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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pS2 gene is estrogen responsive in hepatocarcinoma cells (HepG2) in the presence of estrogen receptor alpha (ERalpha). The estrogenic activity is mediated through an estrogen response element (ERE) in the 5'-flanking region of the pS2 gene; however, an activator protein 1 (AP1) response element located close to the ERE in the pS2 promoter has also proven essential for a maximum response to estrogen. In the present study, we show estrogen-induced synergistic activity by the p160 coactivator steroid receptor coactivator-1 (SRC-1), mediated via the ERE and the AP1 response element in the pS2 promoter. In addition, we present data that support an interaction between the ERE and the AP1 motif via SRC-1. The related but distinct p160 coactivator, transcriptional intermediary factor-2, was a more potent activator of pS2 gene expression. In addition, transcriptional intermediary factor-2 was less dependent on an intact AP1 response element in the pS2 promoter than SRC-1. Furthermore, the type of ERE in the pS2 promoter influenced the potentiation by SRC-1, supported by less dependence on the AP1 motif when the natural ERE was substituted for by a consensus ERE. These results highlight several mechanisms whereby fine-tuning of estrogen responsiveness of an individual gene may be achieved.
Mol Endocrinol 2002 Nov
PMID:Transcriptional synergism on the pS2 gene promoter between a p160 coactivator and estrogen receptor-alpha depends on the coactivator subtype, the type of estrogen response element, and the promoter context. 1240 46

Although platelet-activating factor receptor (PAFr) gene was well characterized in the human, little was known about it in domestic animals. Porcine PAFr gene was mapped using fluorescence in situ hybridization (FISH). The structure of this gene was investigated using a 5' rapid amplification of cDNA ends (RACE) technique. Temporal expression of PAFr and estrogen receptor alpha genes (ER), and distribution of the PAFr transcripts in porcine endometrial and embryonic tissues on days 0, 10, 12, 14, 16, and 18 were analyzed using DNA competitors and reverse transcription and polymerase chain reaction (RT-PCR). The porcine PAFr gene was mapped to SSC6q26-27. Alternative splicing of primary transcripts of the PAFr gene produced two different transcripts. Transcript 1 was expressed in all tissues and cells, and transcript 2 was detected in all tissues but white blood cells. The temporal expression of the PAFr gene in endometrial (P > 0.05) and embryonic (P < 0.05) tissues of pregnant sows increased from day 10 to 16. The temporal expression of ER genes in endometrial tissues of pregnant sows decreased from day 10 to 18 (P < 0.05). In addition, ER expression was detectable in 20-60% of embryonic tissue samples, which generally decreased. In combination with previously obtained data on PAF and estradiol-17beta (E(2)) concentrations in pregnant uterine luminal fluids (pULF), endometrial and embryonic tissues, the present results indicated that the increasing PAFr transcripts were positively associated with increasing levels of PAF. Both ER transcripts and E(2) found in pULF decreased correspondingly from day 13 to 16. These results indicate that via PAFr, PAF could play a dominant role in peri-implantation development in pigs as compared to E(2).
Mol Reprod Dev 2003 Jan
PMID:Chromosomal location, structure, and temporal expression of the platelet-activating factor receptor (PAFr) gene in porcine endometrium and embryos relative to estrogen receptor alpha gene expression. 1242 Feb 94

The mouse knockout of the estrogen receptor alpha (ERalpha) gene, known as alphaERKO, has been extensively used for several years to study the role and function of ERalpha. Residual estradiol binding capacity in uterine tissue of 5-10% raised doubts if this knockout is a genuine null mutation of ERalpha. Although alternatively spliced ERalpha mRNA variants in the alphaERKO mouse were reported previously, the corresponding protein isoforms have not been detected to date. Here we show that a variant ERalpha protein, 61 kDa in size, is expressed in the uterine tissue of alphaERKO mice as a result of an alternative splicing. The transactivation capability of this protein is cell dependent and can be as high as 75% of the wild type ERalpha.
J Mol Endocrinol 2002 Dec
PMID:Down but not out? A novel protein isoform of the estrogen receptor alpha is expressed in the estrogen receptor alpha knockout mouse. 1245 30

Transferrin (Tf) is an iron transport protein expressed in MCF-7 human breast cancer cells. In nuclear run-on assays, 17beta-estradiol (E2) increased the rate of Tf gene expression approximately 3-fold within 1 h after treatment and reporter gene activity was also induced in MCF-7 cells transfected with a construct containing a -3600 to +39 Tf gene promoter insert. Deletion and mutation analysis identified an E2-responsive promoter region between -811 and -762, which was GC-rich (80%) and contained two nonconsensus estrogen response elements (EREs). E2-responsiveness of this region was associated with a GGACA(N)(3)TGGCC motif (-803 to -791) which bound human estrogen receptor alpha (hERalpha) in gel mobility shift assays. In Drosophila Schneider SL-2 cells, the -811 to -752 was E2-responsive after cotransfection with hERalpha expression plasmid plus E2, whereas Sp1 protein did not induce transactivation. These studies confirm that E2 induces Tf gene expression through a nonconsensus distal ERE.
J Mol Endocrinol 2002 Dec
PMID:Estrogen regulation of transferrin gene expression in MCF-7 human breast cancer cells. 1245 33

The results of homology modelling of the human glucorticoid receptor (hGR) ligand-binding domain (LBD) based on the ligand-bound domain of the human estrogen receptor alpha (hERalpha) are reported. It is shown that known hGR ligands which induce the human cytochrome P450 enzyme CYP3A4 are able to fit the putative ligand-binding site of the nuclear hormone receptor and form hydrogen bonds with key amino acid residues within the binding pocket. Quantitative structure-activity relationships (QSARs) have been derived for hGR-mediated CYP3A4 induction which involve certain molecular structural and physicochemical properties of the ligand themselves, yielding good correlations (R=0.96-0.98) with fold induction of CYP3A4 known to be mediated via hGR involvement.
J Steroid Biochem Mol Biol 2002 Oct
PMID:Molecular modelling of the human glucocorticoid receptor (hGR) ligand-binding domain (LBD) by homology with the human estrogen receptor alpha (hERalpha) LBD: quantitative structure-activity relationships within a series of CYP3A4 inducers where induction is mediated via hGR involvement. 1247 85

Our recent report has revealed the existence of the progesterone receptor (PR) isoform S, which consists of the novel PR exon S and exons 4-8 of the PR gene in the human testicular cDNA library. More recently, we have cloned the human estrogen receptor alpha (ERalpha) isoform S cDNA from the library. The ERalpha isoform S cDNA also contains the novel ERalpha exon S and exons 4-8 of the ERalpha cDNA. Based on these findings, we assumed that the novel isoform of cDNA like the PR- and ERalpha isoforms might exist in the human ER beta (ERbeta). In order to investigate this possibility, we have screened the human testicular cDNA library using the exons 4-8 corresponding sequence of the human ERbeta cDNA. Consequently, we have cloned a novel isoform of the ERbeta cDNA that consists of a previously unidentified 5'-sequence and the exons 5-8 of the ERbeta gene. We termed this isoform cDNA the "ERbeta isoform M cDNA". The 5'-sequence of the ERbeta isoform M cDNA was confirmed to be derived from a novel exon (termed the "exon M") by analysis of the genomic DNA. Moreover, we have analyzed the molecular size of the ERbeta isoform M encoded by the ERbeta isoform M mRNA by transient expression of the ERbeta isoform M cDNA in the 293T cell. The approximately 28 kDa protein, which was recognized by the anti-rat ERbeta antibody against the carboxyl-terminal region, was synthesized in the cells. Thus, we concluded that the ATG in the exon M could be used as the translation initiation codon. This report revealed for the first time the existence of the ERbeta mRNA isoform that is not caused by the skipping of one or more exons, by the alternative usage of the multiple exon 8s, nor by the alternative utilization of the untranslated 5'-exons located on the upstream region of the exon 1.
J Steroid Biochem Mol Biol 2002 Oct
PMID:Cloning of the novel isoform of the estrogen receptor beta cDNA (ERbeta isoform M cDNA) from the human testicular cDNA library. 1247 86

Ovarian hormones have a pivotal role in the control of proliferation in the mammary gland, and cumulative life-time exposure to ovarian hormones is known to be a determinant of breast cancer risk. We have shown previously that a p.o.-active, long-acting butyrate analogue, sodium phenylbutyrate (PB), reduced proliferation in normal and malignant human breast cells in culture and reduced expression of ovarian hormone receptors, suggesting that PB had cellular effects consistent with decreasing breast cancer risk. The aim of this study was to determine the in vivo effects of PB in the normal mammary gland on epithelial cell proliferation, estrogen receptor alpha (ER alpha) expression, and cyclin D1 expression. BALB/c mice were treated with PB, delivered by mini-osmotic pumps, for 7 days. Moderate (250 mg/kg/day) and high (500 mg/kg/day) PB treatment resulted in a decrease in proliferation in mammary epithelial cells (P < 0.001), determined by bromodeoxyuridine incorporation. Analysis of ER alpha immunostaining revealed a significant reduction in moderate- and high-treatment groups (P = 0.01 and P = 0.02), and expression of cyclin D1 was virtually ablated (P < 0.001). Histone deacetylase inhibition is a known mechanism of butyrate action, and consistent with this, PB increased levels of acetylated histone H3 in the mammary gland. In summary, PB decreased proliferation in the mammary gland in vivo at clinically achievable doses. Decreased proliferation was accompanied by changes in the levels of ER alpha and cyclin D1. These data show that PB modulates parameters thought to be involved in the carcinogenic process in the normal mammary gland, and compounds in this class may therefore be useful candidates for breast cancer chemoprevention.
Mol Cancer Ther 2002 Oct
PMID:Cell proliferation in the normal mouse mammary gland and inhibition by phenylbutyrate. 1248 25

Ligand-dependent transcriptional activation by nuclear receptors involves the recruitment of various coactivators to the promoters of hormone-regulated genes assembled into chromatin. Nuclear receptor coactivators include histone acetyltransferase complexes, such as p300/CBP-steroid receptor coactivator (SRC), as well as the multisubunit mediator complexes ("Mediator"), which may help recruit RNA polymerase II to the promoter. We have used a biochemical approach, including an in vitro chromatin assembly and transcription system, to examine the functional role for Mediator in the transcriptional activity of estrogen receptor alpha (ERalpha) with chromatin templates, as well as functional interplay between Mediator and p300/CBP during ERalpha-dependent transcription. Using three different approaches to functionally inactivate Mediator (immunoneutralization, immunodepletion, and inhibitory polypeptides), we find that Mediator is required for maximal transcriptional activation by ligand-activated ERalpha. In addition, we demonstrate synergism between Mediator and p300/CBP-SRC during ERalpha-dependent transcription with chromatin templates, but not with naked DNA. This synergism is important for promoting the formation of a stable transcription preinitiation complex leading to the initiation of transcription. Interestingly, we find that Mediator has an additional distinct role during ERalpha-dependent transcription not shared by p300/CBP-SRC: namely, to promote preinitiation complex formation for subsequent rounds of transcription reinitiation. These results suggest that one functional consequence of Mediator-ERalpha interactions is the stimulation of multiple cycles of transcription reinitiation. Collectively, our results indicate an important role for Mediator, as well as its functional interplay with p300/CBP-SRC, in the enhancement of ERalpha-dependent transcription with chromatin templates.
Mol Cell Biol 2003 Jan
PMID:Mediator and p300/CBP-steroid receptor coactivator complexes have distinct roles, but function synergistically, during estrogen receptor alpha-dependent transcription with chromatin templates. 1248 85

LCoR (ligand-dependent corepressor) is a transcriptional corepressor widely expressed in fetal and adult tissues that is recruited to agonist-bound nuclear receptors through a single LXXLL motif. LCoR binding to estrogen receptor alpha depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2. Repression by LCoR is abolished by histone deacetylase inhibitor trichostatin A in a receptor-dependent fashion, indicating HDAC-dependent and -independent modes of action. LCoR binds directly to specific HDACs in vitro and in vivo. Moreover, LCoR functions by recruiting C-terminal binding protein corepressors through two consensus binding motifs and colocalizes with CtBPs in the nucleus. LCoR represents a class of corepressor that attenuates agonist-activated nuclear receptor signaling by multiple mechanisms.
Mol Cell 2003 Jan
PMID:Ligand-dependent nuclear receptor corepressor LCoR functions by histone deacetylase-dependent and -independent mechanisms. 1253 28

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) ligands suppress 17beta-estradiol (E)-induced responses in the rodent uterus and mammary tumors and in human breast cancer cells. Treatment of ZR-75, T47D, and MCF-7 human breast cancer cells with TCDD induces proteasome-dependent degradation of endogenous estrogen receptor alpha (ERalpha). The proteasome inhibitors MG132, PSI, and PSII inhibit the proteasome-dependent effects induced by TCDD, whereas the protease inhibitors EST, calpain inhibitor II, and chloroquine do not affect this response. ERalpha levels in the mouse uterus and breast cancer cells were significantly lower after cotreatment with E plus TCDD than after treatment with E or TCDD alone, and our results indicate that AhR-mediated inhibition of E-induced transactivation is mainly due to limiting levels of ERalpha in cells cotreated with E plus TCDD. TCDD alone or in combination with E increases formation of ubiquitinated forms of ERalpha, and both coimmunoprecipitation and mammalian two-hybrid assays demonstrate that TCDD induces interaction of the AhR with ERalpha in the presence or absence of E. In contrast, E does not induce AhR-ERalpha interactions. Thus, inhibitory AhR-ERalpha cross talk is linked to a novel pathway for degradation of ERalpha in which TCDD initially induces formation of a nuclear AhR complex which coordinately recruits ERalpha and the proteasome complex, resulting in degradation of both receptors.
Mol Cell Biol 2003 Mar
PMID:The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. 1261 60


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