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)

Exposure to nitrous oxide (N2O) may result in decreased fertility and other reproductive problems in women working in dental offices. This study explored direct effects of N2O on gonadotropin-releasing hormone (GnRH) neurons involved in pituitary-gonadal function. An immortalized GnRH-secreting GT1-7 cell line was used to evaluate the effects of 60% N2O exposure for 24 hours on pro-GnRH mRNA levels, KCl-stimulated GnRH levels, and certain signaling pathways. N2O exposure for 24 hours decreased pro-GnRH mRNA levels by approximately 80% without affecting cell viability or intracellular GnRH levels. The ability of KCl to release GnRH stores was also significantly reduced. Western blot analyses of ERK1/2, and p38 phosphorylation and IkappaB did not indicate any change in phosphorylation, although p63 tyrosine phosphorylation was increased after short-term N2O exposure. Levels of c-fos, a nuclear transcription factor, were not changed by N2O exposure. These results indicate that N2O significantly decreases evoked release of GnRH as well as GnRH mRNA levels either by decreased synthesis or by mRNA stability. These results may be important in understanding adverse effects of N2O on female workers in dental practice where the gas is not scavenged.
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PMID:Effect of nitrous oxide on intracellular events of GT1-7 GnRH-secreting neurons. 1286 1

Astrocytes have become a focal point for research in neurobiology, especially regarding their purported ability to regulate neuronal communication and survival. The present study addressed a poorly understood but important focus in this area, the mechanism(s) underlying astrocyte-induced survival of neurons. The results of the study show that soluble factors in astrocyte-conditioned media (ACM) protect murine GT1-7 neurons from serum deprivation-induced cell death and that this neuroprotection is correlated with enhanced activation/phosphorylation of the AP-1 transcription factor, c-JunSer-63. A parallel and correlated activation of the upstream kinases, c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase-4 (MKK4) was also demonstrated. Furthermore, co-administration of JNK inhibitors, but not a MEK inhibitor, significantly attenuated ACM-induced phosphorylation of c-JunSer-63 and blocked its neuroprotective action. Gel shift analysis demonstrated that ACM enhanced AP-1 binding, an effect that appears functionally important, since an AP-1 binding inhibitor significantly attenuated the neuroprotective action of ACM. Further studies implicated transforming growth factor (TGF)-beta1 and TGF-beta2 as critical active soluble factors released by astrocytes, since both were demonstrated in ACM, and immunoneutralization of the conditioned media with a panspecific TGF-beta antibody significantly attenuated the enhanced AP-1 binding and neuroprotective action of the ACM. Furthermore, exogenous application of TGF-beta1 and TGF-beta2 was found to enhance c-JunSer-63 phosphorylation and to be neuroprotective, and co-administration of JNK inhibitors or an AP-1 binding inhibitor blocked TGF-beta-induced neuroprotection. Taken together, these studies suggest that astrocytes can protect neurons from serum deprivation-induced cell death, at least in part, by release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.
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PMID:Astrocyte protection of neurons: role of transforming growth factor-beta signaling via a c-Jun-AP-1 protective pathway. 1288 49

Numerous external stimuli, including G protein-coupled receptor agonists, cytokines, growth factors, and steroids activate mitogen-activated protein kinases (MAPKs) through phosphorylation of the epidermal growth factor receptor (EGF-R). In immortalized hypothalamic neurons (GT1-7 cells), agonist binding to the gonadotropin-releasing hormone receptor (GnRH-R) causes phosphorylation of MAPKs that is mediated by protein kinase C (PKC)-dependent transactivation of the EGF-R. An analysis of the mechanisms involved in this process showed that GnRH stimulation of GT1-7 cells causes release/shedding of the soluble ligand, heparin binding epidermal growth factor (HB-EGF), as a consequence of metalloprotease activation. GnRH-induced phosphorylation of the EGF-R and, subsequently, of Shc, ERK1/2, and its dependent protein, p90RSK-1 (p90 ribosomal S6 kinase 1 or RSK-1), was abolished by metalloprotease inhibition. Similarly, blockade of the effect of HB-EGF with the selective inhibitor CRM197 or a neutralizing antibody attenuated signals generated by GnRH and phorbol 12-myristate 13-acetate, but not those stimulated by EGF. In contrast, phosphorylation of the EGF-R, Shc, and ERK1/2 by EGF and HB-EGF was independent of PKC and metalloprotease activity. The signaling characteristics of HB-EGF closely resembled those of GnRH and EGF in terms of the phosphorylation of EGF-R, Shc, ERK1/2, and RSK-1 as well as the nuclear translocation of RSK-1. However, neither the selective Src kinase inhibitor PP2 nor the overexpression of negative regulatory Src kinase and dominant negative Pyk2 had any effect on HB-EGF-induced responses. In contrast to GT1-7 cells, human embryonic kidney 293 cells expressing the GnRH-R did not exhibit metalloprotease induction and EGF-R transactivation during GnRH stimulation. These data indicate that the GnRH-induced transactivation of the EGF-R and the subsequent ERK1/2 phosphorylation result from ectodomain shedding of HBEGF through PKC-dependent activation of metalloprotease(s) in neuronal GT1-7 cells.
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PMID:Neuropeptide-induced transactivation of a neuronal epidermal growth factor receptor is mediated by metalloprotease-dependent formation of heparin-binding epidermal growth factor. 1457 93

Putative functions of the cellular prion protein, PrPC, include resistance to oxidative stress, copper uptake, cell adhesion, and cell signaling. Here, we report NADPH oxidase-dependent reactive oxygen species (ROS) production and extracellular regulated kinases 1/2 (ERK1/2) phosphorylation on PrPC stimulation in the 1C11 neuroectodermal precursor, in its neuronal differentiated progenies, and in GT1-7 neurohypothalamic and BW5147 lymphoid cells. In neuroprogenitor, hypothalamic, and lymphoid cells, ERK1/2 activation is fully controlled by the NADPH oxidase-dependent ROS production. In 1C11-derived bioaminergic cells, ROS signaling and ERK1/2 phosphorylation are both controlled by Fyn kinase activation, introducing some specificity in PrPC transduction associated with this neuronal context. These data argue for an ubiquitous function of PrPC in cell-redox homeostasis through ROS production.
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PMID:NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells. 1459 99

Dehydroepiandrosterone (DHEA) is synthesized in the brain, but whether DHEA is involved in modulating neuronal cell survival is not yet fully understood. Herein we show that when deprived of trophic support, GT1-7 hypothalamic neurons undergo apoptosis following exposure to DHEA, as demonstrated both by morphological and biochemical criteria. This proapoptotic effect appeared to be specific to DHEA itself, and not through conversion of DHEA to other steroids such as androgen or estrogen. Importantly, we determined that IGF-I protects GT1-7 neurons from DHEA-induced cell death. DHEA-induced apoptosis was associated with increased activation of caspase 3 and decreased PARP, which were both attenuated with addition of IGF-I. Addition of DHEA prevented phosphorylation of both Akt and glycogen synthase kinase-3 beta (GSK-3beta), downstream effector molecules of the phosphatidylinositol 3-kinase (PI3K) pathway. Further IGF-I was able to sustain Akt activity and thus preventing GSK-3beta activation in the presence of DHEA. On the other hand, the MAP kinases, ERK, p38, and JNK, were not affected by DHEA. These findings suggest that in GT1-7 hypothalamic neurons, DHEA acts detrimentally to induce cell death and IGF-I is able to rescue the neurons by preserving the activity of Akt, and therefore maintaining the proapoptotic kinase GSK-3beta, in a phosphorylated catalytically inactive state.
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PMID:IGF-I signaling prevents dehydroepiandrosterone (DHEA)-induced apoptosis in hypothalamic neurons. 1506 51

The physiological role of the prion protein is largely unknown. Here, clustering of prion at the surface of GT1-7 cells was observed upon anti-prion antibody treatments. This clustering was associated with a rapid and transient phosphorylation of the mitogen activated protein kinases (MAPKs) extracellular receptor kinases 1 and 2 (ERK1/2), and also of the microtubule-destabilizing protein stathmin at serine 16. The specificity of this antibody-mediated activation was ascertained by its inhibition by prion small interfering RNA. The phosphorylation of ERK1/2 but not that of stathmin was abolished by the MAPK/ERK kinase 1 inhibitor U0126, whereas both signaling pathways were blocked by the specific inhibitor of the epidermal growth factor receptor AG1478, suggesting the likely recruitment of this receptor upon prion clustering.
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PMID:Clustering of cellular prion protein induces ERK1/2 and stathmin phosphorylation in GT1-7 neuronal cells. 1547 21

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes. In comparison to single-deficient mice, double-mutant animals exhibited a further delay in the onset of puberty and a strikingly diminished adult reproductive capacity. Ligand-dependent erbB receptor phosphorylation and erbB-mediated MAPK (ERK 1/2) phosphorylation were impaired in mutant astrocytes. Wa-2+/+ or double-mutant astrocytes failed to respond to TGF alpha with production of prostaglandin E2, one of the factors mediating the stimulatory effect of astroglial erbB receptor activation on LHRH release. Medium conditioned by Wa-2+/+ or double-mutant astrocytes treated with TGF alpha failed to stimulate LHRH release from GT1-7 cells. The LH response to ovariectomy was significantly attenuated in mutant mice in comparison with wild-type controls. Although the Wa-2 mutation affects all cells bearing erbB-1 receptors, these results suggest that a major defect underlying the reproductive defects of animals with impaired erbB signaling is a decreased ability of glial cells to stimulate LHRH release. Thus, a coordinated involvement of erbB-1 and erbB-4 signaling systems is required for the normalcy of sexual development and the maintenance of mature female reproductive function.
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PMID:erbB-1 and erbB-4 receptors act in concert to facilitate female sexual development and mature reproductive function. 1559 Nov 45

Many G protein coupled receptors (GPCRs) cause phosphorylation of MAP kinases through transactivation of the epidermal growth factor receptor (EGF-R), leading to increased cell survival and growth, motility, and migration. Phosphoinositide 3-kinase (PI3K) is one of the important cell survival signaling molecules activated by EGF-R stimulation. However, the extent to which EGF-R transactivation is essential for GPCR agonist-stimulated PI3K activation is not known. Here we examined the mechanism of PI3K activation that elicits GPCR-mediated ERK1/2 activation by pathways dependent and/or independent of EGF-R transactivation in specific cell types. Immortalized hypothalamic neurons (GT1-7 cells) express endogenous gonadotropin-releasing hormone receptors (GnRH-R) and their stimulation causes marked phosphorylation of ERK1/2 and Akt (Ser 473) through transactivation of the EGF-R and recruitment of PI3K. In C9 hepatocytes, agonist activation of AT1 angiotensin II (AT1-R), lysophosphatidic acid (LPA), and EGF receptors caused phosphorylation of Akt through activation of the EGF-R in a PI3K-dependent manner. However, ERK1/2 activation by these agonists in these cells was independent of PI3K activation. In contrast, agonist stimulation of HEK 293 cells stably expressing AT1-R caused ERK1/2 phosphorylation that was independent of EGF-R transactivation but required PI3K activation. LPA signaling in these cells showed partial and complete dependence on EGF-R and PI3K, respectively. These data indicate that GPCR-induced ERK1/2 phosphorylation is dependent or independent of PI3K in specific cell types, and that the involvement of PI3K during ERK1/2 activation is not dependent solely on agonist-induced transactivation of the EGF-R.
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PMID:Role of EGF receptor transactivation in phosphoinositide 3-kinase-dependent activation of MAP kinase by GPCRs. 1592 Jul 62

Adrenoceptors (ARs) are involved in the regulation of gonadotropin-releasing hormone (GnRH) release from native and immortalized hypothalamic (GT1-7) neurons. However, the AR-mediated signaling mechanisms and their functional significance in these cells are not known. Stimulation of GT1-7 cells with the alpha1-AR agonist, phenylephrine (Phe), causes phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinases that is mediated by protein kinase C (PKC)-dependent transactivation of the epidermal growth factor receptor (EGF-R). Phe stimulation causes shedding of the soluble ligand, heparin-binding EGF (HB-EGF), as a consequence of matrix metalloproteinase (MMP) activation. Phe-induced phosphorylation of the EGF-R, and subsequently of Shc and ERK1/2, was attenuated by inhibition of MMP or HB-EGF with the selective inhibitor, CRM197, or by a neutralizing antibody. In contrast, phosphorylation of the EGF-R, Shc and ERK1/2 by EGF and HB-EGF was independent of PKC and MMP activity. Moreover, inhibition of Src attenuated ERK1/2 responses by Phe, but not by HB-EGF and EGF, indicating that Src acts upstream of the EGF-R. Consistent with a potential role of reactive oxygen species (ROS), Phe-induced phosphorylation of EGF-R was attenuated by the antioxidant, N-acetylcysteine. These data suggest that activation of the alpha1-AR causes phosphorylation of ERK1/2 through activation of PKC, ROS and Src, and shedding of HB-EGF, which binds to and activates the EGF-R.
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PMID:Role of metalloproteinase-dependent EGF receptor activation in alpha-adrenoceptor-stimulated MAP kinase phosphorylation in GT1-7 neurons. 1633 26

Hypothalamic astrocytes secrete TGF-beta and 3 alpha,5 alpha-tetrahydro progesterone (3 alpha,5 alpha-THP) in culture. When the astrocyte-conditioned medium (ACM) was incubated with the hypothalamic cell line GT1-7, it resulted in the secretion of GnRH. Immunoneutralization with TGF-beta antibody or ultra-filteration with a 10 kDa cut off filter resulted in attenuation of the GnRH releasing ability of ACM, indicating that TGF-beta was a major factor involved with GnRH release. Treatment with estrogens increases TGF-beta secretion. These observations indicate a significant role of astrocytes in GnRH secretion. Serum-deprivation results in the death of GT1-7 neurons in culture and addition of ACM or TGF-beta to the culture, attenuates cell death. The mechanism of protection from cell death appears to involve phosphorylation of MKK4, JNK, c-Jun(Ser63), and enhancement of AP-1 binding. Co-administration of JNK inhibitors, but not MEK inhibitors attenuated ACM or TGF-beta-induced c-Jun(Ser63) phosphorylation and their neuroprotective effects. These studies suggest that astrocytes can protect neurons, at least in part, by the release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.
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PMID:Role of astrocytes in reproduction and neuroprotection. 1638 90


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