represent a promising combination for the treatment of triple-negative/basal-like breast tumors that are dependent upon EGFR/MEK/ERK signaling. We evaluated the growth and molecular interactions of the anti-EGFR antibody cetuximab (erbitux) and the DNA cross-linking agent cisplatin (cis-diammedichloroplatinum; CDDP) in the gefitinib-resistant MDA-MB-468 breast cancer cell line, an in vitro model system that shows many of the recurrent basal-like molecular abnormalities including ER-PR-HER2-negative status, TP53 deficiency, EGFR overexpression, PTEN loss and constitutive activation of the MEK/ERK pathway. Unlike other basal-like breast cancer models, MDA-MB-468 cells do not carry mutations of the key DNA repair gene BRCA1. Concurrent treatment with sub-optimal doses of cetuximab significantly enhanced CDDP-induced apoptotic cell death. However, an isobologram-based mathematical assessment of the nature of the interaction revealed a loss of synergism when employing a high-dose of cetuximab. Since BRCA1 depletion has been found to decrease DNA damage repair and cell survival in MDA-MB-468 cells when treated with DNA-damaging drugs, we employed ELISA-based quantitative analyses to measure BRCA1 protein levels in CDDP+/- cetuximab-treated cells. Cetuximab as single agent was as efficient as CDDP at increasing BRCA1 protein expression. Interestingly, cetuximab co-exposure significantly antagonized the ability of CDDP to up-regulate BRCA1 expression. Low-scale phosphor-proteomic approaches [i.e. phospho-receptor tyrosine kinase (RTK) and phospho-mitogen-activated protein kinases (MAPKs) Array Proteome Profiler capable of simultaneously identifying the relative levels of phosphorylation of 42 different RTKs and 23 different MAPKs and other serine/threonine kinases, respectively] revealed the ability of Cetuximab, as single agent, to paradoxically induce hyper-phosphorylation of EGFR while concomitantly deactivating p42/44 (ERK1/ERK2) MAPK. Unexpectedly, ELISA-based quantitative analyses of EGFR protein content demonstrated that simultaneous exposure to cetuximab and optimal doses of CDDP completely depleted EGFR protein in MDA-MB-468 cells. Although these findings preclinically support, at least in part, ongoing clinical trials for 'triple-negative/basal-like' metastatic breast cancer patients who are receiving either cetuximab alone versus cetuximab plus carboplatin (http://www.clinicaltrials.gov/ct/show/NCT00232505), the unexpected ability of CDDP to promote a complete depletion of the cetuximab target EGFR further suggests that treatment schedules, cetuximab/CDDP doses and BRCA1 status should be carefully considered when combining anti-EGFR antibodies and platinum derivatives in triple-negative/basal-like breast carcinomas.
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PMID:Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer. 1902 Jul 49

Recent studies demonstrate that activation of Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors upregulates phosphorylation of mitogen-activated protein kinases (MAPKs) in heterologous cells and neurons. In cultured rat striatal neurons, the present work systematically evaluated the role of a number of protein kinases in forming a signaling cascade transducing NMDA receptor signals to MAPKs. It was found that a brief NMDA application consistently induced rapid and transient phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), a best characterized subclass of MAPKs. This ERK1/2 phosphorylation was resistant to the inhibition of protein kinase C, p38 MAPK, cyclin-dependent kinase 5, receptor tyrosine kinase (epidermal growth factor receptors), or non-receptor tyrosine kinases (including Src) by their selective inhibitors. However, the increase in ERK1/2 phosphorylation was partially blocked by a protein kinase A (PKA) inhibitor. The inhibitors for Ca(2+)/calmodulin-dependent protein kinase (CaMK) or phosphatidylinositol 3-kinase (PI3-kinase) completely blocked the NMDA-stimulated ERK1/2 phosphorylation. In an attempt to characterize the sequential role of CaMK and PI3-kinase, we found that NMDA increased PI3-kinase phosphorylation on Tyr(508), which kinetically corresponded to the ERK1/2 phosphorylation and was blocked by the CaMK inhibitor. These results indicate that the protein kinases are differentially involved in linking NMDA receptors to ERK1/2 in striatal neurons.
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PMID:Regulation of extracellular signal-regulated kinase phosphorylation in cultured rat striatal neurons. 1905 70


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