Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells

J Steroid Biochem Mol Biol. 2014 Jan;139:45-53. doi: 10.1016/j.jsbmb.2013.09.010. Epub 2013 Oct 10.

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.

Keywords: Estrogen receptor phosphorylation; G-protein coupled receptor; Kinases; Signaling; Transcription.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Enzyme Activation
  • Estradiol / pharmacology
  • Estradiol / physiology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Neuroblastoma
  • Nitriles / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / metabolism
  • Response Elements
  • Serum Albumin, Bovine / pharmacology
  • Serum Albumin, Bovine / physiology
  • Transcription, Genetic
  • Transcriptional Activation
  • Wortmannin

Substances

  • Androstadienes
  • Butadienes
  • Estrogen Receptor alpha
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • U 0126
  • estradiol-bovine serum albumin
  • estrogen receptor alpha, human
  • Serum Albumin, Bovine
  • Estradiol
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Wortmannin