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)

Cellular response to oestradiol stimuli is mediated both by oestrogen receptor (ER) binding to oestrogen response elements (EREs) and by non-nuclear actions like activation of mitogen-activated protein kinase (MAPK) signal transduction. Therefore, oestradiol stimuli might be able to interfere with the action of antitumoral substances directed against receptor tyrosine kinase signalling. We investigated the effect of oestradiol on the inhibition of HER2 signalling by trastuzumab (Herceptin) in two human endometrial adenocarcinoma cell lines. Activation of the extracellular signal-regulated kinase (ERK-1/2), a major mediator of HER2 signalling, was measured by means of western blotting experiments and ERE activation was determined in transient reporter-gene assays. In endometrial Ishikawa and HEC-1A adenocarcinoma cells, HER2 signalling was inhibited by trastuzumab only in the absence of oestradiol. We were able to demonstrate that oestradiol counteracted the inhibitory effects of trastuzumab by rapid phosphorylation of ERK-1/2, a kinase downstream of the HER2 receptor. The pure anti-oestrogen ICI 182,780 was able to restore both the trastuzumab-triggered inhibition of the ERK-1/2 pathway and the antiproliferative action of this substance in Ishikawa cells. Our data suggest that combinations of trastuzumab with anti-oestrogens may be effective in the treatment of endometrial cancers with a positive ER and HER2 receptor status.
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PMID:The activation of an extracellular signal-regulated kinase by oestradiol interferes with the effects of trastuzumab on HER2 signalling in endometrial adenocarcinoma cell lines. 1276 21

Low physiological concentrations of 17beta-estradiol increased the intracellular pH of rat aortic smooth muscle cells by a rapid nongenomic mechanism. This effect was due to stimulation of the Na+/H+ exchanger activity, measured using the intracellular pH-sensitive fluorescent probe 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. The 17beta-estradiol gave rise to a bell-shaped dose response, with a maximum at 10-12 m and no significant effect at 10-9 m. The specificity of the effect was verified by the use of the Na+/H+ exchanger inhibitor 5-(ethyl-N-isopropyl)amiloride and the lack of effect of the isomer 17alpha-estradiol. Inhibitors of the nuclear estrogen receptors, tamoxifen and ICI 182,780, completely prevented activation of the exchanger by 17beta-estradiol. The effect of low estrogen concentrations on the intracellular pH was mimicked by both norepinephrine and phenylephrine, suggesting a connection between the increase of intracellular pH and the muscle contraction process. The transduction mechanism for this nongenomic effect of estrogens did not involve modulation of the cAMP content, whereas inositol 1,4,5-trisphosphate, protein kinase C and MAPK pathways appear to play a role, as indicated by both pharmacological approaches and immunoblot experiments on protein kinase C translocation and ERK phosphorylation. These results for the first time provide evidence for a nongenomic effect of low physiological concentrations of 17beta-estradiol on intracellular pH that, together with other factors, may contribute to the development of hypertension and atherosclerosis in men and postmenopausal women and increase the risk of cardiovascular disease. Paradoxically, the lack of stimulation at high physiological estradiol levels could explain the protective effects found in premenopausal women.
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PMID:Short-term activation by low 17beta-estradiol concentrations of the Na+/H+ exchanger in rat aortic smooth muscle cells: physiopathological implications. 1295 86

Rapid uterine vasodilatation after estrogen administration is believed to be mediated by endothelial production of nitric oxide (NO) via endothelial NO synthase (eNOS). However, the mechanism(s) by which estrogen activates eNOS in uterine artery endothelial cells (UAEC) is unknown. In this study, we observed that estradiol-17beta (E2) and E2-BSA rapidly (<2 min) increased total NOx production in UAEC in vitro. This was associated with rapid eNOS phosphorylation and activation but was unaltered by pretreatment with actinomycin-D. Estrogen receptor-alpha protein was detectable in isolated plasma membrane proteins by immunoblotting, and E2-BSA-fluorescein isothiocyanate binding was evident on the plasma membrane of UAEC. E2 did not mobilize intracellular Ca2+, but E2 and ionomycin in combination induced greater eNOS phosphorylation than either E2 or ionomycin alone. E2 did not stimulate rapid Akt phosphorylation. E2 stimulated rapid ERK2/1 activation in a time- and dose-dependent manner, with maximal responses observed at 5-10 min with E2 (10 nm to 1 microm) treatment. Acute activation of eNOS and NOx production by E2 could be inhibited by PD98059 but not by LY294002. When E2-BSA was applied, similar responses in NOx production, eNOS, and ERK2/1 activation to those of E2 were achieved. In addition, E2 and E2-BSA-induced ERK2/1 activation and ICI 182,780 could inhibit NOx production by E2. Thus, acute activation of eNOS to produce NO in UAEC by estrogen is at least partially through an ERK pathway, possibly via estrogen receptor localized on the plasma membrane. This pathway may provide a novel mechanism for NO-mediated rapid uterine vasodilatation by estrogen.
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PMID:Membrane estrogen receptor-dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells. 1451 34

Vascular endothelial growth factor (VEGF) is an endothelium-specific growth factor with potent angiogenic activity and a stimulator of microvascular permeability. Because endometrial cyclic development is associated with vascular growth, we examined the expression of VEGF protein throughout the menstrual cycle and studied the regulation of VEGF mRNA by ovarian steroids in isolated human endometrial stromal cells. VEGF was localized immunohistochemically in glandular epithelial cells and in the surrounding stroma, as well as in capillaries and spiral arterioles, a localization which has not been described before. The strongest immunoreactivity for VEGF on endothelial cells was detected in the late proliferative and secretory phases. The localization of VEGF bound to the endothelium correlates with the presence of flt-1 and flk/KDR receptors on vascular structures, including capillary strands which have not yet formed a lumen, present during the mid-secretory period, which corresponds to a high estroprogestin influence and to implantation. Heparinase treatment of the sections decreases the staining intensity of VEGF bound to endothelial cells, suggesting that VEGF also binds to heparin-like molecules on the cell surface. These new results demonstrate a major role of VEGF on capillary formation and on hyperpermeability and edema during the menstrual cycle. Consistent with these in vivo observations, the treatment of isolated endometrial stromal cells with estradiol (E2) or E2 plus progesterone, significantly increased VEGF mRNA over the control value in a dose-dependent manner; the VEGF mRNA response to E2 was rapid (3h) and persisted with continuous estradiol treatment up to 12 days. Three species, VEGF_121, VEGF165 and VEGF189, were observed upon hormonal stimulation. The estradiol up-regulation of VEGF response did not require de novo protein synthesis as it was not blocked by cycloheximide. Also, the ability of the pure anti-estrogen ICI 182,780 to significantly block induction of VEGF mRNA by E2 suggests estrogen receptor-mediated transcriptional regulation. These results demonstrate that VEGF is an estrogen-responsive angiogenic factor that acts on vascular endothelium in a paracrine fashion, as previously suggested. This growth factor controls angiogenesis and hyperpermeability required for adequate receptivity to implantation of the cycling human endometrium. These findings also raise the possibility that estrogen effects on uterine edema, proliferation and tumoral transformation may involve local increases in tissue VEGF production.
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PMID:Paracrine action of vascular endothelial growth factor in the human endometrium: production and target sites, and hormonal regulation. 1451 72

Repeated administration of micro-opioid receptor agonist, morphine induces tolerance not only to the antinociceptive effect but also to other pharmacological effects, resulting in shortened working duration and decreased efficacy. But less is known about kappa-opioid agonist-induced tolerance. The tolerance-development potency of kappa-opioid receptor agonists with a focus on TRK-820 was characterized. After five administrations of kappa-opioid receptor agonists, TRK-820 (0.1-0.8 mg/kg), U-50,488H (10-80 mg/kg) and ICI-199,441 (0.025-0.2 mg/kg) subcutaneously over 3 days, tolerance to the antinociceptive effects, assessed by an acetic acid-induced abdominal constriction test, developed in a repeated dose-dependent manner. The tolerance-development potency of TRK-820 was the least among these kappa-opioid receptor agonists. Similarly, TRK-820 and U-50,488H induced tolerance to their sedative effects as judged by a wheel-running test in mice. Greater tolerance was developed to the sedative effect than to the antinociceptive effect in both compounds. After repeated administration, the number of kappa-opioid receptors in the mouse brain was reduced by U-50,488H (80 mg/kg) but not by TRK-820 (0.4 mg/kg). There was no change of the affinity by the treatment with both compounds. These results demonstrated that the kappa-opioid receptor agonists developed tolerance both to the antinociceptive and the sedative effects, though the tolerance to the sedative effect developed more readily than tolerance to the antinociceptive effect. The difference in the potency for down-regulating the kappa-opioid receptors in the brain may account for the tolerance-development potency of the compounds.
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PMID:Effect of repeated administration of TRK-820, a kappa-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions. 1467 6

Ovarian steroids are important modulators of normal cell growth and differentiation as well as of carcinogenesis. External stimuli trigger cell surface receptors, resulting in activation of central signal transduction pathways, that are mediated by members of the mitogen-activated protein kinase (MAPK) family. These in turn, indirectly regulate cellular functions such as cell proliferation, cell cycle, and maintenance of malignant phenotype. In our in vitro study, we have investigated the effects of two synthetic estrogens on ERK 2 activation. Estrogen receptor positive cells were incubated with the synthetic estrogens, ethinylestradiol (10(-9) mol/l) and 17 beta-estradiol valerate (10(-9) mol/l), epidermal growth factor (EGF) (10 ng/ml) and the natural estrogen 17 beta-estradiol (10(-9) mol/l), for 5 min. The same experiments were repeated prior to preincubation with the antiestrogen ICI 182780. ERK 2 or the active form alone were detected by immunoblotting. A cell proliferation assay was used to study the response of cells to various treatments. Time kinetics were performed to study duration of kinase activated state. Cell incubation with EGF as well as with either natural or synthetic estrogen stimulated proliferation. ICI 182780 inhibited this effect, but only in the case of estrogen. Synthetic estrogens activated MAP kinase in a time-dependent fashion, similar to 17 beta-estradiol. The estrogen receptor antagonist ICI 182780 blocked this effect. EGF induced a more pronounced and prolonged activation, even in the presence of the antiestrogen. Ethinylestradiol as used in oral contraceptives, and 17 beta-estradiol and 17 beta-estradiol valerate as used in hormone replacement therapy, are able to activate MAP kinase. This activation was blocked by an antiestrogen.
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PMID:Synthetic estrogen-mediated activation of ERK 2 intracellular signaling molecule. 1471 May 92

Estrogen has a variety of neurotrophic effects mediated via different signaling cascades, including ERK and phosphatidylinositol 3-kinase (PI3K) pathways. In this study, we investigated effects of estrogen and inhibitors for ERK and PI3K applied directly onto the cut sciatic nerve on retrograde labeling of lumbar motoneurons. A mix of retrograde tracer (Fluorogold) and 17beta-estradiol, in combination with an antagonist for estrogen receptors ICI 182,780, an inhibitor of ERK1/2 pathway (U0126), an inhibitor of PI3K (LY-294002), or a protein synthesis inhibitor (cycloheximide), was applied to the proximal stump of the transected sciatic nerve for 24 h. Coapplication of Fluorogold with 17beta-estradiol produced a significant increase in the number of retrograde-labeled lumbar motoneurons, compared with Fluorogold alone. Estrogen potentiation of retrograde labeling was inhibited by application of ICI 182,780, U0126, LY-294002, and cycloheximide. Immunohistochemical analysis of the sciatic nerve, 24 h following crush injury, revealed accumulation of phospho-ERK in regenerating nerve fibers. The data suggest a role for estrogen, ERK, PI3K, and protein synthesis in the uptake and retrograde transport of Fluorogold. We propose that estrogen action in peripheral nerve fibers is mediated via the ERK and PI3K signaling pathways and is reliant on local protein synthesis.
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PMID:Estrogen increases retrograde labeling of motoneurons: evidence of a nongenomic mechanism. 1504 55

We explored, by cDNA mini-arrays, gene expression measurements of MVLN, a human breast carcinoma cell line derived from MCF-7, after 4 days of exposure to 17beta-estradiol (E(2)) treatment, in order to extend our understanding of the mechanism of the pharmacological action of estrogens. We focused on 22 genes involved in estrogen metabolism, cell proliferation regulation and cell transformation. The specificity of the E(2) response was reinforced by comparison with 4-hydroxytamoxifen (OH-Tam), ICI 182,780 and E(2)+OH-Tam expression profiles. Real-time quantitative PCR (RTQ-PCR) confirmed the variation of expression of known (TFF1, AREG, IRS1, IGFBP4, PCNA, ERBB2, CTSD, MYC) as well as novel (DLEU2, CCNA2, UGT1A1, ABCC3, ABCC5, TACC1, EFNA1, NOV, CSTA, MMP15, ZNF217) genes. The temporal response of these gene expression regulations was then investigated after 6 and 18 h of E(2) treatment and this allowed the identification of different time-course patterns. Cycloheximide treatment studies indicated first that estrogen affected the transcript levels of ABCC3 and ABCC5 through dissimilar pathways, and secondly that protein synthesis was needed for modulation of the expression of the CCNA2 and TACC1 genes by estrogens. Western blot analysis performed on TFF1, IRS1, IGFBP4, amphiregulin, PCNA, cyclin A2, TACC1 and ABCC5 proteins confirmed the mini-array and RTQ-PCR data, even for genes harboring low variations of mRNA expression. Our findings should enhance the understanding of changes induced by E(2) on the transcriptional program of human E(2)-responsive cells and permit the identification of new potential diagnostic/prognostic tools for the monitoring of estrogen-related disease conditions such as breast cancer.
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PMID:Estrogen regulation in human breast cancer cells of new downstream gene targets involved in estrogen metabolism, cell proliferation and cell transformation. 1507 47

It has been demonstrated that the newly synthesized kappa-opioid receptor agonist TRK-820, which has a unique structure that is different from those of other prototypical kappa-opioid receptor agonists such as U-50,488H, exert some behavioral effects that differ from those induced by U-50,488H. Therefore, the present study was designed to examine the possible difference between the discriminative stimulus effects of TRK-820 and U-50,488H in rats. Substitution tests with several kappa-opioid receptor agonists were initiated in rats trained to discriminate between TRK-820 (40 microg/kg) or U-50,488H (3.0 mg/kg) and saline. In the cross-substitution tests, U-50,488H substituted for the discriminative stimulus effects of TRK-820, whereas TRK-820 did not substitute completely for those of U-50,488H, indicating that the discriminative stimulus effects of TRK-820 and U-50,488H were somewhat different. In the substitution tests, E-2078, but not R-84760, substituted for the discriminative stimulus effects of both TRK-820 and U-50,488H. KT-90, CI-977 and ICI-199441 each substituted for the discriminative stimulus effects of U-50,488H, but not to those of TRK-820. These results imply that these kappa-opioid receptor agonists possess U-50,488H-like discriminative stimulus effects. Furthermore, that U-50,488H and the other kappa-opioid receptor agonists substituted for the discriminative stimulus effects of U-50,488H, produced aversive effects in rats. These findings suggest the possibility that unlike those of TRK-820, the cue of the discriminative stimulus effects of U-50,488H may be, at least in part, associated with its aversive effects.
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PMID:Differential properties between TRK-820 and U-50,488H on the discriminative stimulus effects in rats. 1535 Aug 22

Chemotherapy of malaria fever with chloroquine is often associated with generalized pruritus of unknown pathogenesis. This adverse side effect leads to diminished compliance. We report that chloroquine (1.25-40 mg/kg, s.c.) elicits dose-related, compulsive, and vigorous scratching in mice. This frenzied behavior is essentially abolished when the mice are pretreated s.c. or orally with nalfurafine (TRK-820), a centrally penetrating kappa opioid agonist. Peripheral kappa receptors are involved because chloroquine-induced scratching is also antagonized by the peripherally restricted kappa agonist, ICI 204,448: R,S-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl) ethyl]pyrrolidine. We propose that combination therapy for malaria with chloroquine and a kappa agonist (probably one targeting peripheral receptors) will lead to better treatment compliance because of a reduced incidence of pruritus.
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PMID:Kappa opioid agonists suppress chloroquine-induced scratching in mice. 1547 49


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