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 journalArticlepeer-review

234 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

Fingerprint

Dive into the research topics of 'Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-α knock-out mice'. Together they form a unique fingerprint.

Cite this