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

Estrogen receptors (ER) are ligand-dependent transcription factors that regulate growth, differentiation, and maintenance of cellular functions in a wide variety of tissues. We report here that p21WAF1/CIP1, a cyclin-dependent kinase (Cdk) inhibitor, cooperates with CBP to regulate the ERalpha-mediated transcription of endogenous target genes in a promoter-specific manner. The estrogen-induced expression of the progesterone receptor and WISP-2 mRNA transcripts in MCF-7 cells was enhanced by p21WAF1/CIP1, whereas that of the cyclin D1 mRNA was reduced and the pS2 mRNA was not affected. Chromatin immunoprecipitation assays revealed that p21WAF1/CIP1 was recruited simultaneously with ERalpha and CBP to the endogenous progesterone receptor gene promoter in an estrogen-dependent manner. Experiments in which the p21WAF1/CIP1 protein was knocked down by RNA interference showed that the induction of the expression of the gene encoding the progesterone receptor required p21WAF1/CIP1, in contrast with that of the cyclin D1 and pS2 genes. p21WAF1/CIP1 induced not only cell cycle arrest in breast cancer cells but also milk fat globule protein and lipid droplets, indicators of the differentiated phenotype, as well as cell flattening and increase of the volume of the cytoplasm. These results indicate that p21WAF1/CIP1, in addition to its Cdk-regulatory role, behaves as a transcriptional coactivator in a gene-specific manner implicated in cell differentiation.
Mol Cell Biol 2005 Mar
PMID:p21WAF1/CIP1 selectively controls the transcriptional activity of estrogen receptor alpha. 1574 34

In the described studies, we have developed a variant of the MCF-7 cell line, M-ERd3/g8, for analysis of 17-beta-estradiol (E2)-action without direct DNA interaction by E2-receptors. M-ERd3/g8 cells principally express the estrogen receptor alpha (ER) form ERDelta3 which, due to skipping of exon 3, lacks the second zinc finger of ER that is required for direct DNA interaction. This was achieved by introduction of siRNA targeting exon 3 to a Tamoxifen-selected MCF-7 variant, TMX 2-11, expressing approximately equal amount of full-length ER and ERDelta3 proteins. M-ERd3/g8 cells exhibited a normal nuclear ER localization, and ERDelta3 expression levels were similar to those for full-length ER protein in MCF-7 cells. Ser 118 phosphorylation of the ERDelta3 was triggered by E2 treatment. The expression of several well characterized E2-responsive markers was strongly modified in the M-ERd3/g8 cells. The E2-induction of progesterone receptor (PR) and HEM45 mRNAs was abolished. The effect on pS2 mRNA expression was complex: the pS2 mRNA levels fell approximately 50-fold in control M-ERd3/g8 cells. There was E2-induction of pS2-expression but with an altered temporal pattern. This was blocked by inhibitors of the p42/44 mitogen activated protein (MAP) kinase and inositol triphosphate (PI3) kinase pathways suggesting a role for cytoplasmic signaling pathways. Gene array analysis and real-time polymerase chain reaction (PCR) studies identified several genes whose expressions were induced in E2-treated M-ERd3/g8 cells. These included A-Myb, a homolog to the avian myoblastosis virus oncogene, carbonic anhydrase XII (CAXII), chemokine ligand 12 (CXCL-12), early growth response 3 (EGR 3), fibrinogen B beta (FibBbeta), along with serine protease 23 (SPUVE). The responses fell into several temporal patterns. A-Myb, CAXII, CXCL-12 and EGR 3 were E2-induced within 2 h. The expression of CXCL-12 and EGR 3 was persistent to 24 h, while that of A-Myb and CAXII was not persistent in M-ERd3/g8 cells. FibBbeta and SPUVE expression was not induced until times later than 6 h. Expression of none of the genes was elevated prior to 2 h, but the utilization of a 24 h time point for the gene array analysis may have eliminated the most transiently responsive genes. Immediate early 3 (IE3) was down-regulated by E2 in the M-ERd3/g8 cells but was transiently up-regulated during the 2-6 h period in MCF-7 cells. Basal levels of several of the genes were strongly reduced in M-ERd3/g8, compared to MCF-7. The studies suggest that M-ERd3/g8 cells provide a new model for studies of E2-action without direct ER binding to DNA and where E2-action must be via alternate pathways.
Mol Cell Endocrinol 2005 Jun 30
PMID:Gene regulation in an MCF-7 cell line that naturally expresses an estrogen receptor unable to directly bind DNA. 1591 82

Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several co-regulators to the CYP1A1 promoter. AhR displayed a time-dependent recruitment, reaching a peak at 75 min and maintaining promoter occupancy for the remainder of the time course. Recruitment of AhR was followed by TIF2/SRC2, which preceded CBP, histone H3 acetylation, and RNA polymerase II (RNAPII). Simultaneous recruitment to the enhancer and the TATA box region suggests the formation of a large multiprotein complex bridging the two promoter regions. Interestingly, estrogen receptor alpha (ERalpha) displayed a TCDD- and time-dependent recruitment to the CYP1A1 promoter, which was increased by co-treatment with estradiol. Transfection in HuH7 human liver cells confirmed previously reported ERalpha enhancement of AhR activity. In contrast, TCDD did not induce the recruitment of ERalpha to the estrogen-responsive pS2 promoter, and after 120 min of co-treatment with estradiol, ERalpha is still present on the CYP1A1 promoter but no longer at pS2. RNA interference studies with T47D cells support a role for ERalpha in TCDD-dependent CYP1A1 expression. Our data suggest that ERalpha acts as a coregulator of AhR-mediated transcriptional activation and that the recruitment of ERalpha by AhR represents a novel mechanism AhR-ERalpha cross talk.
Mol Cell Biol 2005 Jul
PMID:Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor alpha to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters. 1596 90

Sp1 and Sp3 are ubiquitously expressed mammalian transcription factors that activate or repress the expression of a variety of genes and are thought to compete for the same DNA binding site. We used indirect immunofluorescence microscopy and image deconvolution to show that Sp1 and Sp3 are organized into distinct nonoverlapping domains in human breast and ovarian cells. Domains of Sp1 and Sp3 infrequently associate with sites of transcription. Sp3 partitions with the tightly bound nuclear protein fraction of hormone responsive MCF-7 breast cancer cells, whereas only a subpopulation of Sp1 is found in that fraction. Both Sp1 and Sp3 are bound to the nuclear matrix, and the nuclear matrix-associated sites of Sp1 and Sp3 are different. Indirect immunofluorescence studies demonstrate that Sp1 and Sp3 associate with histone deacetylases 1 and 2 and with the estrogen receptor alpha, albeit at low frequencies in MCF-7 cells. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that although both Sp1 and Sp3 bind to the estrogen-responsive trefoil factor 1 promoter in MCF-7 cells, they do not occupy the same promoter. Our results demonstrate the different features of Sp1 and Sp3, providing further evidence that Sp3 is not a functional equivalent of Sp1.
Mol Biol Cell 2005 Sep
PMID:Differential intranuclear organization of transcription factors Sp1 and Sp3. 1598 35

Nuclear receptors (NRs) regulate target gene transcription through the recruitment of multiple coactivator complexes to the promoter regions of target genes. One important coactivator complex includes a p160 coactivator (GRIP1, SRC-1, or ACTR) and its downstream coactivators (e.g., p300, CARM1, CoCoA, and Fli-I), which contribute to transcriptional activation by protein acetylation, protein methylation, and protein-protein interactions. In this study, we identified a novel NR coactivator, GAC63, which binds to the N-terminal region of p160 coactivators as well as the ligand binding domains of some NRs. GAC63 enhanced transcriptional activation by NRs in a hormone-dependent and GRIP1-dependent manner in transient transfection assays and cooperated synergistically and selectively with other NR coactivators, including GRIP1 and CARM1, to enhance estrogen receptor function. Endogenous GAC63 was recruited to the estrogen-responsive pS2 gene promoter of MCF-7 cells in response to the hormone. Reduction of the endogenous GAC63 level by small interfering RNA inhibited transcriptional activation by the hormone-activated estrogen receptor. Thus, GAC63 is a physiologically relevant part of the p160 coactivator signaling pathway that mediates transcriptional activation by NRs.
Mol Cell Biol 2005 Jul
PMID:GAC63, a GRIP1-dependent nuclear receptor coactivator. 1598 12

Nuclear receptors (NRs) are a large family of ligand-dependent transcription factors that regulate important physiological processes. To activate or repress genes assembled naturally as chromatin, NRs recruit two distinct enzymatic activities, namely histone-modifying enzymes and ATP-dependent chromatin remodeling complexes, to alter local chromatin structure at target gene promoters. In this review, we examine the functional relationship between ATP-dependent chromatin remodeling complexes and NRs in the context of transcriptional regulation. Using the steroid-responsive mouse mammary tumor virus promoter as a model system, we discuss in detail the molecular mechanisms underlying the recruitment of these complexes and subsequent chromatin structure changes catalyzed by this group of enzymes. In addition, we extend the discussion to other NR-regulated promoters including the pS2 promoter. Finally, we summarize specific principles governing this critical relationship, identify unanswered questions and discuss the potential application of these principles in rational drug design.
Mol Endocrinol 2006 Jan
PMID:Changes in attitude, changes in latitude: nuclear receptors remodeling chromatin to regulate transcription. 1600 33

Certain plant-derived compounds show selective estrogen receptor modulator (SERM) activity and may therefore be an alternative to the conventional hormone replacement therapy, which prevents osteoporosis but is also associated with an increased risk of breast and endometrial cancers. In the current study, we tested the effects of the hop-derived compounds 8-prenylnaringenin, 6-prenylnaringenin, xanthohumol and isoxanthohumol (1) to modulate markers of differentiation and gene expression in osteoblasts and (2) to regulate proliferation in MCF-7 breast cancer cells. Additionally, we analyzed the ER-binding affinities of these hop compounds as well as the ER-mediation of their effects. Bone-forming activity and ER-subtype specificity were investigated by measuring alkaline phosphatase (AP) activity in hFOB/ERalpha cells and regulation of gene transcription for AP, interleukin-6, pS2 and von Willebrand factor (VWF) in U-2 OS/ERalpha and U-2 OS/ERbeta cells. Our results demonstrate that AP, pS2 and VWF mRNA levels are significantly increased by the compounds in an estrogen-like manner via both ERalpha and ERbeta, while IL-6 is down-regulated in U-2 OS/ERalpha cells. Consistently, AP enzymatic activity is up-regulated by all compounds in hFOB/ERalpha9 cells. Depending on their concentration, all compounds show proliferative effects in MCF-7 cells. Except for 8-PN the hop constituents display an ERbeta-preference. Reversal of estrogen-specific AP-induction in Ishikawa cells indicates an ER-regulated mechanism. Finally, the flavonoids display cytotoxic effects only at high concentrations (> or =10(-4)M). In summary, we have demonstrated for the first time that specific phytoestrogen compounds found in hop extracts exert estrogen-like activities on bone metabolism. Regarding a potential for use in osteoporosis-prevention therapy, the dosage of a phytoestrogen, which is taken, will play an important role concerning a desired in vivo profile.
J Steroid Biochem Mol Biol 2005 Sep
PMID:Regulation of osteoblastic phenotype and gene expression by hop-derived phytoestrogens. 1601 5

Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 micromol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10(-7) mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Delta16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ER(alpha) mRNA and protein without an effect on ER(beta) levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE(2)e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ER(alpha) levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
Mol Cancer Ther 2005 Aug
PMID:Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells. 1609 40

The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha, NR3B1) is a constitutively active transcription factor that controls multiple processes, most notably mitochondrial function. ERRalpha preferentially binds to a nine-nucleotide extended half-site sequence TNAAGGTCA, referred to as the ERRE, as either a monomer or a dimer, although how the mode of DNA binding is dictated remains to be determined. Here, we used variants of the extended half-site sequence and selective DNA binding domain mutants of ERRalpha to investigate the effects of ERRE sequence specificity on ERRalpha DNA binding mode, transactivation and interaction with the coactivator protein peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). We found that the base at the N position of the TNAAGGTCA sequence dictated ERRalpha binding preference as a monomer or dimer. In addition, we demonstrated that the threonine residue at position 124 (Thr(124)) was a determinant of ERRalpha DNA-dependent dimerization. Transfection experiments also indicated that substituting a thymidine for a cytosine at the N position in the ERRE of the native ERRalpha target promoter trefoil factor 1 (TFF1) considerably diminished the transcriptional response of the ERRalpha/PGC-1alpha complex. These results suggest that a single nucleotide in an ERRalpha binding site can determine specific configuration to the receptor and productive interaction with the coactivator PGC-1alpha.
Mol Endocrinol 2006 Feb
PMID:A single nucleotide in an estrogen-related receptor alpha site can dictate mode of binding and peroxisome proliferator-activated receptor gamma coactivator 1alpha activation of target promoters. 1615 Aug 65

Activity of the estrogen receptor (ER) is regulated through interaction with coactivators and corepressors. These proteins are present in large complexes, suggesting functional interactions among various cofactors. Scaffold attachment factors B1 and B2 (SAFB1/2) and nuclear receptor corepressor (N-CoR) function as ERalpha corepressors--they directly interact with ERalpha, and repress transcription via repression domains. We asked the question whether SAFB1/2 and N-CoR could directly interact with each other, and whether this interaction results in altered repressive activities. Employing coimmunoprecipitation, cofractionation, and colocalization experiments, we have shown that SAFB1/2 interact with the nuclear receptor corepressor N-CoR. This interaction was direct, and was mediated in vitro and in vivo through the C-terminal region of SAFB1 (amino acids 600-915 and the N-terminal region of N-CoR (amino acids 1-373)). Decrease of SAFB1 or N-CoR expression by small interfering RNA resulted in an increase of the estrogen response in reporter assays, confirming prior data that both proteins are attenuating estrogen-mediated induction of genes. Importantly, the effect of SAFB1 on this attenuation was significantly decreased in the presence of N-CoR small interfering RNA. Using chromatin immunoprecipitation assays, we observed that SAFB1/2 and N-CoR were recruited to the pS2 promoter in the absence of estrogen, and this recruitment was enhanced in the presence of Tamoxifen. Detailed kinetic studies showed that the addition of estrogen resulted in the concurrent release of SAFB1/2 and N-CoR from the promoter. Finally, we measured expression of SAFB1/2 and N-CoR in 289 clinical breast cancer specimens, and detected a strong and highly significant correlation between their expression levels. Taken together, our studies demonstrate that SAFB1/2 and N-CoR interact, and that this interaction is, at least in part, necessary for SAFB1's repressive activities. The coexpression of these proteins in breast cancer specimens, and the combined recruitment (and release) of SAFB1/2 and N-CoR furthermore suggests that this interaction has functional relevance.
Mol Endocrinol 2006 Feb
PMID:Scaffold attachment factor SAFB1 suppresses estrogen receptor alpha-mediated transcription in part via interaction with nuclear receptor corepressor. 1619 51


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