title: Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells.
abstract: While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17β-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Gαq coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERα phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERα is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.
authors.affiliation: Cell and Molecular Biology Department, Tulane University, New Orleans, LA 70118, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Clark
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rainville
authors.forename: Xing
authors.initials: X
authors.lastname: Zhao
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: Donald
authors.initials: D
authors.lastname: Pfaff
authors.forename: Nandini
authors.initials: N
authors.lastname: Vasudevan
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009447:Neuroblastoma; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements; D012710:Serum Albumin, Bovine / Q000494:pharmacology / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002070:Butadienes; D004958:Estradiol; D047628:Estrogen Receptor alpha; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012710:Serum Albumin, Bovine; D000077191:Wortmannin; C506487:ESR1 protein, human; C113580:U 0126; C043090:estradiol-bovine serum albumin
keywords: Estrogen receptor phosphorylation; G-protein coupled receptor; Kinases; Signaling; Transcription