Association of estrogen receptor   with plasma-membrane caveola components: implication in control of vitamin D receptor

Abstract

This study was designed to provide a direct demonstration of the importance of caveolin-1 in the compartmentalization of estrogen receptor b (ERb) to the membrane, thus allowing 7b-estradiol (E2) to control vitamin D receptor (VDR) transcription and expression. Our strategy was to obtain cell lines expressing different levels of caveolin-1. To this end, we transfected human embryonic kidney 293 cells with a caveolin-1-expressing vector and obtained three cell-line variants: one expressing high amounts of caveolin-1 (clone A), one expressing low amounts of caveolin-1 (clone B), and one expressing high amounts of the nonfunctional P132L caveolin-1 mutant (clone C), and compared these with parental (wild-type, WT) cells expressing negligible levels of caveolin-1. In clone A, ERb colocalized to membrane preparations and E2 treatment induced significant ERK 1/2 phosphorylation and enhanced VDR expression. In clones B and C and the WT, ERb did not localize to membrane preparations and E2 treatment was ineffective at inducing VDR upregulation associated with ERK 1/2 phosphorylation. Luciferase reporter gene expression assays showed that the human VDR promoter is only highly responsive to E2 treatment in clone A, except in the presence of the ER-specific inhibitor ICI182 780. Cotransfection of clone A with the VDR promoter and several mutants of MAPK kinase (MEK) demonstrated that the constitutively active form of MEK significantly increases VDR promoter activation, while the catalytically inactive construct is ineffective in this regard. In clone A cells transfected with an activation protein-1 (AP-1)-luciferase construct, E2 significantly upregulated the promoter activity, while ICI182 780 completely eliminated this E2-mediated effect. Clone A cells transfected with a VDR promoter bearing a targeted mutation towards the AP-1 site showed reduced E2-mediated activation of luciferase activity. Taken together, our data confirm the importance of caveolin-1 in the association of ERb to the membrane caveolae, allowing ERK 1/2 phosphorylation and upregulation of VDR.

Heritability and Environmental Factors Affecting Vitamin D Status in Rural Chinese Adolescent Twins

“…Therefore, when 25(OH)D level is low, a genetic component does not contribute further to variation among individual adolescent females as it does among males. It is also possible that there are strong gender-specific hormonal effects that regulate 25(OH)D levels, such as in one animal study where estradiol up-regulated the expression of vitamin D receptors (36). Further studies are needed to examine these possibilities.…”

Caveolae and caveolin-1 are implicated in 1α,25(OH)2-vitamin D3-dependent modulation of Src, MAPK cascades and VDR localization in skeletal muscle cells

“…Specifically, the regulation of growth plate chondrocytes by 1␣,25(OH) 2 D 3 requires caveolae and cav-1 [4]. Recently it was reported the key role of cav-1 in the compartmentalization of estrogen receptor ␤ (ER␤) to the plasma membrane, thus allowing estradiol to control VDR transcription and expression [20]. In view of the data described, our aim was to investigate the role of caveolae and cav-1 in 1␣,25(OH) 2 D 3 -dependent modulation of kinase cascades and VDR localization in skeletal muscle cells.…”

Tanshinone IIA promotes non-amyloidogenic processing of amyloid precursor protein in platelets via estrogen receptor signaling to phosphatidylinositol 3-kinase/Akt

“…In platelets, Tan IIA modulates APP metabolism possibly via membrane ER-mediated nongenomic signaling. It was demonstrated that membrane ERs reside in the lipid rafts (15,16), where the ER isoform, ERα, activates PI3K through membrane recruitment and direct interaction with PI3K (17). ERα binds in a ligand-dependent manner to the p85α regulatory subunit of PI3K, leading to the phosphorylation of Akt (18).…”