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)

Nuclear receptor-mediated gene expression is regulated by corepressors and coactivators. In this study we demonstrate that prohibitin (PHB), a potential tumor suppressor, functions as a potent transcriptional corepressor for estrogen receptor alpha (ERalpha). Overexpression of PHB inhibits ERalpha transcriptional activity, whereas depletion of endogenous PHB increases the expression of ERalpha target genes in MCF-7 breast cancer cells. Chromatin immunoprecipitation experiments demonstrate that PHB is associated with the estrogen-regulated pS2 promoter in the absence of hormone and dissociates after estradiol treatment. We demonstrate that PHB interacts with the repressor of estrogen receptor activity (REA), a protein related to PHB, to form heteromers and enhance the protein stability of both corepressors. Interestingly, the corepressor activity of PHB is cross-squelched by the coexpression of REA (and vice versa), suggesting that PHB and REA repress transcription only when they are not paired. We further demonstrate that coiled-coil domains located in the middle of PHB and REA are responsible for their heteromerization, stabilization, and cross-squelching actions. Finally, ablation of PHB function in the mouse results in early embryonic lethality, whereas mice heterozygous for the PHB null allele exhibit a hyperproliferative mammary gland phenotype. Our results indicate that PHB functions as a transcriptional corepressor for ERalpha in vitro and in vivo, and that its heteromerization with REA acts as a novel mechanism to limit its corepressor activity.
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PMID:A repressive role for prohibitin in estrogen signaling. 1793 4

HMGN1, an abundant nucleosomal binding protein, can affect both the chromatin higher order structure and the modification of nucleosomal histones, but it alters the expression of only a subset of genes. We investigated specific gene targeting by HMGN1 in the context of estrogen induction of gene expression. Knockdown and overexpression experiments indicated that HMGN1 limits the induction of several estrogen-regulated genes, including TFF1 and FOS, which are induced by estrogen through entirely distinct mechanisms. HMGN1 specifically interacts with estrogen receptor alpha (ER alpha), both in vitro and in vivo. At the TFF1 promoter, estrogen increases HMGN1 association through recruitment by the ER alpha. HMGN1 S20E/S24E, although deficient in binding nucleosomal DNA, still interacts with ER alpha and, strikingly, still represses estrogen-driven activation of the TFF1 gene. On the FOS promoter, which lacks the ER alpha binding sites, constitutively bound serum response factor (SRF) mediates estrogen stimulation. HMGN1 also interacts specifically with SRF, but HMGN1 S20E/S24E does not. Consistent with the protein interactions, only wild-type HMGN1 significantly inhibits the estrogen-driven activation of the FOS gene. Mechanistically, the inhibition of estrogen induction of several ER alpha-associated genes, including TFF1, by HMGN1 correlates with decreased levels of acetylation of Lys9 on histone H3. Together, these findings indicate that HMGN1 regulates the expression of particular genes via specific protein-protein interactions with transcription factors at target gene regulatory regions.
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PMID:HMGN1 modulates estrogen-mediated transcriptional activation through interactions with specific DNA-binding transcription factors. 1793 9

Metastasis of cancer cells from the primary tumor is associated with poor prognosis and decreased overall survival. One protein implicated in inhibiting metastasis is the tumor metastasis suppressor nonmetastatic protein 23 homologue 1 (NM23-H1). NM23-H1 is a multifunctional protein, which, in addition to limiting metastasis, has DNase and histidine protein kinase activities. We have identified new functions for NM23-H1 in influencing estrogen receptor alpha (ER alpha)-mediated gene expression. Using a battery of molecular and biochemical techniques, we show that NM23-H1 interacts with ER alpha and increases the ER alpha-estrogen response element (ERE) interaction. When NM23-H1 expression is increased in U2 osteosarcoma and MDA-MB-231 breast cancer cells, transcription of a transiently transfected, estrogen-responsive reporter plasmid is decreased. More importantly, when endogenous NM23-H1 expression is knocked down in MCF-7 human breast cancer cells using small interfering RNA, estrogen responsiveness of the progesterone receptor (PR), Bcl-2, cathepsin D, and cyclin D1 genes, but not the pS2 gene, is enhanced. Furthermore, NM23-H1 associates with the region of the PR gene containing the +90 activator protein 1 site, but not with the ERE-containing region of the pS2 gene, indicating that NM23-H1 mediates gene-specific effects by association with endogenous chromatin. Our studies suggest that the capacity of NM23-H1 to limit the expression of estrogen-responsive genes such as cathepsin D and Bcl-2, which are involved in cell migration, apoptosis, and angiogenesis, may help to explain the metastasis-suppressive effects of this protein. The complementary abilities of ER alpha and NM23-H1 together to influence gene expression, cell migration, and apoptosis could be key factors in helping to determine tumor cell fate.
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PMID:Interaction of the tumor metastasis suppressor nonmetastatic protein 23 homologue H1 and estrogen receptor alpha alters estrogen-responsive gene expression. 1797 5

To further explore the role of Sp1 and Sp3 in the estrogen regulated TFF1 gene transcription, chromatin immunoprecipitation (ChIP) assay was used to determine the association of estrogen receptor alpha (ERalpha), Sp1 and Sp3 with the endogenous trefoil factor 1 (TFF1) gene promoter in MCF-7 breast cancer cells. ERalpha and serine 5 phosphorylated RNA polymerase II, the form of RNA polymerase II associated with transcription initiation, were recruited to the TFF1 gene promoter following estrogen addition to MCF-7 cells cultured under estrogen deplete conditions. Both Sp1 and Sp3 were bound to the TFF1 gene promoter before and after estrogen treatment. Using the re-ChIP assay, we demonstrate that either Sp1 or Sp3 but not both bind to a TFF1 promoter. The co-occupancy of ERalpha and Sp1 on TFF1 promoter remains at similar level with and without estrogen, while that of ERalpha and Sp3 increased in the presence of estrogen. Further, we observed increased co-occupancy of Sp3 and serine 5 phosphorylated RNA polymerase II on the TFF1 promoter after estrogen treatment of cells. Taken together, these results provide evidence that Sp3 and ERalpha are involved in the estrogen induced transcription of the TFF1 gene.
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PMID:Association of Sp3 and estrogen receptor alpha with the transcriptionally active trefoil factor 1 promoter in MCF-7 breast cancer cells. 1854 53

Chromatin structure and transcription factor activity collaborate to set the transcription level of a gene. Our understanding of the relative contributions of each of these factors at a specific gene is limited. We studied the effects of an altered chromatin environment on the activity of the estrogen-responsive pS2 promoter. We created stable cell lines with the pS2 promoter situated in an alternative chromatin site in addition to it being in its native site. Both promoters were estrogen-responsive for estrogen receptor alpha (ERalpha) recruitment, but transcription was inducible only at the native site. At the recombinant site, transcription was high and constitutive. Higher histone H3 and H4 acetylation (acH3 and acH4), as well as trimethylated lysine 4 on histone H3 levels, was observed at the recombinant site compared to the native site in vehicle treated cells. Inhibition of histone deacetylases (HDACs) resulted in increased acH4, but only modest increases in acH3, ERalpha binding and basal transcription at the native pS2 site. Inhibiting HDACs had no effect on transcription from the recombinant site. These data suggest that highly active chromatin is not only permissive for transcription, but can override the requirement for the transcription factor at an inducible promoter.
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PMID:Chromatin context dominates estrogen regulation of pS2 gene expression. 1866 86

Research increasingly suggests that selectivity between enantiomers may exist in acute and chronic toxicological effects of chiral contaminants. In this study, we used the human breast carcinoma MCF-7 cell line to evaluate enantioselectivity of o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT). Baseline separation of o,p'-DDT enantiomers was achieved on the Chiralcel OJ chiral column by high-performance liquid chromatography, and the absolute configuration and optical rotation of the resolved enantiomers were further identified. Significant differences in estrogenic potential were observed between the two enantiomers of o,p'-DDT in the MCF-7 cell proliferation assay (i.e., the E-Screen assay) and the real-time quantitative polymerase chain reaction (PCR). In the E-Screen assay, the relative proliferative effect ratios of R-(-)-o,p'-DDT and S-(+)-o,p'-DDT were 89.4 and 27.9%, respectively, and the relative proliferative potency ratios were 0.1 and 0.001%, respectively. Compared to the solvent control, R-(-)-o,p'-DDT induced the maximal increase of 2.31-fold at a concentration of 10(-6) mol/L, while S-(+)-o,p'-DDT at 10(-5) mol/L induced the maximal increase of 1.65-fold in estrogenic biomarker pS2 mRNA level. The maximal down-regulation of the transcription levels of estrogen receptor alpha (ERa) and ER3 by R-(-)-o,p'-DDT were 49 and 40% at the concentration of 10(-6) mol/L, while those by S-(+)-o,p'-DDT were 24 and 26% at the concentration of 10(-5) mol/L. The cell proliferation, the up-regulation of pS2, and the down-regulation of ERalpha and ERbeta gene expressions induced by the racemate and enantiomers of o,p'-DDT were all reversed by cotreatment with 10(-6) mol/L ICI 182,780. Therefore, the enantioselective estrogenicity of o,p'-DDT was likely through the ERalpha and ERbeta signaling pathways. Results from this study suggest the need for considering enantioselectivity of chiral contaminants in chronic ecological toxicities.
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PMID:Enantioselective estrogenicity of o,p'-dichlorodiphenyltrichloroethane in the MCF-7 human breast carcinoma cell line. 1870 Aug 9

The isothiocyanates (ITCs) have long been known to possess chemopreventive activities for a variety of neoplasms including breast cancer, but the molecular mechanism by which ITCs prevent breast cancer development has not been established. In this study, we investigated the effects of benzyl and phenethyl isothiocyanate (BITC and PEITC) on the estrogen-stimulated growth of estrogen receptor alpha (ERalpha)-positive breast cancer MCF7 and T-47D cells. BITC and PEITC inhibited estrogen-stimulated cell growth and reduced the expression levels of ERalpha in MCF7 and T-47D cells in a dose- and time-dependent and reversible manner. In addition, BITC and PEITC also abrogated the transcriptional activity of ERalpha and hence inhibited estrogen-stimulated expression of the estrogen responsive gene, pS2. These results demonstrated that BITC and PEITC function as potent ERalpha disruptors to abrogate mitogenic estrogen signaling in ER-positive breast cancer cells, which provides a molecular explanation for the growth inhibitory function of ITCs in breast cancer development, and a rational for further exploration of ITCs as chemopreventive agents for human mammary carcinogenesis.
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PMID:Isothiocyanates repress estrogen receptor alpha expression in breast cancer cells. 1908 60

We studied the estrogenic activity and cellular effect of wild yam extract in MCF-7 human breast cancer cells. The extract increased the activity of the progesterone receptor and pS2 genes at the mRNA levels in human breast cancer MCF-7 cells, although the effects were not as prominent as those of 17beta-estradiol (E(2)). Western blot analysis showed that the level of estrogen receptor alpha protein was down-regulated after treatment with E(2) or wild yam extract. Wild yam extract also inhibited proliferation of MCF-7 cells. These data indicate that wild yam extract acts as a weak phytoestrogen and protects against proliferation in human breast carcinoma MCF-7 cells.
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PMID:Estrogen activities and the cellular effects of natural progesterone from wild yam extract in mcf-7 human breast cancer cells. 1922 19

One third of all breast cancers are estrogen receptor alpha (ERalpha) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERalpha in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERalpha and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERalpha-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERalpha expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ERalpha promoter. Up-regulated ERalpha could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERalpha responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ERalpha expression in an in vivo model of ERalpha-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERalpha expression in ERalpha-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERalpha-negative breast cancer patients.
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PMID:Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells. 2112 65

Apurinic/apyrimidinic endonuclease 1 or redox factor-1 (Ape1/Ref-1) is a pleiotropic cellular protein involved in DNA repair and, through its redox activity, enhances the binding of a select group of transcription factors to their cognate recognition sequences in DNA. Thus, we were intrigued when we identified Ape1/Ref-1 and a number of DNA repair and oxidative stress proteins in a complex associated with the DNA-bound estrogen receptor alpha (ERalpha). Because Ape1/Ref-1 interacts with a number of transcription factors and influences their activity, we determined whether it might also influence ERalpha activity. We found that endogenously expressed Ape1/Ref-1 and ERalpha from MCF-7 human breast cancer cells interact and that Ape1/Ref-1 enhances the interaction of ERalpha with estrogen-response elements (EREs) in DNA. More importantly, Ape1/Ref-1 alters expression of the endogenous, estrogen-responsive progesterone receptor and pS2 genes in MCF-7 cells and associates with ERE-containing regions of these genes in native chromatin. Interestingly, knocking down Ape1/Ref-1 expression or inhibiting its redox activity with the small molecule inhibitor E3330 enhances estrogen responsiveness of the progesterone receptor and pS2 genes but does not alter the expression of the constitutively active 36B4 gene. Additionally, the reduced form of Ape1/Ref-1 increases and E3330 limits ERalpha-ERE complex formation in vitro and in native chromatin. Our studies demonstrate that Ape1/Ref-1 mediates its gene-specific effects, in part, by associating with endogenous, estrogen-responsive genes and that the redox activity of Ape1/Ref-1 is instrumental in altering estrogen-responsive gene expression.
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PMID:Apurinic/apyrimidinic endonuclease 1 alters estrogen receptor activity and estrogen-responsive gene expression. 1946 Aug 60


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