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)

Antidepressants, which increase monoamine levels, induce glial cell line-derived neurotrophic factor (GDNF) release in C6 cells. Thus, we examined whether monoamines affect on GDNF release in C6 cells. We found that serotonin (5-HT) specifically increased GDNF mRNA expression and GDNF release in a dose- and time-dependent manner. The 5-HT-induced GDNF release was mediated through the MEK/mitogen-activated protein kinase (MAPK) pathway and, at least, 5-HT(2A) receptors. The action of 5-HT on GDNF release may provide important insights into the mechanism of antidepressants.
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PMID:Serotonin increases glial cell line-derived neurotrophic factor release in rat C6 glioblastoma cells. 1498 48

Pancreatic carcinoma cells exhibit a pronounced tendency to invade along and into intra- and extrapancreatic nerves, even at early stages of the disease. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) has been shown to promote pancreatic cancer cell invasion. Here, we demonstrate that pancreatic carcinoma cell lines, such as PANC-1, expressed the RET and GDNF family receptor alpha receptor components for GDNF and that primary pancreatic tumor samples, derived from carcinomas with regional lymph node metastasis, exhibited marked expression of the mRNA encoding the RET51 isoform. Moreover, GDNF was an efficacious and potent chemoattractant for pancreatic carcinoma cells as examined in in vitro and in vivo model systems. Treatment of PANC-1 cells with GDNF resulted in activation of the monomeric GTPases N-Ras, Rac1, and RhoA, in activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK) and in activation of the phosphatidylinositol 3-kinase/Akt pathway. Both inhibition of the Ras-Raf-MEK (mitogen-activated protein/ERK kinase)-ERK cascade by either stable expression of dominant-negative H-Ras(N17) or addition of the MEK1 inhibitor PD98059 as well as inhibition of the phosphatidylinositol 3-kinase pathway by LY294002 prevented GDNF-induced migration and invasion of PANC-1 cells. These results demonstrate that pancreatic tumor cell migration and possibly perineural invasion in response to GDNF is critically controlled by activation of the Ras-Raf-MEK-ERK and the phosphatidylinositol 3-kinase pathway.
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PMID:Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. 1528 35

Glial cell line-derived neurotrophic factor (GDNF) can induce neuron-like differentiation of mouse pheochromocytoma (MPC) cell lines derived from mice with a heterozygous knockout mutation of nf1, the murine counterpart of the human gene mutated in neurofibromatosis type 1 (NF1). Here, we show that GDNF-induced differentiation in the MPC 862L cell line is mediated by the MEK/extracellular signal-regulated kinase (ERK) pathway. Neurite outgrowth, increased expression of growth-associated protein 43, and decreased incorporation of bromodeoxyuridine (BrdU) were induced by treatment with GDNF, H-RasV12, or a constitutively active MEK2. GDNF also induces leukemia inhibitory factor (LIF) via the MEK/ERK pathway, and LIF itself can elicit these differentiative changes via a cell-extrinsic autocrine/paracrine pathway. Treatment with anti-LIF neutralizing antibody depleted the differentiative activity of the conditioned medium from cells stimulated for MEK/ERK signaling, while recombinant LIF could induce differentiation in MPC cells, indicating that LIF is the sole factor with differentiative activity. LIF could activate MEK1/2 and STAT3, but LIF-induced differentiation was blocked only by the MEK1/2-specific inhibitor U0126, indicating that the MEK/ERK pathway is necessary for LIF action in MPC cells. Our findings suggest that LIF may be utilized for signaling mediated by GDNF and may be important in the pathobiology of neuroendocrine tumors.
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PMID:GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice. 1557 29

Apomorphine (APO), a potent D1/D2 dopamine receptor agonist, is currently used as an antiparkinsonian drug. We have shown previously that APO stimulates synthesis and release of multiple trophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in both mesencephalic and striatal neurons, thereby effectively preventing dopaminergic neuron loss in vitro. The present study was designed to investigate the effects of APO on fibroblast growth factor-2 (FGF-2) expression and regulation in astrocytes, and furthermore, to identify signaling mechanisms underlying these effects. Here, we show that FGF-2 expression is robustly induced in cultured astrocytes in response to APO. FGF-2 expression was proportional to APO concentration and time-dependent. Conversely, treatment with S-APO, a derivative of R-APO lacking DA receptor agonist activity, did not alter FGF-2 levels. APO treatment resulted in enhanced cytosol FGF-2 immunoreactivity, export of high MW forms of FGF-2 to the cytoplasm from the nucleus and increased extracellular release of FGF-2. Interestingly, both high and low MW forms of FGF-2 were detectable in conditioned medium of APO-treated cultures. This APO-induced effect was correlated with activation of D1 and D2 receptors, as it could be either mimicked by dopamine receptor agonists (SKF38393, quinpirole) or partially blocked by antagonists (SCH23390, SKF83566, haloperidol). Activation of the D1 receptor preferentially increased PKA activity, whereas activation of the D2 receptor only promoted phosphorylation of MAPK. Importantly, APO-modulated FGF-2 expression was independent of Akt/phosphoinositide 3-kinase signaling. These data suggest that APO can enhance biosynthesis and release of FGF-2 through activation of dopamine receptors in striatal astrocytes. Both cAMP/PKA and MEK/MAPK signaling cascades are major steps mediating this process.
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PMID:Apomorphine-induced activation of dopamine receptors modulates FGF-2 expression in astrocytic cultures and promotes survival of dopaminergic neurons. 1663 1

Glial cell line-derived neurotrophic factor (GDNF), a neurotrophic and differentiation factor, is expressed under several pathophysiological conditions but its regulatory signals have not yet been clarified. Here, we found that endoplasmic reticulum (ER) Ca(2+) discharge by thapsigargin induced GDNF mRNA as well as COX2 and GRP78 expression in rat C6 glioblastoma cells. GDNF mRNA was immediately induced and peaked at 2h by thapsigargin, and the alternative transcript consisting of exon 3 and exon 4 appeared to be most inducible. In spite of intracellular Ca(2+) perturbation, Ca(2+)-dependent PKC was not responsible for this induction. Instead, a PKCdelta-specific inhibitor, rottlerin, suppressed the thapsigargin-induced GDNF mRNA expression. On the other hand, thapsigargin transiently enhanced phosphorylation status of mitogen-activated protein kinase (MAPK) pathway, including extracellular signal-regulated kinase (Erk), p38 MAPK and c-JUN amino-terminal kinase1 (JNK1) simultaneously; whereas specific inhibitors against MEK1 and JNK only reduced the thapsigargin-induced GDNF mRNA expression. In addition, a pan-PKC inhibitor (Ro-31-8220) attenuated the thapsigargin-enhanced phosphorylation levels of Erk1/2 and JNK1, whereas rottlerin did not. Thus, the present study demonstrated that the thapsigargin-stimulated ER Ca(2+) discharge up-regulated GDNF gene expression through both MAPK-dependent and -independent pathways in C6 glioblastoma cells.
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PMID:ER calcium discharge stimulates GDNF gene expression through MAPK-dependent and -independent pathways in rat C6 glioblastoma cells. 1683 15

Recent studies show that neuronal and glial plasticity are important for therapeutic action of antidepressants. We previously reported that antidepressants increase glial cell line-derived neurotrophic factor (GDNF) production in rat C6 glioma cells (C6 cells). Here, we found that amitriptyline, a tricyclic antidepressant, increased both GDNF mRNA expression and release, which were selectively and completely inhibited by mitogen-activated protein kinase kinase inhibitors. Indeed, treatment of amitriptyline rapidly increased extracellular signal-regulated kinase (ERK) activity, as well as p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase activities. Furthermore, different classes of antidepressants also rapidly increased ERK activity. The extent of acute ERK activation and GDNF release were significantly correlated to each other in individual antidepressants, suggesting an important role of acute ERK activation in GDNF production. Furthermore, antidepressants increased the acute ERK activation and GDNF mRNA expression in normal human astrocytes as well as C6 cells. Although 5-hydroxytryptamine (serotonin) (5-HT), but not noradrenaline or dopamine, increased ERK activation and GDNF release via 5-HT2A receptors, ketanserin, a 5-HT2A receptor antagonist, did not have any effect on the amitriptyline-induced ERK activation. Thus, GDNF production by amitriptyline was independent of monoamine. Both of the amitriptyline-induced ERK activation and GDNF mRNA expression were blocked by genistein, a general protein tyrosine kinase (PTK) inhibitor. Actually, we found that amitriptyline acutely increased phosphorylation levels of several phosphotyrosine-containing proteins. Taken together, these findings indicate that ERK activation through PTK regulates antidepressant-induced GDNF production and that the GDNF production in glial cells may be a novel action of the antidepressant, which is independent of monoamine.
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PMID:Antidepressants increase glial cell line-derived neurotrophic factor production through monoamine-independent activation of protein tyrosine kinase and extracellular signal-regulated kinase in glial cells. 1721 Jul 98

Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in regulating the proliferation of spermatogonial stem cells (SSC). The signaling pathways mediating the function of GDNF in SSC remain unclear. This study was designed to determine whether GDNF signals via the Ras/ERK1/2 pathway in the C18-4 cells, a mouse SSC line. The identity of this cell line was confirmed by the expression of various markers for germ cells, proliferating spermatogonia, and SSC, including GCNA1, Vasa, Dazl, PCNA, Oct-4, GFRalpha1, Ret, and Plzf. Western blot analysis revealed that GDNF activated Ret tyrosine phosphorylation. All 3 isoforms of Shc were phosphorylated upon GDNF stimulation, and GDNF induced the binding of the phosphorylated Ret to Shc and Grb2 as indicated by immunoprecipitation and Western blotting. The active Ras was induced by GDNF, which further activated ERK1/2 phosphorylation. GDNF stimulated the phosphorylation of CREB-1, ATF-1, and CREM-1, and c-fos transcription. Notably, the increase in ERK1/2 phosphorylation, c-fos transcription, bromodeoxyuridine incorporation, and metaphase counts induced by GDNF, was completely blocked by pretreatment with PD98059, a specific inhibitor for MEK1, the upstream regulator of ERK1/2. GDNF stimulation eventually upregulated cyclin A and CDK2 expression. Together, these data suggest that GDNF induces CREB/ATF-1 family member phosphorylation and c-fos transcription via the Ras/ERK1/2 pathway to promote the proliferation of SSC. Unveiling GDNF signaling cascades in SSC has important implications in providing attractive targets for male contraception as well as for the regulation of stem cell renewal vs. differentiation.
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PMID:Gdnf upregulates c-Fos transcription via the Ras/Erk1/2 pathway to promote mouse spermatogonial stem cell proliferation. 1796 2

We previously reported that serotonin (5-HT) increased glial cell line-derived neurotrophic factor (GDNF) release in a 5-HT(2) receptor (5-HT(2)R) and mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK)-dependent manner in rat C6 glioma cells (C6 cells), a model of astrocytes. We herein found that 5-HT-induced rapid ERK phosphorylation was blocked by 5-HT(2)R antagonists in C6 cells. We therefore examined 5-HT-induced ERK phosphorylation to reveal the mechanism of 5-HT-induced GDNF mRNA expression. As 5-HT-induced ERK phosphorylation was blocked by inhibitors for Galpha(q/11) and fibroblast growth factor receptor (FGFR), but not for second messengers downstream of Galpha(q/11), 5-HT(2)R-mediated FGFR transactivation was suggested to be involved in the ERK phosphorylation. Although FGFR1 and 2 were functionally expressed in C6 cells, 5-HT selectively phosphorylated FGFR2. Indeed, small interfering RNA for FGFR2, but not for FGFR1, blocked 5-HT-induced ERK phosphorylation. As Src family tyrosine kinase inhibitors and microtubule depolymerizing agents blocked 5-HT-induced FGFR2 phosphorylation, Src family tyrosine kinase and stabilized microtubules were suggested to act upstream of FGFR2. Finally, 5-HT-induced GDNF mRNA expression was also inhibited by the blockade of 5-HT(2)R, FGFR, and Src family tyrosine kinase. In conclusion, our findings suggest that 5-HT induces GDNF mRNA expression via 5-HT(2)R-mediated FGFR2 transactivation in C6 cells.
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PMID:Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells. 1836 29

Germline mutations in the RET tyrosine kinase gene are responsible for the development of multiple endocrine neoplasia 2A and 2B (MEN2A and MEN2B). However, knowledge of the fundamental principles that determine the mutant RET-mediated signaling remains elusive. Here, we report increased expression of mitogen-activated protein kinase phosphatase-2 (MKP-2) in carcinomas developed in transgenic mice carrying RET with the MEN2A mutation (RET-MEN2A). The expression of MKP-2 was not only induced by RET-MEN2A or RET-MEN2B mutant proteins but also by the activation of endogenous RET by its ligand, glial cell line-derived neurotrophic factor (GDNF). MKP-2 expression was also evident in the MKK-f cell line, which was established from a mammary tumor developed in a RET-MEN2A transgenic mouse. Inhibition of MKP-2 attenuated the in vitro and in vivo proliferation of MKK-f cells, which was mediated by the suppression of cyclin B1 expression. Furthermore, we found that MKP-2 is highly expressed in medullary thyroid carcinomas derived from MEN2A patients. These findings suggest that the increased expression of MKP-2 may play a crucial role in oncogenic signaling downstream of mutant RET, leading to deregulation of cell cycle.
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PMID:Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice. 1854 59

Genetic studies have established the crucial roles of FGF signaling, FGF-induced gene expression and morphogenesis during embryogenesis. In this study, we showed that overexpressing a signaling adaptor protein, SH2B1beta, enhanced FGF1-induced neurite outgrowth in PC12 cells. SH2B1beta has previously been shown to promote nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF)-induced neurite outgrowth, in part, through prolonging NGF and GDNF-induced signaling. To delineate how SH2B1beta promotes FGF1-induced neurite outgrowth, we examined its role in FGF1-dependent signaling. Our data suggest that SH2B1beta enhances and prolongs FGF1-induced MEK-ERK1/2 and PI3K-AKT pathways. We also provided the first evidence that FGF1 induces the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at serine 727 [pSTAT3(S727)] in PC12 cells. SH2B1beta enhances this phosphorylation and the expression of the immediate early gene, Egr1. Through inhibitor assays, we have further shown that MEK-ERK1/2 is required for FGF1-induced neurite outgrowth, pSTAT3(S727) and Egr1 expression. Moreover, inhibiting Rho kinase, ROCK, enhances FGF1-induced neurite outgrowth through pSTAT3(S727)-independent manner. Taken together, our results demonstrate, for the first time, that SH2B1beta enhances FGF1-induced neurite outgrowth in PC12 cells mainly through MEK-ERK1/2-STAT3-Egr1 pathway.
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PMID:SH2B1beta enhances fibroblast growth factor 1 (FGF1)-induced neurite outgrowth through MEK-ERK1/2-STAT3-Egr1 pathway. 1924 49


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