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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to examine the effects of bone marrow stromal cells (MSCs) cultured in vitro with or without neurotrophic factors transplanted into adult male Wistar rats after traumatic brain injury (TBI). MSCs harvested from donor Wistar rats were cultured with either the culture medium containing brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) or the same culture media without these factors. Control and experimental animals were then traumatized by a controlled cortical impact. One day after the impact, either the placebo or the washed MSCs (1 x 10(6)) cultured with or without NGF and BDNF were transplanted adjacent to the site of injury. In addition, a nontreated group of rats was employed. Motor function of the animals was evaluated by the Rotarod test both before and after the injury. All animals were sacrificed 8 days after TBI, and the brain sections were stained by H&E as well as for immunohistochemistry. MSCs survived and migrated toward the injury site. The group treated with MSCs cultured with BDNF and NGF had a significantly higher number of engrafted cells than the group treated with MSCs cultured without BDNF and NGF (6.3 x 10(4) +/- 4250 compared to 4.1 x 10(4) +/- 3684; p < 0.05). In both groups, some transplanted MSCs showed positive staining for astrocytic (GFAP) and neuronal markers (Neu N and MAP-2). The groups treated with MSCs had better motor function than the groups receiving no treatment or receiving the placebo (PBS; p < 0.05); however, the improvement reached statistical significance only in the group treated with MSCs cultured with neurotrophic factors. These data suggest that more robust motor function described in rats subjected to TBI and treated with intracerebral transplantation of MSCs was achieved by the use of MSCs cultured with neurotrophic factors.
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PMID:Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. 1254 61

Olfactory ensheathing cells (OEC) constitute a specialized population of glia that accompany primary olfactory axons and have been reported to facilitate axonal regeneration after spinal cord injury in vivo. In the present report we describe OEC neurotrophic factor expression and neurotrophic properties of OECs in vitro. Investigation of the rat olfactory system during development and adulthood by radioactive in situ hybridization revealed positive labeling in the olfactory nerve layer for the neurotrophic molecules S-100beta, CNTF, BMP-7/OP-1, and artemin, as well as for the neurotrophic factor receptors RET and TrkC. Ribonuclease protection assay of cultured OEC revealed expression of NGF, BDNF, GDNF, and CNTF mRNA, while NT3 and NT4 mRNA were not detectable. In vitro bioassays of neurotrophic activity involved coculturing of adult OEC with embryonic chick ganglia and demonstrated increased neurite outgrowth from sympathetic, ciliary, and Remak's ganglia. However, when culturing the ganglia with OEC-conditioned medium, neurite outgrowth was not stimulated to any detectable extent. Our results suggest that the neurotrophic properties of OEC may involve secretion of neurotrophic molecules but that cellular interactions are crucial.
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PMID:Neurotrophic properties of olfactory ensheathing glia. 1268 30

Cultured embryonic cortical progenitor cells will mimic the temporal differentiation pattern observed in vivo, producing neurons first and then glia. Here, we investigated the role of two endogenously produced growth factors, the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 (NT-3), in the early progenitor-to-neuron transition. Cultured cortical progenitors express BDNF and NT-3, as well as their receptors TrkB (tyrosine kinase receptor B) and TrkC. Inhibition of these endogenously expressed neurotrophins using function-blocking antibodies resulted in a marked decrease in the survival of cortical progenitors, accompanied by decreased proliferation and inhibition of neurogenesis. Inhibition of neurotrophin function also suppressed the downstream Trk receptor signaling pathways, PI3-kinase (phosphatidyl inositol-3-kinase) and MEK-ERK (MAP kinase kinase-extracellular signal-regulated kinase), indicating the presence of autocrine-paracrine neurotrophin:Trk receptor signaling in these cells. Moreover, specific inhibition of these two Trk signaling pathways led to distinct biological effects; inhibition of PI3-kinase decreased progenitor cell survival, whereas inhibition of MEK selectively blocked the generation of neurons, with no effects on survival or proliferation. Thus, neurotrophins made by cortical progenitor cells themselves signal through the TrkB and TrkC receptors to mediate cortical progenitor cell survival and neurogenesis via two distinct downstream signaling pathways.
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PMID:Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. 1283 39

Astrocytes play key roles in CNS development, inflammation, and repair by producing a wide variety of cytokines, chemokines, and growth factors. Understanding the regulation of this network is important for a full understanding of astrocyte functioning. In this study, expression levels of 268 genes encoding cytokines, chemokines, growth factors, and their receptors were established in cultured human adult astrocytes using cDNA arrays. Also, changes in this gene profile were determined following stimulation with TNFalpha, IL-1beta, and IFNgamma. The data obtained reveal a highly reproducible pattern of gene expression not only between different astrocyte cultures from a single source, but also between astrocytes from different donors. They also identify several gene products not previously described for human astrocytes, including a.o. IL-17, CD70, CD147, and BIGH3. When stimulated with TNFalpha astrocytes respond with increased expression of several genes, notably including those encoding the chemokines CCL2 (MCP-1), CCL5 (RANTES), and CXCL8 (IL-8), growth factors including BMP-2A, BMP-3, neuromodulin (GAP43), BDNF, and G-CSF, and receptors such as the CRF receptor, the calcitonin receptor (CTR), and TKT. The response to IL-1beta involves largely the same range of genes, but responses were blunted in comparison to the TNFalpha response. Treatment with IFNgamma had no or only marginal effects on expression of any of the 268 genes analyzed. Astrocytes treated with a mixture of all three stimuli together displayed responses that are largely similar to those found in response to TNFalpha or IL-1beta alone, with only few additional synergistic effects.
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PMID:Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. 1289 3

The neurotrophin brain-derived neurotrophic factor (BDNF), via activation of its receptor, tyrosine receptor kinase B (trkB), regulates a wide variety of cellular processes in the nervous system, including neuron survival and synaptic plasticity. Although the expression of BDNF is known to be Ca2+-dependent, the regulation of trkB expression has not been extensively studied. Here we report that depolarization of cultured mouse cortical neurons increased the expression of the full-length, catalytically active isoform of trkB without affecting expression of the truncated isoform. This increase in protein expression was accompanied by increased levels of transcripts encoding full-length, but not truncated, trkB. Depolarization also regulated transcription of the gene, TRKB, via entry of Ca2+ through voltage-gated Ca2+ channels and subsequent activation of Ca2+-responsive elements in the two TRKB promoters. Using transient transfection of neurons with TRKB promoter-luciferase constructs, we found that Ca2+ inhibited the upstream promoter P1 but activated the downstream promoter P2. Ca2+-dependent stimulation of TRKB expression requires two adjacent, non-identical CRE sites located within P2. The coordinated regulation of BDNF and trkB by Ca2+ may play a role in activity-dependent survival and synaptic plasticity by enhancing BDNF signaling in electrically active neurons.
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PMID:Ca(2+)-dependent regulation of TrkB expression in neurons. 1290 Apr 19

Injuries to the brain result in the decline of glial glutamate transporter expression within hours and a recovery after several days. One consequence of this disturbed expression seems to consist in the temporary accumulation of toxic extracellular glutamate levels followed by secondary neuronal cell death. Whereas evidence exists that the decline in glutamate transporter expression results from a loss of neuronal PACAP influences on astroglia, the mechanism(s) inducing the reexpression of glial glutamate transporters is presently unknown. We now demonstrate that the injury-induced growth factors EGF, TGFalpha, FGF-2, and PDGF all promote the expression of the glutamate transporters GLT-1 and/or GLAST in cultured cortical astroglia. In contrast, similar stimulatory influences were absent with GDNF and BDNF, growth factors not affected by brain injuries. The effects of EGF, TGFalpha, FGF-2, and PDGF on glial glutamate transport were only partly redundant and involved distinctly different signaling pathways. Unlike EGF, TGFalpha, and FGF-2, PDGF promoted GLT-1, but not GLAST expression and further failed to increase the maximal velocity of sodium-dependent glutamate uptake. Moreover, FGF-2 only affected glial glutamate transport when the RAF-MEK-ERK signaling pathway was concomitantly inhibited with PD98059. Depending on the extracellular growth factor and glutamate transporter subtype, the observed stimulatory effects required the activation of PKA, PKC, and/or AKT. We suggest that after brain injury, reactive processes may limit secondary neuronal cell death by promoting glial glutamate transport. The detailed knowledge of these compensatory mechanisms will eventually allow us to therapeutically interfere with glutamate-associated neuronal cell death in the brain.
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PMID:Regulation of glial glutamate transporter expression by growth factors. 1295 96

The Vesl-1S/Homer-1a protein is induced during long-term potentiation (LTP), and contains a motif that binds postsynaptic proteins. We have previously reported that synaptic accumulation of Vesl-1S/Homer-1a immunoreactivity (IR) at synapses on the contour of neuronal somata is promoted by stimulation of cells with phorbol esters, 90 mM KCl or proteasome inhibitors. In the present study, we investigated the intracellular mechanism that results in the synaptic accumulation of this protein at synapses. MEK inhibitors completely blocked the effects of phorbol esters and KCl on the accumulation of Vesl-1S/Homer-1a and partially blocked the effect of proteasome inhibitors. Conversely, brain-derived neurotrophic factor (BDNF) and NT3 promoted the accumulation of Vesl-1S/Homer-1a IR at synapses. The extent of this accumulation is correlated with the level of activation of extracellular signal-regulated kinases, ERK following treatment with BDNF. BDNF also caused an increase in the amount of Vesl-1S/Homer-1a protein, but this occurred after Vesl-1S/Homer-1a had accumulated at the synapses. In addition, inhibition of de novo protein synthesis did not affect the phorbol ester-mediated accumulation of Vesl-1S/Homer-1a IR at synapses. These results indicate that activation of the ERK cascade plays a crucial role in the synaptic accumulation of Vesl-1S/Homer-1a IR, and suggest that this accumulation occurs mainly by re-localization of Vesl-1S/Homer-1a protein, and not through an increase in the level of Vesl-1S/Homer-1a. Activity-dependent release of neurotrophins or depolarization may cause local activation of the ERK cascade to produce the synapse-specific localization of Vesl-1S/Homer-1a.
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PMID:Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses. 1455 52

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a disorder characterized by an idiopathic failure of the automatic control of breathing. CCHS is frequently complicated with neurocristopathies such as Hirschsprung's disease (HSCR). The genes involved in the RET-GDNF signaling and/or EDN3-EDNRB signaling pathways have been analyzed as candidates for CCHS; however, only a few patients have mutations of the RET, EDN3, and GDNF genes. Recently, mutations of the PHOX2B gene, especially polyalanine expansions, have been detected in two thirds of patients. We studied the RET, GDNF, GFRA1, PHOX2A, PHOX2B, HASH-1, EDN1, EDN3, EDNRB, and BDNF genes in seven patients with isolated CCHS and three patients with HSCR. We detected polyalanine expansions and a novel frameshift mutation of the PHOX2B gene in four patients and one patient, respectively. We also found several mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes in patients with or without mutations of the PHOX2B gene. Our study confirmed the prominent role of mutations in the PHOX2B gene in the pathogenesis of CCHS. Mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes may also be involved in the pathogenesis of CCHS. To make clear the pathogenesis of CCHS, the analysis of more cases and further candidates concerned with the development of the autonomic nervous system is required.
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PMID:Molecular analysis of congenital central hypoventilation syndrome. 1456 59

The stimulation of C-fiber sensory neurons is known to induce activation of the ERK MAP kinase signaling pathway in the spinal cord dorsal horn. In this study we have elucidated some of the signaling components of C-fiber transmission responsible for ERK activation. Using an in vitro slice preparation of the mouse spinal cord dorsal horn, we compared the release of substance P (SP) and BDNF with the activation of ERK in postsynaptic neurons. We observed that primary afferent stimulation recruiting C-fibers was required for both SP and BDNF release and ERK activation in post-synaptic dorsal horn neurons. Glutamate transmission via NMDA and mGluR1 but not AMPA receptors was critical to this ERK activation. BDNF signaling via TrkB receptors but not SP signaling via NK(1) were also involved in ERK recruitment. In conclusion, glutamate and BDNF are the important C-fiber signaling components for ERK activation in dorsal horn neurons.
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PMID:The signaling components of sensory fiber transmission involved in the activation of ERK MAP kinase in the mouse dorsal horn. 1457 51

Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT(1B) and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others.
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PMID:Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. 1465 7


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