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)

We tested the hypothesis that 5-HT promotes the differentiation of enteric neurons by stimulating a developmentally regulated receptor expressed by crest-derived neuronal progenitors. 5-HT and the 5-HT(2) agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine(.)HCl (DOI) enhanced in vitro differentiation of enteric neurons, both in dissociated cultures of mixed cells and in cultures of crest-derived cells isolated from the gut by immunoselection with antibodies to p75(NTR). The promotion of in vitro neuronal differentiation by 5-HT and DOI was blocked by the 5-HT(1/2) antagonist methysergide, the pan-5-HT(2) antagonist ritanserin, and the 5-HT(2B/2C)-selective antagonist SB206553. The 5-HT(2A)-selective antagonist ketanserin did not completely block the developmental effects of 5-HT. 5-HT induced the nuclear translocation of mitogen-activated protein kinase. This effect was blocked by ritanserin. mRNA encoding 5-HT(2A) and 5-HT(2B) receptors was detected in the fetal bowel (stomach and small and large intestine), but that encoding the 5-HT(2C) receptor was not. mRNA encoding the 5-HT(2B) receptor and 5-HT(2B) immunoreactivity were found to be abundant in primordial [embryonic day 15 (E15)-E16] but not in mature myenteric ganglia. 5-HT(2B)-immunoreactive cells were found to be a subset of cells that expressed the neuronal marker PGP9.5. These data demonstrate for the first time that the 5-HT(2B) receptor is expressed in the small intestine as well as the stomach and that it is expressed by enteric neurons as well as by muscle. It is possible that by stimulating 5-HT(2B) receptors, 5-HT affects the fate of the large subset of enteric neurons that arises after the development of endogenous sources of 5-HT.
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PMID:Serotonin and the 5-HT(2B) receptor in the development of enteric neurons. 1062 7

The sIgG(+) lymphoblastoid B cell line CESS spontaneously produces a high amount of NGF and expresses both high affinity (p140(Trk-A)) and low affinity (p75(NTR)) NGF receptors. Blocking NGF signals with neutralizing antibodies or specific Trk-A inhibitors induces a rapid phosphorylation of antiapoptotic Bcl-2 protein, followed by caspase activation, and apoptotic death of CESS cells. Bcl-2 phosphorylation in several sites within a approximately 60 aa "loop" domain of protein is known to regulate its antiapoptotic function. Accordingly, CESS cells expressing the loop deletional mutant cDNA constructs Bcl-2 Delta40-91 were completely resistant to apoptosis induced by NGF withdrawal, indicating that Bcl-2 phosphorylation is a critical event. NGF withdrawal induces p38 MAPK, but not JNK, activation in CESS cells, and SB203580, a specific inhibitor of p38 MAPK, is able to prevent both Bcl-2 phosphorylation and apoptosis, indicating that p38 MAPK is the enzyme responsible for these events.
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PMID:NGF withdrawal induces apoptosis in CESS B cell line through p38 MAPK activation and Bcl-2 phosphorylation. 1109 80

We show here that the neurotrophin nerve growth factor (NGF), which has been shown to be a mitogen for breast cancer cells, also stimulates cell survival through a distinct signaling pathway. Breast cancer cell lines (MCF-7, T47-D, BT-20, and MDA-MB-231) were found to express both types of NGF receptors: p140(trkA) and p75(NTR). The two other tyrosine kinase receptors for neurotrophins, TrkB and TrkC, were not expressed. The mitogenic effect of NGF on breast cancer cells required the tyrosine kinase activity of p140(trkA) as well as the mitogen-activated protein kinase (MAPK) cascade, but was independent of p75(NTR). In contrast, the anti-apoptotic effect of NGF (studied using the ceramide analogue C2) required p75(NTR) as well as the activation of the transcription factor NF-kB, but neither p140(trkA) nor MAPK was necessary. Other neurotrophins (BDNF, NT-3, NT-4/5) also induced cell survival, although not proliferation, emphasizing the importance of p75(NTR) in NGF-mediated survival. Both the pharmacological NF-kappaB inhibitor SN50, and cell transfection with IkBm, resulted in a diminution of NGF anti-apoptotic effect. These data show that two distinct signaling pathways are required for NGF activity and confirm the roles played by p75(NTR) and NF-kappaB in the activation of the survival pathway in breast cancer cells.
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PMID:Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. 1135 88

Zinc is one of the most abundant transition metals in the brain. A substantial fraction (10-15%) of brain zinc is located inside presynaptic vesicles of certain glutamatergic terminals in a free or loosely bound state. This vesicle zinc is released with neuronal activity or depolarization, probably serving physiologic functions. However, with excess release, as may occur in a variety of pathologic conditions, zinc may translocate to and accumulate in postsynaptic neurons, events which may contribute to selective neuronal cell death. Intracellular mechanisms of zinc neurotoxicity may include disturbances in energy metabolism, increases in oxidative stress, and activation of apoptosis cascades. Zinc inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and depletes nicotinamide adenine dinucleotide (NAD(+)) and adenosine triphosphate (ATP). On the other hand, zinc activates protein kinase C (PKC) and extracellular signal-regulated kinase (Erk-1/2), and induces NADPH oxidase; these events result in oxidative neuronal injury. Zinc can also trigger caspase activation and apoptosis via the p75(NTR) pathway. Interestingly, the converse-depletion of intracellular zinc-also induces neuronal death, but in this case, exclusively via classical apoptosis. In addition to the neurotoxic effect, zinc may contribute to the pathogenesis of chronic neurodegenerative disease. For example, in Alzheimer's disease (AD), mature amyloid plaques, but not preamyloid deposits, are found to contain high levels of zinc, suggesting the role of zinc in the process of plaque maturation. Further insights into roles of zinc in brain diseases may help set a new direction toward the development of effective treatments.
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PMID:Zinc and disease of the brain. 1183 57

P19 embryonic carcinoma cells can be differentiated into neurons that form synaptic connections and that produce a variety of neurotransmitters. Results of RT-PCR indicate that P19 neurons express several neurotrophin receptors (p75(NTR), trkB, and trkC, but not trkA) but they do not express any of the four neurotrophins. Consistent with the presence of trkB but not trkA, BDNF causes rapid phosphorylation of MAP kinases ERK1 and ERK2, but NGF does not. Neurotrophins induce translocation of NF-kappaB into the nucleus. All four neurotrophins induce activation of NF-kappaB in a biphasic manner. This effect is apparently mediated by p75(NTR), because an inhibitor of trk receptors, K252a, does not inhibit activation of NF-kappaB. Instead, K252a itself promotes activation of NF-kappaB and this effect is additive with the effect of neurotrophins. Inhibition of reactive oxygen intermediates with PDTC completely abolishes basal activity of NF-kappaB and strongly inhibits activation of NF-kappaB by neurotrophins, indicating an important role of reactive oxygen intermediates in the pathway by which neurotrophins activate NF-kappaB. NF-kappaB is known to promote expression of the iNOS gene. We found that all four neurotrophins increased iNOS mRNA levels, resulting in increased accumulation of iNOS protein. In contrast, none of the neurotrophins stimulated nNOS mRNA or protein synthesis. PDTC abolishes constitutive and neurotrophin-induced expression of iNOS mRNA and protein and abolishes constitutive expression of nNOS mRNA, suggesting that reactive oxygen intermediates promote expression of nNOS.
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PMID:p75 neurotrophin receptor mediates neurotrophin activation of NF-kappa B and induction of iNOS expression in P19 neurons. 1267 17

Neurotrophins interact with two distinct classes of cell-surface receptors, the Trk receptor tyrosine kinase family and the common neurotrophin receptor p75(NTR). For many years, the biological role of p75(NTR) remained obscure, being relegated to modulating Trk binding of neurotrophins. Recently, the importance of p75(NTR) as a signaling receptor in itself has become increasingly clear. The signals initiated by p75(NTR) are likely to be as complex as those for the Trk family and probably depend on the cell system in which such signaling is being studied. In this study, all members of the neurotrophin family were demonstrated to be capable of stimulating p75(NTR)-mediated activation of the mitogen-activated protein kinase (MAPK) family (ERK1,2). This activation is rapid and transient, peaking at 5-15 min, depending on the cell system. The classical MAPK cascade consists of the reaction series Ras-Raf-MEK-MAPK. The p75(NTR)-induced MAPK activation is MEK dependent but Raf independent. This result implies that neurotrophin activation of p75(NTR) results in some cascade (as yet unknown) that bypasses Raf and converges on MEK to result in activation of MAPK. This activated MAPK is then able to translocate to the nucleus. The effect of this MAPK activation on cell survival is dependent on cell type. These results support the concept that signaling from the p75(NTR) receptor is more diverse and extensive than previously believed.
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PMID:Activation of the mitogen-activated protein kinase pathway through p75NTR: a common mechanism for the neurotrophin family. 1292 29

The sIgG(+) lymphoblastoid B cell line CESS spontaneously produces a high amount of nerve growth factor (NGF) and expresses both high affinity (p140(Trk-A)) and low affinity (p75(NTR)) NGF receptors. Autocrine production of NGF maintains the survival of CESS cells through the continuous deactivation of p38 MAPK, an enzyme able to induce Bcl-2 phosphorylation and subsequent cytochrome c release and caspase activation. In this paper, we show that NGF induces transcriptional activation and synthesis of MAPK phosphatase 1 (MKP-1), a dual specificity phosphatase that dephosphorylates p38 MAPK, thus preventing Bcl-2 phosphorylation. Furthermore, NGF increases MKP-1 protein stability by preventing its degradation through the proteasome pathway. Following NGF stimulation, MKP-1 protein mainly localizes on mitochondria, suggesting an interaction with p38 MAPK in this compartment. Incubation of CESS cells with MKP-1-specific antisense oligonucleotides induces cell death, which was not prevented by exogenous NGF. By contrast, overexpression of native MKP-1, but not of its catalytically impaired form, inhibits apoptosis induced by NGF neutralization in CESS cells. Thus, the molecular mechanisms underlying the survival function of NGF in CESS B cell line predominantly consist in maintaining elevated levels of MKP-1 protein, which controls p38 MAPK activation.
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PMID:Nerve growth factor-dependent survival of CESS B cell line is mediated by increased expression and decreased degradation of MAPK phosphatase 1. 1472 91

Early spherical Xenopus laevis embryos are transformed into a streamlined shape through convergent extension movements. Here we report that a p75(NTR)-related transmembrane protein, NRH1, has an essential function in the regulation of these movements. NRH1 was expressed in marginal zone tissues of the gastrula and in the posterior ectoderm of the neurula. Attenuation of the NRH1 function inhibited convergent extension movements in the embryo and in activin-treated animal caps. NRH1 activated downstream effectors of the Wnt/planar cell polarity pathway: small GTPases and the cascade of MKK7-JNK. Furthermore, gain- and loss-of-function phenotypes of NRH1 were rescued by co-injection of dominant-negative and constitutively active forms of these downstream effectors, respectively, suggesting that NRH1 functions as a positive modulator of planar cell polarity signalling. Interestingly, NRH1 does not require Dishevelled (Xdsh) for the activation of these downstream effectors or translocation of Xdsh to the membrane, suggesting that NRH1 signalling interacts with planar cell polarity signalling downstream of Xdsh. This demonstrates an essential role for p75(NTR)-related signalling in early embryonic morphogenesis.
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PMID:The neurotrophin-receptor-related protein NRH1 is essential for convergent extension movements. 1530 94

Excitotoxicity may be critical in the formation of brain lesions associated with cerebral palsy. When injected into the murine neopallium at postnatal day (P) 5, ibotenate (activating NMDA and metabotropic glutamate receptors) produces neuronal death and white matter cysts. Such white matter cysts resemble those seen in periventricular leukomalacia, a lesion evident in numerous human premature newborns. The goal of this study was to assess BDNF neuroprotection against neonatal excitotoxic lesions. Cortical and white matter lesions induced by ibotenate at P5 were reduced by BDNF by up to 36 and 60%, respectively. BDNF neuroprotection involved TrkB receptors, MAPK pathway and reduced apoptosis. Although BDNF did not prevent the initial appearance of white matter lesions, it promoted secondary decrease of the lesion size. BDNF neuroprotection at P5 was maximal against lesions induced by NMDA or ibotenate but was moderate against lesions produced by an AMPA-kainate agonist. Finally, BDNF exacerbated neuronal death produced by ibotenate at P0 through increased apoptosis and p75(NTR) receptors, while BDNF had no detectable effect on lesions induced at P10. Altogether, these data showed that BDNF neuroprotection against neonatal excitotoxicity is dependent upon the type of activated glutamate receptors, the lesion localization and the developmental stage.
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PMID:BDNF-induced white matter neuroprotection and stage-dependent neuronal survival following a neonatal excitotoxic challenge. 1526 8

Basic fibroblast growth factor (bFGF) induces cell death in cells of the Ewing's sarcoma family of tumors in vivo and in vitro. In this study we demonstrate that this is dependent on the rapid and sustained activation of p38(MAPK), in contrast to the transient activation of p38(MAPK) associated with bFGF-induced cell proliferation. Stem cell factor-induced survival of TC-32 cells was also associated with transient activation of p38(MAPK). Inhibition of p38(MAPK) by SB202190 and p38(MAPK) small interfering RNA reduces bFGF-induced death in TC-32 cells, consistent with the hypothesis that activation of p38(MAPK) is essential for induction of death by bFGF. This appears to be dependent on sustained activation of p38(MAPK), demonstrated by inhibition of bFGF-induced cell death following addition of SB202190 to TC-32 cells 5 min after exposure to bFGF (20 ng/ml) and activation of p38(MAPK). Prolonged activation of p38(MAPK) is accompanied by a rapid and sustained phosphorylation of Ras and ERK; inhibition of ERK phosphorylation using the MEK-1 inhibitor PD98059 rescued approximately 30% of cells from bFGF-induced death suggesting ERK plays a secondary role in the induction of death. This hypothesis is supported by observations in the A673 cell line; bFGF induced sustained activation of ERK and transient activation of p38(MAPK), which was not associated with cell death. These data demonstrate that sustained activation of p38(MAPK) is essential for activation of the death cascade following exposure of Ewing's sarcoma family of tumors cells to bFGF and provide evidence that activation of p38(MAPK) results in an up-regulation of the death receptor p75(NTR).
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PMID:Basic fibroblast growth factor-induced cell death is effected through sustained activation of p38MAPK and up-regulation of the death receptor p75NTR. 1531 Jul 53


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