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      17β-Estradiol Stimulates Mouse Neuropeptide Y-Y 1 Receptor Gene Transcription by Binding to Estrogen Receptor Alpha in Neuroblastoma Cells

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          Several studies have shown that neuropeptide Y (NPY) is involved in the stimulation of gonadotropin hormone releasing hormone (GnRH) and luteinizing hormone (LH) secretion and that these effects are modulated by gonadal steroid feedback. The NPY regulation of GnRH release is probably mediated by the activation of the Y<sub>1</sub> receptor subtype. In this study we examined the regulation of the Y<sub>1</sub> receptor gene transcription by estrogens in transiently transfected NG108-15 neuroblastoma glioma cells. A chimeric plasmid containing the murine Y<sub>1</sub> receptor promoter fused to the firefly luciferase reporter gene was induced by approximately 2-fold in response to 17β-estradiol treatment. The estrogen-mediated enhancement of luciferase activity was dose-dependent, blocked by the estrogen receptor (ER) antagonist ICI 182,780, and was strictly dependent on the presence of ERα, since it occurred only in NG108-15 cells cotransfected with an expression vector for the human ER. Mutational analysis was performed to investigate whether the hemipalindromic estrogen-responsive elements (EREs) flanking the Y<sub>1</sub> receptor gene are responsible for conferring estradiol inducibility to the Y<sub>1</sub> receptor gene promoter. Mutation of the ERE1 half site at position –932, or mutation of the ERE2 half site at position –809, relative to the ATG, failed to affect the 17β-estradiol-mediated enhancement of luciferase activity. Conversely, mutation of both ERE1 and ERE2 half sites completely abolished activation of luciferase activity induced by estrogen. We also examined whether 17β-estradiol stimulates the transcriptional activity of the Y<sub>1</sub> receptor gene by binding to ERβ. Results demonstrated that luciferase activity was not modulated by estrogens when cells were transfected with the expression plasmid bearing the human ERβ. Moreover coexpression of both ERα and ERβ completely abolished the estrogen-induced activation of luciferase activity observed in the presence of ERα. Our data suggest that estrogens activate Y<sub>1</sub> receptor gene transcription possibly via a direct interaction of ERα with the hemipalindromic EREs flanking the Y<sub>1</sub> receptor gene.

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          Most cited references 11

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          Interacting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weight

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            Differential Ligand Activation of Estrogen Receptors ER and ER at AP1 Sites

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              Estrogen receptors alpha and beta in the rodent mammary gland.

              An obligatory role for estrogen in growth, development, and functions of the mammary gland is well established, but the roles of the two estrogen receptors remain unclear. With the use of specific antibodies, it was found that both estrogen receptors, ERalpha and ERbeta, are expressed in the rat mammary gland but the presence and cellular distribution of the two receptors are distinct. In prepubertal rats, ERalpha was detected in 40% of the epithelial cell nuclei. This decreased to 30% at puberty and continued to decrease throughout pregnancy to a low of 5% at day 14. During lactation there was a large induction of ERalpha with up to 70% of the nuclei positive at day 21. Approximately 60-70% of epithelial cells expressed ERbeta at all stages of breast development. Cells coexpressing ERalpha and ERbeta were rare during pregnancy, a proliferative phase, but they represented up to 60% of the epithelial cells during lactation, a postproliferative phase. Western blot analysis and sucrose gradient centrifugation confirmed this pattern of expression. During pregnancy, the proliferating cell nuclear antigen was not expressed in ERalpha-positive cells but was observed in 3-7% of ERbeta-containing cells. Because more than 90% of ERbeta-bearing cells do not proliferate, and 55-70% of the dividing cells have neither ERalpha nor ERbeta, it is clear that the presence of these receptors in epithelial cells is not a prerequisite for estrogen-mediated proliferation.

                Author and article information

                S. Karger AG
                December 2000
                22 December 2000
                : 72
                : 6
                : 360-367
                aSection of Pharmacology, Department of Anatomy, Pharmacology and Forensic Medicine, Torino, and bCenter MPL, Institute of Pharmacological Sciences, University of Milano, Italy
                54605 Neuroendocrinology 2000;72:360–367
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 44, Pages: 8
                Central Effects of Gonadal Steroids


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