Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-α knock-out mice

Meharvan Singh, György Sétáló, Xiaoping Guan, Donald E. Frail, C. Dominique Toran-Allerand

Research output: Contribution to journalArticle

233 Scopus citations

Abstract

We have shown previously in the developing cerebral cortex that estrogen elicits the rapid and sustained activation of multiple signaling proteins within the mitogen-activated protein (MAP) kinase cascade, including B-Raf and extracellular signal-regulated kinase (ERK). Using estrogen receptor (ER)-α gene-disrupted (ERKO) mice, we addressed the role of ER-α in mediating this action of estrogen in the brain. 17β-Estradiol increased B- Raf activity and MEK (MAP kinase/ERK kinase)dependent ERK phosphorylation in cerebral cortical explants derived from both ERKO and their wild-type littermates. The ERK response was stronger in ERKO-derived cultures but, unlike that of wild-type cultures, was not blocked by the estrogen receptor antagonist ICI 182,780. Surprisingly, both the ER-α selective ligand 16α- iodo-17β-estradiol and the ER-β selective ligand genistein failed to elicit ERK phosphorylation, suggesting that a different mechanism or receptor may mediate estrogen-induced ERK phosphorylation in the cerebral cortex. Interestingly, the transcriptionally inactive stereoisomer 17α-estradiol did elicit a strong induction of ERK phosphorylation, which, together with the inability of the ER-α- and ER-β-selective ligands to elicit ERK phosphorylation, and of ICI 182,780 to block the actions of estradiol in ERKO cultures, supports the hypothesis that a novel, estradiol-sensitive and ICI- insensitive estrogen receptor may mediate 17β-estradiol-induced activation of ERK in the brain.

Original languageEnglish
Pages (from-to)1694-1700
Number of pages7
JournalJournal of Neuroscience
Volume20
Issue number5
DOIs
StatePublished - 1 Mar 2000

Keywords

  • Brain
  • Cerebral cortex
  • ERK
  • ERKO
  • Estradiol
  • Estrogen receptor
  • Signal transduction

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