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
Source: OAI


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
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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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    • "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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    • "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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