Integration of the Non-genomic and Genomic Actions of Estrogen

Abstract

Estrogen binds to receptors that translocate to the plasma membrane and to the nucleus. The rapid, nongenomic actions of this sex steroid are attributed to membrane action, while gene transcription occurs through nuclear receptor function. However, gene transcription can also result from estrogen signaling initiated at the membrane, but the relative importance of this mechanism is not known. In vascular endothelial cells (EC), estradiol (E 2 ) activates several kinase cascades, including phosphatidylinositol 3-phosphate (PI3K)/Akt, a signaling pathway that impacts EC biology. We determined here by DNA microarray that 40-min exposure to E 2 significantly increased 250 genes in EC, up-regulation that was substantially prevented by the PI3K inhibitor, LY294002. This coincided with maximum E 2 -induced PI3K activity at 15-30 min. An important vascular gene strongly up-regulated by E 2 in our array produces cyclooxygenase-2 (Cox-2). In cultured EC, E 2 induced both Cox-2 gene expression and new Cox-2 protein synthesis by 40 and 60 min, respectively, and rapidly stimulated the secretion of prostaglandins PGI 2 and PGE 2 . The up-regulation of gene expression reflected transcriptional transactivation, shown using Cox-2 promoter/luciferase reporters in the EC. Soluble inhibitors or dominant negative constructs for PI3K and Akt prevented all these actions of E 2 . Functionally, EC migration was induced by the sex steroid, and this was significantly reversed by NS-398, a Cox-2 inhibitor. Gene transcription and cell biological effects of estrogen emanate from rapid and specific signaling, integrating cell surface and nuclear actions of this steroid.

Estradiol Binding to Maxi-K Channels Induces Their Down-regulation via Proteasomal Degradation

“…However, other data show that estrogen-containing preparations can negatively affect the health of premenopausal as well as post-menopausal women (1)(2)(3)(4)(5)(6). These results indicate the existence of complex estradiol-signaling mechanisms, possibly mediated by proteins other than classical intracellular estradiol receptors (7).…”

Estrogen Receptor Activation of Phosphoinositide-3 Kinase, Akt, and Nitric Oxide Signaling in Cerebral Blood Vessels: Rapid and Long-Term Effects

“…It was shown recently that stimulation of PI-3 kinase by estrogen up-regulates gene expression in cultured umbilical vein endothelial cells (Pedram et al, 2002). Akt also regulates endothelial cell survival and angiogenesis (Shiojima and Walsh, 2002), a mechanism that may underlie 17␤-estradiol inhibition of endothelial apoptosis (Alvarez et al, 1997).…”

Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH) 2 -vitamin D 3 signaling

“…1A), other steroid hormones, retinoids, and thyroid hormones form the family of ligands for the nuclear receptor (NR) superfamily (1), the members of which produce genomic responses through selective interaction of the liganded receptor with promoters of appropriate genes and basal transcription machinery. Many of these hormones also activate rapid, nongenomic (NG), cellular signaling cascades (2, 3) (except retinoids) that range from activation of ion channels (4,5) to promoting kinase and other cytosolic signaling cascades (6)(7)(8)(9). Defining the structure-function requirements for 1,25D and 17␤-estradiol (E 2 ) rapid actions has been aided by the synthesis of analogs that are NG agonists like 1␣,25(OH) 2 -lumisterol (JN) (ref.…”