Simoncini T, Haferzi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JKInteraction of oestrogen receptor with the regulatory subunit of Phosphatidyl-insostol-3-OH-kinase. Nature 407: 538-541

Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 10/2000; 407(6803). DOI: 10.1038/35035131
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Oestrogen produces diverse biological effects through binding to the oestrogen receptor (ER). The ER is a steroid hormone nuclear receptor, which, when bound to oestrogen, modulates the transcriptional activity of target genes. Controversy exists, however, concerning whether ER has a role outside the nucleus, particularly in mediating the cardiovascular protective effects of oestrogen. Here we show that the ER isoform, ER alpha, binds in a ligand-dependent manner to the p85alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases ER alpha-associated PI(3)K activity, leading to the activation of protein kinase B/Akt and endothelial nitric oxide synthase (eNOS). Recruitment and activation of PI(3)K by ligand-bound ER alpha are independent of gene transcription, do not involve phosphotyrosine adapter molecules or src-homology domains of p85alpha, and extend to other steroid hormone receptors. Mice treated with oestrogen show increased eNOS activity and decreased vascular leukocyte accumulation after ischaemia and reperfusion injury. This vascular protective effect of oestrogen was abolished in the presence of PI(3)K or eNOS inhibitors. Our findings define a physiologically important non-nuclear oestrogen-signalling pathway involving the direct interaction of ER alpha with PI(3)K.

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Available from: Klaus Ley, Oct 06, 2015
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    • "Estrogen has a cardioprotective role, regulating lipid profile and improving endothelial function [10]. A few studies suggested that estrogens increase endothelium-nitric oxide synthase, which subsequently increases the production of nitric oxide as an endothelium-derived relaxing factor [11]. It was reported that, in premenopausal women, estrogen administration improved Case Reports in Medicine endothelium dependent coronary vasodilator function, manifested as increased coronary flow [12]. "
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    ABSTRACT: Premenopausal women with chest pain syndrome may have nonatherosclerotic coronary arteries with abnormal coronary flow. Estrogens have cardioprotective effect improving coronary vasodilatation. This case report discusses the consequences of leuprolide use by decreasing estrogen levels which led to acute myocardial infarction.
    Case Reports in Medicine 07/2015; 2015:390642. DOI:10.1155/2015/390642
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    • "The biological effects of E2 are mediated by its binding to the structurally and functionally distinct estrogen receptor (ER), α and β. It has been documented that besides classical E2 signaling, ligand activated ERα regulates a series of non-genomic events in the cytoplasm including PI3-kinase (PI3K) activation [61], [102], [103]. The present observation of decreased ER expression and inhibition of Akt phosphorylation post PGF2α treatment point to loss of PI3K activity during luteal regression as reported previously by others [25], [37]. "
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    ABSTRACT: In several species including the buffalo cow, prostaglandin (PG) F2α is the key molecule responsible for regression of corpus luteum (CL). Experiments were carried out to characterize gene expression changes in the CL tissue at various time points after administration of luteolytic dose of PGF2α in buffalo cows. Circulating progesterone levels decreased within 1 h of PGF2α treatment and evidence of apoptosis was demonstrable at 18 h post treatment. Microarray analysis indicated expression changes in several of immediate early genes and transcription factors within 3 h of treatment. Also, changes in expression of genes associated with cell to cell signaling, cytokine signaling, steroidogenesis, PG synthesis and apoptosis were observed. Analysis of various components of LH/CGR signaling in CL tissues indicated decreased LH/CGR protein expression, pCREB levels and PKA activity post PGF2α treatment. The novel finding of this study is the down regulation of CYP19A1 gene expression accompanied by decrease in expression of E2 receptors and circulating and intra luteal E2 post PGF2α treatment. Mining of microarray data revealed several differentially expressed E2 responsive genes. Since CYP19A1 gene expression is low in the bovine CL, mining of microarray data of PGF2α-treated macaques, the species with high luteal CYP19A1 expression, showed good correlation between differentially expressed E2 responsive genes between both the species. Taken together, the results of this study suggest that PGF2α interferes with luteotrophic signaling, impairs intra-luteal E2 levels and regulates various signaling pathways before the effects on structural luteolysis are manifest.
    PLoS ONE 08/2014; 9(8):e104127. DOI:10.1371/journal.pone.0104127 · 3.23 Impact Factor
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    • "This activation is essential for some physiologic responses to hormones, such as cell proliferation or inhibition of apoptosis [7]. Moreover, estrogen receptor alpha (ERa) also interacts with the regulatory subunit of the phosphoinositol-3- kinase, leading to the ER activation as well as the activation of AKT [8]. Activation of cytoplasmic cascades could be involved in the transcriptional regulation of some ovarian hormone target genes. "
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    ABSTRACT: Although non-genomic steroid receptor pathways have been studied over the past decade, little is known about the direct gene expression changes that take place as a consequence of their activation. Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. We showed that picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERb) and without transcriptional activity of endogenous PR and ER. Here we identify early downstream targets of cytoplasmic PR signaling and their possible role in endometrial stromal cell proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors and regulatory factors associated with cell proliferation and cell cycle, a large fraction of which were repressors down-regulated by hormone. Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR-mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding. ChIP experiments show that progestin promoted the interaction of USF1 with the proximal promoter of the Cdc2 gene. Usf1 knockdown abolished Cdc2 progestin-dependent transcriptional regulation and cell proliferation, which also blocked Cdc2 knockdown. We conclude that progestin-induced proliferation of endometrial stromal cells is mediated by ERK1-2 and AKT dependent early regulation of USF1, which directly induces Cdc2. To our knowledge, this is the first description of early target genes of progestin-activated classical PR via crosstalk with protein kinases and independently of hormone receptor binding to the genomic targets.
    PLoS ONE 05/2014; 9(5):e97311. DOI:10.1371/journal.pone.0097311 · 3.23 Impact Factor
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