TY - JOUR
T1 - Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-α knock-out mice
AU - Singh, Meharvan
AU - Sétáló, György
AU - Guan, Xiaoping
AU - Frail, Donald E.
AU - Toran-Allerand, C. Dominique
PY - 2000/3/1
Y1 - 2000/3/1
N2 - 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.
AB - 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.
KW - Brain
KW - Cerebral cortex
KW - ERK
KW - ERKO
KW - Estradiol
KW - Estrogen receptor
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=0342803689&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.20-05-01694.2000
DO - 10.1523/jneurosci.20-05-01694.2000
M3 - Article
C2 - 10684871
AN - SCOPUS:0342803689
SN - 0270-6474
VL - 20
SP - 1694
EP - 1700
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 5
ER -