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 the mammary gland. Specifically we are interested in examining the ability of ER action to modulate MAPK signaling as well as other key signaling molecules and our main goals with this research are to: 1) better define the mechanism responsible for the observed cross-talk 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 Erk-1 and -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 preliminary evidence that demonstrated that E2 administration to ovariectomized immature rats can induce Erk-1 and -2 phosphorylation in the uterine horn. We show here our continued investigation of ER-mediated Erk-1 and -2 activation in vivo and that E2 administration can in fact result in a significant increase of Erk-1 and -2 phosphorylation over saline control in both the uterine horn and brain. In each case E2-induced Erk-1 and -2 activation is at least partially decreased by the co-administration of raloxifene a selective estrogen receptor modulator (SERM). Additionally we have identified CaMKII as an important player in ER-mediated Erk-1 and -2 activation. In cultured neuronal cells the inhibition of CaMKII with KN-62 blocks E2- induced Erk-1 and -2 phosphorylation. Interestingly as little as 15 minutes of E2 administration to ovariectomized rats results in a significant increase in CaMKII autophosphorylation and thus its activation in the brain.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2006
- Accession Number
- ADA462667
Entities
People
- Erin O'neill
- Geoffrey L Greene
Organizations
- University of Chicago