Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The estrogen receptor alpha gene is a candidate locus for genetic influence on bone mass. The possible association between two polymorphisms in the first intron of this gene, alone or in combination, and bone mineral density at various sites was examined in participants in the National Institute for Longevity Sciences Longitudinal Study of Aging, a population-based prospective cohort study of aging and age-related diseases. The relationship of the TC ( PvuII) and AG ( XbaI) polymorphisms in the first intron of the estrogen receptor alpha gene to bone mineral density was determined in 2230 subjects (1120 men, 1110 women) and in 2238 subjects (1128 men, 1110 women), respectively, all of whom were community-dwelling individuals aged 40-79 years. Bone mineral density at the radius was measured by peripheral quantitative computed tomography and that for the lumbar spine, right femoral neck, right trochanter, right Ward's triangle, and total body was measured by dual-energy X-ray absorptiometry. Estrogen receptor alpha genotypes were determined with an automated fluorescent allele-specific DNA primer assay system. Analysis of the TC ( PvuII) polymorphism revealed that bone mineral density for the total body, femoral neck, and trochanter was significantly lower in women aged 60 years or over with the CC genotype than in those with the TT genotype, but statistical significance was not achieved after adjustment for age, body mass index, and smoking status. Analysis of the AG ( XbaI) polymorphism revealed that bone mineral density for the femoral neck was significantly lower in women aged 60 years or over with the GG genotype than in those with the AA genotype. After adjustment for age, body mass index, and smoking status, bone mineral density for the femoral neck was significantly lower in women aged 60 years or over with the GG genotype than in those with the AA or AG genotypes. Analysis of combined genotypes in women aged 60 years or over revealed that bone mineral density for the femoral neck was significantly lower in women with the CC/ GG genotype than in those with the TT/ AA or TC/ AA genotypes. After adjustment for age, body mass index, and smoking status, bone mineral density for the femoral neck was significantly lower in women aged 60 years or over with the CC/ GG genotype than in those with other genotypes. No differences in bone mineral density at the various sites were detected among TC ( PvuII), AG ( XbaI), or combined genotypes in women aged under 60 years or in men. These results suggest that the estrogen receptor alpha gene is a susceptibility locus for bone mass, especially for the femoral neck, in elderly Japanese women.
J Mol Med (Berl) 2002 Jul
PMID:Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density of the femoral neck in elderly Japanese women. 1211 Sep 51

Osteoporosis is a common skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. In the past years, twin and family study have shown that this disease recognizes a strong genetic component and that genetic factors play an important role in regulating bone mineral density (BMD). While in few isolate conditions osteoporosis can be inherited in a simple Mendelian pattern, due to single gene mutations, in the majority of cases has to be considered a multifactorial polygenic disease in which genetic determinants are modulated by hormonal, environmental and nutritional factors. Given the important role that steroid hormones play in bone cell development and in the maintenance of normal bone architecture, polymorphisms at receptor of the steroid/thyroid hormone receptor superfamily, such as estrogen receptor alpha (ERalpha) and Vitamin D receptor (VDR) have been thoroughly investigated in the last years and appeared to represent important candidate genes. The individual contribution of these genetic polymorphisms to the pathogenesis of osteoporosis remains to be universally confirmed and an important aim in future work will be to define their functional molecular consequences and how these polymorphisms interact with each other and with the environment to cause the osteoporotic phenotype. A further promising application of genetic studies in osteoporosis comes from their pharmacogenomic implications, with the possibility to give a better guidance for therapeutic agents commonly used to treat this invalidating disorder or to identify target molecules for new therapeutic agents.
J Steroid Biochem Mol Biol 2002 May
PMID:Genetics of osteoporosis: role of steroid hormone receptor gene polymorphisms. 1212 38

4-Tert-octylphenol (OP) is a breakdown product of 4-tert-octylphenol ethoxylate, which is a surfactant additive widely used in the manufacture of a variety of detergents and plastic products. OP has been reported to exhibit weak estrogenic activity in many assay systems. The studies described herein examined an unusual effect of OP in increasing constitutive testosterone levels of cultured Leydig cells from young adult rats. The increase in testosterone was both dose and time sensitive, and this response was observed in medium lacking both calcium and magnesium and containing a membrane-permeable calcium chelator, suggesting that the increase in testosterone was not mediated by an increase in the permeability of extracellular calcium into cells or the redistribution/release of calcium from intracellular stores, respectively. Cellular cAMP levels also were unaffected by OP alone in cultured Leydig cells. Furthermore, initial exposure to 2000nM OP alone for 4h did not alter the subsequent conversion of endogenous cholesterol or exogenously added 22 (R)hydroxycholesterol to testosterone, suggesting that the increase in testosterone was not due to the enhanced availability of endogenous cholesterol or an increase in cholesterol side-chain cleavage activity, respectively. The increase in testosterone also was observed in the presence of the pure estrogen antagonist, ICI 182,780, or a 5alpha-reductase inhibitor, suggesting that this effect of OP was not mediated through the estrogen receptor alpha or beta pathway or by inhibition of Leydig cell testosterone metabolism, respectively. In addition, exposure of cells to comparable concentrations of two different detergents, Triton X-100 or sodium cholate, did not increase testosterone levels, suggesting that this effect of OP was not due to its potential detergent qualities. Although these studies did not identify specific mechanism(s) that increase constitutive testosterone levels by OP, they identify specific pathways that appear not to be involved. The physiological relevance of this observation is not known; nevertheless, they illustrate potential diverse actions of OP in modulating the level of androgen secreted by Leydig cells, and they emphasize that some actions of OP do not appear to be mediated through the estrogen receptor alpha or beta pathway.
J Steroid Biochem Mol Biol 2002 Jun
PMID:Exposure to octylphenol increases basal testosterone formation by cultured adult rat Leydig cells. 1213 9

Estrogen receptors are phosphoproteins which can be activated by ligands, kinase activators, or phosphatase inhibitors. Our previous study showed that p38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and MEKK1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (Thr(311)), located in helix 1 of the hormone-binding domain. The mutation of threonine-311 to alanine did not affect estrogen binding of the receptor but compromised its interaction with coactivators. Suppression of p38 activity or mutation of the site inhibited the estrogen-induced receptor nuclear localization as well as its transcriptional activation by estrogens and MEKK1. The inhibition of the p38 signal pathway by a specific chemical inhibitor blocked the biological activities of estrogens in regulating endogenous gene expression as well as endometrial cancer cell growth. Our studies demonstrate the role of estrogen receptor phosphorylation induced by the natural ligand in estrogen receptor's cellular distribution and its significant contribution to the growth-stimulating activity of estrogens in endometrial cancer cells.
Mol Cell Biol 2002 Aug
PMID:Regulation of estrogen receptor nuclear export by ligand-induced and p38-mediated receptor phosphorylation. 1213 94

The intratumoral conversion of adrenal androgens into estrogens by the aromatase enzyme complex may be an important mechanism of autocrine stimulation in hormone-dependent breast tumor. The effects of estrogens on tumor development are mediated by the activity of estrogen receptor alpha that induces gene expression and cell proliferation. Thus, estrogen biosynthesis 'in situ' and/or estrogen receptor action are the main targets of endocrine treatment in endocrine-dependent breast carcinoma. In the present study we demonstrate that three major adrenal androgens, dehydroepiandrosterone, 5-androstene-3beta, 17beta-diol and 4-androstene 3,17-dione, all acquire an estradiol-like biological efficacy in aromatase transfected MCF7 breast cancer cells. Our results suggest that in postmenopausal women aromatase inhibitors might be considered as an adjuvant approach to the treatment of hormone-dependent breast tumors that overexpress aromatase.
Mol Cell Endocrinol 2002 Jul 31
PMID:Aromatase overexpression enhances the stimulatory effects of adrenal androgens on MCF7 breast cancer cells. 1216 Sep 97

The liver presents estrogen receptors alpha and beta. As for breast cancer, a variant form of estrogen receptor alpha transcript (ER) has been described in hepatocellular carcinoma (HCC). It is derived by an exon 5-deleted transcript (vER), which lacks the hormone-binding domain of the receptor but, being intact in the DNA-binding domain, maintains constitutive transcriptional activity. HCCs presenting vER have an extremely aggressive clinical course and are unresponsive to the antiestrogen tamoxifen. On the other hand, megestrol, a drug able to block both the wild type and the variant form of ER, influence the clinical course of HCC presenting vER. The presence of vER is associated with elevated cancer cell proliferation rate.
Mol Cell Endocrinol 2002 Jul 31
PMID:Variant estrogen receptors and their role in liver disease. 1216 Oct 3

Estrogens up-regulate expression of the estrogen receptor alpha (ER) gene in most mammalian tissues studied. Using the ovariectomized ewe as a model, we determined that estradiol (E(2)) acted post-transcriptionally to increase endometrial ER mRNA concentrations by enhancing the stability of the message. The purpose of this study was to determine whether a similar E(2) effect occurs in Ishikawa cells, a well-differentiated human endometrial adenocarcinoma cell line. The presence and function of ER protein in Ishikawa cells was demonstrated by transactivation of a transfected plasmid (ERE(2)tkCAT) in response to 10(-)(9) M E(2), resulting in a 550% increase in reporter gene RNA. Ishikawa cells also responded to E(2) by up-regulating their ER mRNA concentration an average of 100% between 7 and 24 h of treatment. The effect of E(2) on ER mRNA stability was measured after blocking transcription with actinomycin D to find that the half-life increased from 6 to 10 h in control and E(2)-treated cells respectively. These results are consistent with cell-free studies which showed significant enhancement of the half-life of radiolabeled ER 3' untranslated region (3'UTR) RNA in extracts from E(2)-treated cells versus those from control cells. Thus, Ishikawa cells provide a relevant model system for the study of E(2)-regulated endometrial gene expression.
J Mol Endocrinol 2002 Aug
PMID:Estradiol up-regulates estrogen receptor messenger ribonucleic acid in endometrial carcinoma (Ishikawa) cells by stabilizing the message. 1220 Feb 34

Oral treatment with 0.4 mg/kg/day of tamoxifen citrate, an antiestrogen, has been reported to reduce the fertility of adult male rat, presumably through estrogen receptors expressed throughout the male reproductive tract. During the course of these studies, tamoxifen was observed to gradually alter the pattern of sperm motility in the cauda epididymides without reducing sperm counts. Studies were carried out to understand the mechanism involved in tamoxifen induced change in the sperm motility pattern. In order to study the direct effects of tamoxifen on motility, biochemical levels/activities of sperm calcium, cAMP, phosphodiesterase and dynein ATPase, normally implicated in sperm motility were studied In view of the fact that tamoxifen is a ligand of estrogen receptor, estrogen receptor alpha protein and transcript were localized on rat sperm membrane and the effect of tamoxifen studied. The present study demonstrated presence of estrogen receptor protein and mRNA in the rat sperm by immunofluorescence, western blotting and in situ hybridization respectively. Specificity of sperm estrogen receptors was confirmed by conventional binding studies using [3H]-estradiol. There was no effect of tamoxifen treatment on estrogen receptors in rat sperms. Biochemical analysis of the sperms from tamoxifen treated cauda epididymides revealed a significant increase in the levels of calcium and cAMP. A significant reduction was also apparent in the activity of dynein ATPase. Tamoxifen treatment did not alter phosphodiesterase activity. Estrogen receptors could be identified both in the control as well as tamoxifen treated rat sperms. It was concluded that tamoxifen treatment mobilized calcium from the intra- or extra-cellular pools with a concomitant increase in cAMP and presumably activation of PKA (protein kinase A). Tamoxifen altered the pattern of sperm motility through a calcium induced block in the activity of dynein ATPase, presumably through the activation of sperm phosphatase. The putative estrogen receptor mediated signal transduction pathway appears to be directly affected in the tamoxifen treated, sub-motile rat sperm.
Mol Cell Biochem 2002 Aug
PMID:Estrogen receptor, calcium mobilization and rat sperm motility. 1223 77

17Beta-estradiol-activated estrogen receptor alpha (ERalpha) and beta (ERbeta) are able to induce transcriptional activation of signal transducer and activator of transcription (Stat)-regulated promoters via cytoplasmic signal transduction pathways. Stat5 and Stat3 are required for promoter induction, which correlates with cytoplasmic sublocalization of ERs and is independent of intact coactivator binding sites and DNA-binding domains. In endothelial cells, Stat5 and Stat3 are rapidly phosphorylated on both tyrosine and serine residues in response to 17beta-estradiol, and nuclear translocation is subsequently induced. 17Beta-estradiol-induced transactivation of a Stat-regulated promoter requires at least three different signal transduction pathways, including MAPK, Src-kinase, and phosphatidylinositol-3-kinase activities. In conclusion, this work identifies a novel pathway involving an agonist-bound ER-activated phosphorylation cascade, resulting in nuclear transcriptional activation of target transcription factors. These findings reveal novel targets for the development of drugs that modulate a nongenomic-to-genomic ER-dependent mechanism.
Mol Endocrinol 2002 Oct
PMID:Signal transducers and activators of transcription as downstream targets of nongenomic estrogen receptor actions. 1235 86

Regulation of estrogen receptor alpha (ERalpha) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O(2)) or hypoxia (1% O(2) or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1alpha protein within 3 h after treatment, whereas ERalpha protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERalpha mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERalpha, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.
Mol Endocrinol 2002 Oct
PMID:Hypoxia induces proteasome-dependent degradation of estrogen receptor alpha in ZR-75 breast cancer cells. 1235 89


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