Extranuclear Signaling Effects Mediated by the Estrogen Receptor
Abstract
Recent evidence has made it clear that ER-mediated extranuclear signaling is involved in the growth and survival of ER-expressing cells and tissues, including both reproductive and nonreproductive. Specifically, we are interested in examining the ability of ER action to rapidly modulate various signaling cascades, and our main goals with this research are to: 1) define the mechanism responsible for the rapid ER signaling, 2) investigate the observed signaling in an animal model, 3) determine and compare the target genes that are regulated by ER rapid signaling versus classical ER transactivation, and 4) examine the subsequent cellular and biological responses to rapid 17beta-estradiol (E2) action. Previously, we confirmed that E2 and other ER-specific ligands can rapidly phosphorylate and activate Erk1/2 in the breast cancer cell line, MCF-7, an effect that is blocked by the potent ER antagonist, ICI 182, 780. We have also provided evidence that E2 administration to ovariectomized immature rats can induce Erk1/2 phosphorylation in the uterine horn and brain and that E2 can also induce alphaCaMKII autophosphorylation in the brain in vivo. alphaCaMKII was also identified as an upstream regulator of E2-induced ERK1/2 phosphorylation We show here that E2 can rapidly and significantly induce alphaCaMKII autophosphorylation, which subsequently mediates ERK1/2 phosphorylation in immortalized GnRH neurons and primary hippocampal cells. This signaling results in p90RSK and CREB phosphorylation that appears to require Ca2+ influx through the Ltype Ca2+ channels. Interestingly, the administration of either E2 or PPT, the ERalpha-selective agonist, but not vehicle, to female ovariectomized rats results in a clear enhancement of alphaCaMKII autophosphorylation in the hippocampus. Our findings suggest a novel model for the activation of ERK1/2 by ERalpha via alphaCaMKII signaling, which increases our understanding of E2 action in the central nervous system.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA471802
Entities
People
- Erin O'neill
Organizations
- University of Chicago