Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The estrogen receptor gene gives rise to variant mRNAs, generated by alternative mRNA splicing, as well as the full-length mRNA containing eight coding exons. It has been postulated that one of these, the exon 5 variant, may be important in the development of hormone-independent and anti-estrogen-resistant breast cancer since it has the potential to encode a truncated receptor that retains the N-terminal activation domain AF-1, but lacks the hormone-binding domain. We have expressed the variant using an inducible promoter in estrogen receptor-positive MCF-7 cells and analyzed the effect of the variant protein on gene expression and cell growth. Inducible expression was validated using a specific antiserum that recognized a novel epitope on the exon 5 variant. The variant was able to stimulate transcription of a reporter gene in transiently transfected chicken embryo fibroblasts in the absence of hormone but showed weak constitutive activity when it was stably expressed in MCF-7 cells. The variant had no effect on the expression of the estrogen target genes, pS2, and the progesterone receptor. Finally, we analyzed whether the proliferation of MCF-7 cells was altered by the expression of the exon 5 variant and found that the stimulatory effects of estrogen and growth inhibitory effects of tamoxifen and ICI 182780 were unchanged. We therefore conclude that expression of the variant alone is not sufficient to give rise to hormone independence or tamoxifen resistance of breast cancers.
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PMID:Effects of an exon 5 variant of the estrogen receptor in MCF-7 breast cancer cells. 860 2

Estrogens act as potent mitogens in a large number of breast cancers, and the use of estrogen receptor (ER) antagonists is, therefore, considered the endocrine therapy of choice in the management of this disease. We describe the molecular properties of EM-652, the active metabolite of EM-800, a novel nonsteroidal antiestrogen compound, on the transcriptional functions of ER alpha and ER beta. Using RT-PCR, we show that ER alpha and ER beta are expressed in mouse mammary glands, suggesting that both receptors should be considered putative targets for antiestrogen action in the breast. In cotransfection assays using a synthetic estrogen-responsive promoter, EM-652 shows no agonistic activity on ER alpha and ER beta transcriptional function and blocks the estradiol (E2)-mediated activation of both ER alpha and ER beta. EM-652 is also very effective in abrogating E2-stimulated ER alpha and ER beta trans-activation of the pS2 promoter in HeLa cells. EM-652 does not alter binding of ER alpha and ER beta to DNA. The Ras-mediated induction of ER alpha and ER beta transcriptional activity in the presence of E2 is also completely abolished by EM-652. In addition, EM-652 blocks the E2-dependent activation of ER alpha and ER beta by the steroid hormone receptor coactivator-1 as well as the in vitro interaction between SRC-1 and the ligand-binding domains of both ERs. These results demonstrate that the novel antiestrogen EM-800 fully impedes AF-1 and AF-2 activities of ER alpha and ER beta and can, therefore, be considered a potent and pure antagonist of both ER subtypes.
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PMID:EM-800, a novel antiestrogen, acts as a pure antagonist of the transcriptional functions of estrogen receptors alpha and beta. 942 5

One class of the nuclear receptor AF-2 coactivator complexes contains the SRC-1/TIF2 family, CBP/p300 and an RNA coactivator, SRA. We identified a subfamily of RNA-binding DEAD-box proteins (p72/p68) as a human estrogen receptor alpha (hER alpha) coactivator in the complex containing these factors. p72/p68 interacted with both the AD2 of any SRC-1/TIF2 family protein and the hER alpha A/B domain, but not with any other nuclear receptor tested. p72/p68, TIF2 (SRC-1) and SRA were co-immunoprecipitated with estrogen-bound hER alpha in MCF7 cells and in partially purified complexes associated with hER alpha from HeLa nuclear extracts. Estrogen induced co-localization of p72 with hER alpha and TIF2 in the nucleus. The presence of p72/p68 potentiated the estrogen-induced expression of the endogenous pS2 gene in MCF7 cells. In a transient expression assay, a combination of p72/p68 with SRA and one TIF2 brought an ultimate synergism to the estrogen-induced transactivation of hER alpha. These findings indicate that p72/p68 acts as an ER subtype-selective coactivator through ER alpha AF-1 by associating with the coactivator complex to bind its AF-2 through direct binding with SRA and the SRC-1/TIF2 family proteins.
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PMID:A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. 2545 82

The basis for the differential repressive effects of antiestrogens on transactivation by estrogen receptor-alpha (ERalpha) remains incompletely understood. Here, we show that the full antiestrogen ICI182,780 and, to a lesser extent, the selective ER modulator raloxifene (Ral), induce accumulation of exogenous ERalpha in a poorly soluble fraction in transiently transfected HepG2 or stably transfected MDA-MB231 cells and of endogenous receptor in MCF7 cells. ERalpha remained nuclear in HepG2 cells treated with either compound. Replacement of selected hydrophobic residues of ERalpha ligand-binding domain helix 12 (H12) enhanced receptor solubility in the presence of ICI182,780 or Ral. These mutations also increased transcriptional activity with Ral or ICI182,780 on reporter genes or on the endogenous estrogen target gene TFF1 in a manner requiring the integrity of the N-terminal AF-1 domain. The antiestrogen-specific effects of single mutations suggest that they affect receptor function by mechanisms other than a simple decrease in hydrophobicity of H12, possibly due to relief from local steric hindrance between these residues and the antiestrogen side chains. Fluorescence anisotropy experiments indicated an enhanced regional stabilization of mutant ligand-binding domains in the presence of antiestrogens. H12 mutations also prevent the increase in bioluminescence resonance energy transfer between ERalpha monomers induced by Ral or ICI182,780 and increase intranuclear receptor mobility in correlation with transcriptional activity in the presence of these antiestrogens. Our data indicate that ICI182,780 and Ral locally alter the ERalpha ligand binding structure via specific hydrophobic residues of H12 and decrease its transcriptional activity through tighter association with an insoluble nuclear structure.
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PMID:Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. 1729 37

Ginsenoside Rg1, an active ingredient commonly found in ginseng root, was previously demonstrated to be a phytoestrogen that exerted estrogen-like activity without direct interaction with estrogen receptors (ERs) in human breast cancer (MCF-7) cells. The present study was designed to determine the molecular mechanism by which Rg1 exerted estrogenic effects. Co-incubation of MCF-7 cells with 1 microM of ER antagonist ICI182780 abolished the inductive effects of Rg1 on pS2 expression as well as ERE-luciferase activity, suggesting that the estrogenic effects of Rg1 were mediated through the endogenous ERs. To evaluate the relative involvement of ERalpha and ERbeta in mediating the actions of Rg1, ER-negative human embryonic kidney (HEK293) cells were co-transfected with the ERE-luciferase reporter construct and either ERalpha or ERbeta construct. The results showed that Rg1 could activate ERE-luciferase activity via the ERalpha-mediated pathway in a dose-dependent manner (10(-14) to 10(-6)M); whereas, the activation of ERbeta-mediated ERE-luciferase activity by Rg1 only occur at high concentration (10(-6)M). Furthermore, the results showed that 1pM Rg1 could rapidly induce phosphorylation of the AF-1 domain of ERalpha at serine 118 residue within the first 5 min of incubation, suggesting that Rg1 activates ERalpha in a ligand-independent manner. Taken together, our results indicate that Rg1 preferentially activates ERalpha via phosphorylation of AF-1 domain in the absence of receptor binding. This study is the first to provide evidence that ginsenoside Rg1 exerts estrogen-like actions via ligand-independent activation of ERalpha pathway.
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PMID:Ginsenoside Rg1 exerts estrogen-like activities via ligand-independent activation of ERalpha pathway. 1793 17