Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothalamic neuropeptide, gonadotropin releasing hormone (GnRH), is a primary regulatory factor in the neuroendocrine control of reproduction. The GnRH decapeptide is released in an episodic manner from hypothalamic GnRH neurons, which are known to express GnRH receptors. Here we examined the signaling pathways by which autocrine GnRH stimulation generates cell survival and proliferative signals in hypothalamic GT1-7 cells. Both GnRH and epidermal growth factor (EGF) caused rapid phosphorylation of cyclic AMP response element binding protein (CREB) and BAD. The selective epidermal growth factor receptor (EGF-R) antagonist, AG1478, attenuates the phosphorylation of these proteins by GnRH and EGF. Inhibition of PKC and Src abolished the stimulatory effects of GnRH, but not that of EGF, consistent with a critical role of these signaling molecules upstream of the EGF-R. All of these effects of GnRH were mimicked by phorbol 12 myristate 13-acetate (PMA). Consistent with the prosurvival and mitogenic effects of phosphoinositide 3-kinase/Akt (P13-K/Akt) downstream of the EGF-R, inhibition of P13-K diminished the activation of these proteins following stimulation with GnRH, EGF, and PMA. Overexpression of dominant negative Akt attenuated agonist-induced phosphorylation of BAD, but not that of ERK1/2 and CREB. Moreover, overexpression of wild-type RSK-1 resulted in enhanced basal as well as agonist-induced phosphorylation of CREB and BAD, indicating a critical role of RSK-1 in activating cytosolic as well as nuclear proteins. These data reveal novel signaling mechanisms of GnRH-induced phosphorylation of CREB and BAD in GT1-7 neurons through transactivation of the EGF-R.
 ...
PMID:Dependence of GnRH-induced phosphorylation of CREB and BAD on EGF receptor transactivation in GT1-7 neuronal cells. 1674 54

The melanocortin-4 receptor (MC4R) is a seven transmembrane member of the melanocortin receptor family. The GT1-1 cell line exhibits endogenous expression of MC4R. In this study, GT1-1 cells were used to study MC4R signaling pathways and to examine the effects of melanocortin receptor agonist NDP-MSH on apoptosis. MC4R mRNA expression was demonstrated by RT-PCR. Functional melanocortin receptor expression was implied by specific binding of NDP-MSH and cAMP production. NDP-MSH-stimulated GnRH release in a dose-dependent manner. Serum deprivation-induced apoptosis in GT1-1 cells, and the NDP-MSH inhibited this effect. The melanocortin receptor antagonist SHU9119 blocked the antiapoptotic actions of NDP-MSH, and the MAP kinase inhibitor PD98059 significantly attenuated the antiapoptotic effect. NDP-MSH-stimulated ERK1/2 phosphorylation in a dose-dependent manner. ERK1/2 phosphorylation could be abolished by SHU9119. In GT1-1 cells, melanocortin receptor activation causes ERK1/2 phosphorylation. In these cells, MC4R activation is also associated with antiapoptotic effects.
 ...
PMID:Melanocortin-4 receptor-mediated inhibition of apoptosis in immortalized hypothalamic neurons via mitogen-activated protein kinase. 1680 84

Transmissible spongiform encephalopathies, also called prion diseases, are characterized by neuronal loss linked to the accumulation of PrP(Sc), a pathologic variant of the cellular prion protein (PrP(C)). Although the molecular and cellular bases of PrP(Sc)-induced neuropathogenesis are not yet fully understood, increasing evidence supports the view that PrP(Sc) accumulation interferes with PrP(C) normal function(s) in neurons. In the present work, we exploit the properties of PrP-(106-126), a synthetic peptide encompassing residues 106-126 of PrP, to investigate into the mechanisms sustaining prion-associated neuronal damage. This peptide shares many physicochemical properties with PrP(Sc) and is neurotoxic in vitro and in vivo. We examined the impact of PrP-(106-126) exposure on 1C11 neuroepithelial cells, their neuronal progenies, and GT1-7 hypothalamic cells. This peptide triggers reactive oxygen species overflow, mitogen-activated protein kinase (ERK1/2), and SAPK (p38 and JNK1/2) sustained activation, and apoptotic signals in 1C11-derived serotonergic and noradrenergic neuronal cells, while having no effect on 1C11 precursor and GT1-7 cells. The neurotoxic action of PrP-(106-126) relies on cell surface expression of PrP(C), recruitment of a PrP(C)-Caveolin-Fyn signaling platform, and overstimulation of NADPH-oxidase activity. Altogether, these findings provide actual evidence that PrP-(106-126)-induced neuronal injury is caused by an amplification of PrP(C)-associated signaling responses, which notably promotes oxidative stress conditions. Distorsion of PrP(C) signaling in neuronal cells could hence represent a causal event in transmissible spongiform encephalopathy pathogenesis.
 ...
PMID:Overstimulation of PrPC signaling pathways by prion peptide 106-126 causes oxidative injury of bioaminergic neuronal cells. 1686 81

The melanocortin-4 (MC4) receptor plays a pivotal role in regulating food intake and energy expenditure, and obesity results from mutations that interfere with the MC4 receptor pathway. We investigated the effect of glucocorticoids on endogenous MC4 receptors expressed in GT1-1 cells, an immortalized hypothalamic neuronal cell line. Dexamethasone (Dex) caused a 5- to 10-fold increase in the cAMP response to the MC4 receptor agonist, NDP-alphaMSH. The stimulatory effect of Dex reached a maximum within 24 h and was blocked by the glucocorticoid antagonist RU486. This glucocorticoid effect was specific for the MC4 receptor and not a result of up-regulation of another component of the cAMP cascade, because the response to endogenous beta-adrenergic receptor stimulation was not altered by Dex. Dex also potentiated NDP-alphaMSH-mediated ERK1/2 activation. After 12 h, Dex caused a 3- to 5-fold increase in [125I]NDP-alphaMSH binding, which was maintained for at least 48 h and prevented by RU486. Dex withdrawal caused a rapid return of MC4 receptor concentration to the basal level. Dex-mediated increases in MC4 receptor concentration resulted from a rapid but transient increase in MC4 receptor mRNA. This regulation apparently requires genomic regulatory sequences because Dex did not increase MC4 receptor expression or signaling in CHO cells expressing the MC4 receptor under the control of a cytomegalovirus promoter. We conclude that in GT1-1 hypothalamic neurons, glucocorticoids increase the amplitude of MC4 receptor signaling. This regulation may serve as a control to limit the effects of glucocorticoids on food intake.
 ...
PMID:Regulation of endogenous melanocortin-4 receptor expression and signaling by glucocorticoids. 1697 23

Orexin A, a recently discovered hypothalamic peptide, has been shown to have a stimulatory effect on release of gonadotropin-releasing hormone (GnRH) from rat hypothalamic explants in vitro. However, it is presently unclear whether in vivo this effect is mediated directly at the level of the GnRH neuron, or via multiple afferent neuronal connections. Therefore, in the present study, we investigated the direct action of orexin A on GnRH neurons using the immortalized GnRH-secreting GT1-7 hypothalamic cells. Orexin-1 receptor (OX1R) expression was detected in GT1-7 cells by RT-PCR and Western blot. Results showed that 0.1-1 nM orexin A, when administered in culture media for 4 h, can significantly stimulate GnRH mRNA expression in GT1-7 cells (p < 0.05). Administration of 1 microM OX1R antagonist, SB-334867, completely blocked the observed orexin A responses in these cells, indicating that orexin A stimulation of GnRH neurons is specifically through OX1R. Moreover, 0.1 nM orexin A stimulated GnRH release after 30-45 min. To examine possible signal transduction pathways involved in mediating these effects, a MEK inhibitor (UO-126), PKC inhibitor (calphostin C), and PKA inhibitor (H-89), were used, with each blocking orexin A-induced GnRH transcription and release from immortalized cells. Collectively, our results show that orexin A is capable of directly stimulating GnRH transcription and neuropeptide release from these immortalized hypothalamic neurons, and that the effects of orexin A appear to be mediated via the OX1R, coupled with activation of the PKC-, MAPK- and PKA-signaling pathways. It is suggested that the stimulatory effect of orexin A on GnRH transcription and release may also occur directly at the level of GnRH neurons in vivo.
 ...
PMID:Orexin A induces GnRH gene expression and secretion from GT1-7 hypothalamic GnRH neurons. 1719 2

Gonadotropin-releasing hormone (GnRH) is secreted from hypothalamic GnRH neurons. There is accumulating evidence that GnRH neurons have GnRH receptors and that the autocrine action of GnRH activates MAP kinase. In this study, we found that KN93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinases (CaM kinases), inhibited the GnRH-induced activation of MAP kinase in immortalized GnRH neurons (GT1-7 cells). Immunoblot analysis indicated that the CaM kinase IIdelta2 isoform (CaM kinase IIdelta2) and synapsin I were expressed in GT1-7 cells. GnRH treatment rapidly increased phosphorylation of synapsin I at serine 603, a specific phosphorylation site for CaM kinase II, suggesting that GnRH treatment rapidly activated CaM kinase IIdelta2. In addition, when we stably overexpressed CaM kinase IIdelta2 in GT1-7 cells, the activation of MAP kinase was strongly enhanced. These results suggest that CaM kinase IIdelta2 was involved in the GnRH-induced activation of MAP kinase in GT1-7 cells.
 ...
PMID:Involvement of CaM kinase II in gonadotropin-releasing hormone-induced activation of MAP kinase in cultured hypothalamic neurons. 1770 88

We have shown previously that chronic exposure to endothelin-1 (ET-1) may stimulate GLUT1-mediated glucose transport in 3T3-L1 adipocytes via both protein kinase C (PKC)- and mitogen-activated protein kinase (p42/p44 MAPK)-dependent pathways. In the present study, by using a luciferase reporter driven by Glut1 promoter and enhancers (pLuc-GT1/E1/E2) and various constitutively active and dominant negative mutants of PKC isoforms, we identified PKCepsilon as the PKC isoform involved. In addition, we provide evidence that there is no direct interaction between ET-1 activated PKCepsilon and MAPK, at least at the kinase activity level. Furthermore, investigations employing deletion mutants of pLuc-GT1/E1/E2 to locate the putative ET-1 responsive sites and inhibitory agents to suppress the activities of putative transcription factors suggested that transcription factors CREB, Sp1 and NF-kappaB were involved. In summary, the results of this study indicate that ET-1 induction of Glut1 transcription involves distinct PKCepsilon- and MAPK-dependent pathways, as well as downstream transcription factors CREB, Sp1 and NF-kappaB.
 ...
PMID:Endothelin-1 induction of Glut1 transcription in 3T3-L1 adipocytes involves distinct PKCepsilon- and p42/p44 MAPK-dependent pathways. 1815 38

Brain-derived neurotrophic factor, which activates the extracellular regulated kinase (ERK) pathway, increases formation of prions in scrapie-infected gonadotropin-releasing hormone (GT1-1) cells. This indicates that conversion of the cellular prion protein PrP(C) to its pathogenic isoform, PrP(Sc), can be regulated by physiological stimuli acting on specific signal transduction pathways. In the present study, we examined the involvement of different mitogen-activated protein (MAP) kinase cascades and the cAMP-PKA pathway in formation of proteinase K-resistant PrP(Sc) (rPrP(Sc)). Long-term depolarization of GT1-1 cells infected with the Rocky Mountain Laboratory strain of scrapie increased the formation of rPrP(Sc). This effect was associated to ERK activation and was blocked by the MAPK/ERK kinase (MEK) inhibitor U0126. Treatment with forskolin caused a similar increase in rPrP(Sc) formation that was prevented by the protein kinase A (PKA) inhibitor H89. Both depolarization and forskolin treatment were accompanied by increased phosphorylation of the S6 ribosomal protein, while phosphorylation of histone H3 occurred only after forskolin treatment. Inhibitors of p38- and c-Jun NH(2)-terminal kinase (JNK) promoted the formation of rPrP(Sc), in contrast to the clearance of rPrP(Sc) produced by inhibitors of the ERK pathway. Thus, the ERK and the p38-JNK MAP kinase pathways appear to exert opposing effects on rPrP(Sc) formation, suggesting that balances between these intracellular signaling cascades may regulate replication of prions.
 ...
PMID:Opposing effects of ERK and p38-JNK MAP kinase pathways on formation of prions in GT1-1 cells. 1882 19

Neuropeptide Y (NPY) regulates reproductive function at the level of the hypothalamus through control of GnRH secretion. However, the direct control of GnRH gene expression by NPY has not yet been studied. GT1-7 neurons were treated with 100 nM of NPY over a 36 h time course. GnRH mRNA levels were significantly increased by NPY up to 12 h. We determined that GT1-7 neurons expressed Y1, Y2, and Y4 NPY receptors, but not Y5. Functional analysis of NPY receptor activation indicated that the Y1/Y4/Y5 receptor agonist [Leu31, Pro34] significantly induced cAMP accumulation in the GT1-7 neurons. Western blot studies demonstrated changes in the phosphorylation status of AKT, ERK1/2, CREB and ATF-1 after NPY exposure. Pharmacological inhibitors of the MAPK and PKA signal transduction pathways attenuated the NPY-mediated increase in GnRH transcription. This NPY-mediated increase in GnRH mRNA was also inhibited with the Y1-receptor specific antagonist BIBP-3226. The mHypoE-38 neurons secrete detectable levels of NPY and can be used as an endogenous source of NPY. Conditioned medium from mHypoE-38 neurons induced an increase in GnRH mRNA, which was inhibited by the Y1 receptor antagonist BIBP-3226. Together, these studies strengthen the evidence for the importance of NPY in the regulation of reproductive function.
 ...
PMID:Neuropeptide Y induces gonadotropin-releasing hormone gene expression directly and through conditioned medium from mHypoE-38 NPY neurons. 1937 63

The melanocortin system is crucial to regulation of energy homeostasis. The melanocortin receptor type 4 (MC4R) modulates insulin signaling via effects on c-Jun N-terminal kinase (JNK). The melanocortin agonist NDP-MSH dose-dependently inhibited JNK activity in HEK293 cells stably expressing the human MC4R; effects were reversed by melanocortin receptor antagonist. NDP-MSH time- and dose-dependently inhibited IRS-1(ser307) phosphorylation, effects also reversed by a specific melanocortin receptor antagonist. NDP-MSH augmented insulin-stimulated AKT phosphorylation in vitro. The melanocortin agonist melanotan II increased insulin-stimulated AKT phosphorylation in the rat hypothalamus in vivo. NDP-MSH increased insulin-stimulated glucose uptake in hypothalamic GT1-1 cells. The current study shows that the melanocortinergic system interacts with insulin signaling via novel effects on JNK activity.
 ...
PMID:Melanocortin-4 receptor activation inhibits c-Jun N-terminal kinase activity and promotes insulin signaling. 1946 42


<< Previous 1 2 3 4 5 6 Next >>