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Definition of Rapid 17β-Estradiol Signaling Networks in Developing Cerebellar Granule Cells

LE, HOA HIEN
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218807307

Abstract Details

2008, PhD, University of Cincinnati, Medicine : Molecular, Cellular and Biochemical Pharmacology.
Estrogens influence the normal function and development of the mammalian nervous system. 17β-Estradiol (E2) mediates many of its effects through modulation of gene transcription via binding to its cognate receptors (ERα and ERβ) which are ligand-activated transcriptional factors. In addition to regulating gene transcription, E2 also affects diverse signal transduction pathways, including the activation of extracellular-signal regulated kinase1/2 (ERK1/2). However, the mechanisms of rapid E2 signal transduction effects are not well defined. In neonatal rat cerebellum, low concentrations of E2, ICI 182,780 (an estradiol-like antagonist of ER-transactivation), and some endocrine disrupting chemicals (EDCs) rapidly induce ERK1/2 activation. In addition to ERK1/2 stimulation, E2 simultaneously induces rapid activation of protein phosphatase PP2A through an independent mechanism, involving intracellular E2 binding. The mechanisms of E2-induced ERK1/2 activation are dependent on pertussis toxin-sensitive G protein, protein kinase A, and non-receptor tyrosine kinase c Src activation, but not epidermal growth factor receptor. Rapid activation of the ERK and PP2A signaling pathways represents extracellularly- and intracellularly-initiated mechanisms of E2 actions and are both involved in calpain-dependent neurotoxicity in response to E2. In addition, four EDCs with estrogenic properties, diethylstilbestrol, bisphenol A, daidzein, and equol induce E2-like neurotoxicity, suggesting a common rapid estrogen-signaling mechanism for neurotoxicity in cerebellar granule cells and supporting that exposure to EDCs may impact the physiology and development of cerebellar granule cells.
Scott Belcher, PhD (Committee Chair)
Nira Ben-Jonathan, PhD (Committee Member)
Keith Jones, PhD (Committee Member)
John Maggio, PhD (Committee Member)
Robert Rapoport, PhD (Committee Member)
299 p.
Pharmacology
estradiol; estrogen; estrogen receptor; endocrine disrupting chemicals; cerebellum; granule cells; viability; rapid actions; intracellular signaling pathways

Recommended Citations

Citations

  • LE, H. H. (2008). Definition of Rapid 17β-Estradiol Signaling Networks in Developing Cerebellar Granule Cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218807307

    APA Style (7th edition)

  • LE, HOA. Definition of Rapid 17β-Estradiol Signaling Networks in Developing Cerebellar Granule Cells. 2008. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218807307.

    MLA Style (8th edition)

  • LE, HOA. "Definition of Rapid 17β-Estradiol Signaling Networks in Developing Cerebellar Granule Cells." Doctoral dissertation, University of Cincinnati, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218807307

    Chicago Manual of Style (17th edition)

ucin1218807307
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© 2008, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.