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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Branching morphogenesis of epithelium is a common and important feature of organogenesis; it is, for example, responsible for development of renal collecting ducts, lung airways, milk ducts of mammary glands and seminal ducts of the prostate. In each case, epithelial development is controlled by a variety of mesenchyme-derived molecules, both soluble (e.g. growth factors) and insoluble (e.g. extracellular matrix). Little is known about how these varied influences are integrated to produce a coherent morphogenetic response, but integration is likely to be achieved at least partly by cytoplasmic signal transduction networks. Work in other systems (Drosophila tracheae, MDCK models) suggests that the mitogen-activated protein (MAP) kinase pathway might be important to epithelial branching. We have investigated the role of the MAP kinase pathway in one of the best characterised mammalian examples of branching morphogenesis, the ureteric bud of the metanephric kidney. We find that Erk MAP kinase is normally active in ureteric bud, and that inhibiting Erk activation with the MAP kinase kinase inhibitor, PD98059, reversibly inhibits branching in a dose-dependent manner, while allowing tubule elongation to continue. When Erk activation is inhibited, ureteric bud tips show less cell proliferation than controls and they also produce fewer laminin-rich processes penetrating the mesenchyme and fail to show the strong concentration of apical actin filaments typical of controls; apoptosis and expression of Ret and Ros, are, however, normal. The activity of the Erk MAP kinase pathway is dependent on at least two known regulators of ureteric bud branching; the GDNF-Ret signalling system and sulphated glycosaminoglycans. MAP kinase is therefore essential for normal branching morphogenesis of the ureteric bud, and lies downstream of significant extracellular regulators of ureteric bud development.
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PMID:Erk MAP kinase regulates branching morphogenesis in the developing mouse kidney. 1168 67

Gene therapy for neurodegenerative diseases may utilize the expression of neurotrophic factors because of their potential to promote survival and regeneration of injured neuronal cells. Increasing numbers of these factors are being considered for gene transfer, but their specificity and efficacy in neuroprotection are greatly variable. The major aims of this study were to carry out gene transfer of various neurotrophic factors and investigate their mechanisms of action as well as their protective effects on the viability of rat pheochromocytoma (PC12) cells. We used glutamate, S-nitroso-N-acetyl-DL-penicillamine (SNAP), and staurosporine to induce excitatory damage, oxidative stress, and apoptosis, respectively, because these mechanisms are thought to participate in various disease processes leading to degeneration of cells. We utilized adenovirus vectors for efficient gene transfer of trophic factors (glial-cell derived neurotrophic factor [GDNF] and cardiotrophin-1 [CT-1]) or calbindin-D28k. We found that GDNF and CT-1 gene transfers were equally effective in saving PC12 cells from injury, but calbindin expression did not show any beneficial effects. GDNF gene transfer was much more efficient in protecting PC12 cells from damage than direct GDNF administration. The protection by GDNF expression against staurosporine was mediated through both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MAPK kinase; MEK) pathways, but only the MEK pathway was involved in the protection against SNAP. In contrast, the protective effect of GDNF against glutamate toxicity was independent of these RET-dependent signal transduction pathways.
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PMID:Gene transfer of glial cell-derived neurotrophic factor and cardiotrophin-1 protects PC12 cells from injury: involvement of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase pathways. 1221 Aug 28

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

Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.
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PMID:[Mechanisms of antidepressants and serotonin (5-HT)-induced glial cell line-derived neurotrophic factor (GDNF) releases in rat C6 gliobrastoma cells]. 1579 67

Protein kinase C (PKC) is able to phosphorylate several cellular components that serve as key regulatory components in signal transduction pathways of nociceptor excitation and sensitisation. Therefore, the present study attempted to assess some of the mechanisms involved in the overt nociception elicited by peripheral administration of the PKC activator, phorbol 12-myristate 13-acetate (PMA), in mice. The intraplantar (i.pl.) injection of PMA (16-1600 pmol/paw), but not its inactive analogue alpha-PMA, produced a long-lasting overt nociception (up to 45 min), as well as the activation of PKCalpha and PKCepsilon isoforms in treated paws. Indeed, the local administration of the PKC inhibitor GF109203X completely blocked PMA-induced nociception. The blockade of NK1, CGRP, NMDA, beta1-adrenergic, B2 or TRPV1 receptors with selective antagonists partially decreased PMA-induced nociception. Similarly, COX-1, COX-2, MEK or p38 MAP kinase inhibitors reduced the nociceptive effect produced by PMA. Notably, the nociceptive effect promoted by PMA was diminished in animals treated with an antagonist of IL-1beta receptor or with antibodies against TNFalpha, NGF or BDNF, but not against GDNF. Finally, mast cells as well as capsaicin-sensitive and sympathetic fibres, but not neutrophil influx, mediated the nociceptive effect produced by PMA. Collectively, the results of the present study have shown that PMA injection into the mouse paw results in PKC activation as well as a relatively delayed, but long-lasting, overt nociceptive behaviour in mice. Moreover, these results demonstrate that PKC activation exerts a critical role in modulating the excitability of sensory neurons.
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PMID:Mechanisms involved in the nociception produced by peripheral protein kinase c activation in mice. 1609 1

Apoptotic cell death of photoreceptors is the final event leading to blindness in the heterogeneous group of inherited retinal degenerations. GDNF (glial cell-line-derived neurotrophic factor) was found to rescue photoreceptor function and survival very effectively in an animal model of retinal degeneration (M. Frasson, S. Picaud, T. Leveillard, M. Simonutti, S. Mohand-Said, H. Dreyfus, D. Hicks, and J. Sahel, Investig. Ophthalmol. Vis. Sci. 40:2724-2734, 1999). However, the cellular mechanism of GDNF action remained unresolved. We show here that in porcine retina, GDNF receptors GFRalpha-1 and RET are expressed on retinal Mueller glial cells (RMG) but not on photoreceptors. Additionally, RMG express the receptors for the GDNF family members artemin and neurturin (GFRalpha-2 and GFRalpha-3). We further investigated GDNF-, artemin-, and neurturin-induced signaling in isolated primary RMG and demonstrate three intracellular cascades, which are activated in vitro: MEK/ERK, stress-activated protein kinase (SAPK), and PKB/AKT pathways with different kinetics in dependence on stimulating GFL. We correlate the findings to intact porcine retina, where GDNF induces phosphorylation of ERK in the perinuclear region of RMG located in the inner nuclear layer. GDNF signaling resulted in transcriptional upregulation of FGF-2, which in turn was found to support photoreceptor survival in an in vitro assay. We provide here a detailed model of GDNF-induced signaling in mammalian retina and propose that the GDNF-induced rescue effect on mutated photoreceptors is an indirect effect mediated by retinal Mueller glial cells.
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PMID:GDNF family ligands trigger indirect neuroprotective signaling in retinal glial cells. 1653 17

Neurons in the adult rat dorsal root ganglion (DRG) can be classified into at least three separate subpopulations based on morphologic and phenotypic differences. In this study we have focused on the growth response of these specific subpopulations in vitro with respect to laminin (LN) and growth factor receptor activation. Using a cell selection approach we show that LN-induced neurite growth occurs in the absence of added trophic factors only in heavy-chain neurofilament-positive and calcitonin gene-related peptide-positive DRG neurons [nerve growth factor (NGF)-responsive population]. In contrast, LN alone is not sufficient to stimulate significant neurite growth from lectin Griffonia simplicifolia IB4-positive neurons (IB4+ve), although it is still required to elicit a growth response from these cells in the presence of glial-derived neurotrophic factor (GDNF, e.g. neurite growth occurred only when cells were plated on LN in the presence of GDNF). By using chemical inhibitors we demonstrate that only the phosphatidylinositol 3 kinase (PI 3-K)/Akt pathway is required for neurite growth from the NGF-responsive cell population. However, both the PI 3-K/Akt and MEK/mitogen-activated protein kinase signaling pathways are required for neurite growth from the IB4+ve cell population. Thus, we have identified specific signaling events and environmental requirements associated with neurite growth for different subpopulations of adult DRG neurons, pointing to potential therapeutic targets while identifying an inability for any one treatment alone to repair peripheral nerve damage.
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PMID:Laminin and growth factor receptor activation stimulates differential growth responses in subpopulations of adult DRG neurons. 1693 Mar 99

We analyzed the survival responses and downstream signaling elicited by GDNF on sympathetic neurons from different Ret knockin mice. Lack of tyrosine 1062, a multidocking site in Ret, completely prevented GDNF-mediated survival. Importantly, lack of tyrosine 981, although abrogating Akt phosphorylation, had no effect on neuronal survival, indicating that the PI 3-K/Akt pathway is not necessary for survival of sympathetic neurons. In contrast, silencing of B-Raf completely prevented not only GDNF-mediated but also NGF-mediated cell survival, independently of MEK-1/2. We identified IKKs as the main effectors of the protective effects of B-Raf. First, B-Raf interacted with and activated IKKs. Second, knockdown of IKKs reversed the protection afforded by a constitutively active form of B-Raf. Third, knockdown of IKKs prevented both NGF- and GDNF-mediated survival. In conclusion, our data delineate a novel survival pathway for sympathetic neurons linking B-Raf to IKKs, independently of both PI 3-K and MEK-1/2 pathways.
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PMID:Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons. 1849 57

We observed that recombinant ciliary neurotrophic factor (CNTF) enhanced survival and neurite outgrowth of cultured adult rat dorsal root ganglion (DRG) neurons. Among other neurotrophic factors (NGF and GDNF) and interleukin (IL)-6 cytokine members [IL-6, LIF, cardiotrophin-1, and oncostatin M (OSM)] at the same concentration (50 ng/ml), CNTF, as well as LIF and OSM, displayed high efficacy for the promotion of the number of viable neurons and neurite-bearing cells. CNTF enhanced the number of neurite-bearing cells in both small neurons (soma diameter <30 microm) and large neurons (soma diameter > or =30 microm), whereas NGF and GDNF promoted that in only small neurons. Western blot analysis revealed that CNTF induced phosphorylation of STAT3, Akt, and ERK1/2 in the neurons. Furthermore, the neurite outgrowth-promoting activity of CNTF was diminished by co-treatment with Janus kinase (JAK) 2 inhibitor, AG490; STAT3 inhibitor, STA-21; phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor, LY294002; and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, in a concentration-dependent manner. Its survival-promoting activity was also affected by AG490, STA-21, and LY294002 at higher concentrations, but not by PD98059. These findings suggest the involvement of JAK2/STAT3, PI3K/Akt, and MEK/ERK signaling pathways in CNTF-induced neurite outgrowth, where the former two pathways are thought to play major roles in mediating the survival response of neurons to CNTF.
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PMID:Neuroprotective properties of ciliary neurotrophic factor for cultured adult rat dorsal root ganglion neurons. 1867 4

Glial cell line-derived trophic factor (GDNF) is a peptide with pleiotropic survival and growth-promoting effects on neurons. We found that intraspinal injection of a non-replicating herpes simplex virus-based vector coding for GDNF 2 h after blunt trauma to the thoraco-lumbar spinal cord produced sustained improvement in motor behavioral outcomes up to 5 weeks following injury. The improvement in behavior correlated with an increase in synaptophysin and glutamic acid decarboxylase (GAD) in the spinal cord at the level of injury. Addition of recombinant GDNF protein to primary spinal cord neurons in-vitro resulted in enhanced neurite growth and a marked increase in protein levels of GAD65 and GAD67, synapsin I and synaptophysin. GDNF-mediated increases in GAD and the synaptic markers were blocked by the MEK inhibitor UO126, but not by the phosphoinositide 3-kinase inhibitor LY294002. These results suggest that GDNF, acting through the MEK-ERK pathway enhances axonal sprouting, synaptic connectivity, and GABAergic neurotransmission in the spinal cord, that result in improved behavioral outcomes after spinal cord contusion injury.
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PMID:Transgene-mediated GDNF expression enhances synaptic connectivity and GABA transmission to improve functional outcome after spinal cord contusion. 2013 84


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