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  1. Article ; Online: Ligands specify estrogen receptor alpha nuclear localization and degradation

    Caze-Subra Stéphanie / Mazaheri Mahta / Kocanova Silvia / Bystricky Kerstin

    BMC Cell Biology, Vol 11, Iss 1, p

    2010  Volume 98

    Abstract: Abstract Background The estrogen receptor alpha (ERα) is found predominately in the nucleus, both in hormone stimulated and untreated cells. Intracellular distribution of the ERα changes in the presence of agonists but the impact of different ... ...

    Abstract Abstract Background The estrogen receptor alpha (ERα) is found predominately in the nucleus, both in hormone stimulated and untreated cells. Intracellular distribution of the ERα changes in the presence of agonists but the impact of different antiestrogens on the fate of ERα is a matter of debate. Results A MCF-7 cell line stably expressing GFP-tagged human ERα (SK19 cell line) was created to examine the localization of ligand-bound GFP-ERα. We combined digitonin-based cell fractionation analyses with fluorescence and immuno-electron microscopy to determine the intracellular distribution of ligand-bound ERα and/or GFP-ERα. Using fluorescence- and electron microscopy we demonstrate that both endogenous ERα and GFP-ERα form numerous nuclear focal accumulations upon addition of agonist, 17β-estradiol (E2), and pure antagonists (selective estrogen regulator disruptor; SERD), ICI 182,780 or RU58,668, while in the presence of partial antagonists (selective estrogen regulator modulator; SERM), 4-hydroxytamoxifen (OHT) or RU39,411, diffuse nuclear staining persisted. Digitonin based cell fractionation analyses confirmed that endogenous ERα and GFP-ERα predominantly reside in the nuclear fraction. Overall ERα protein levels were reduced after estradiol treatment. In the presence of SERMs ERα was stabilized in the nuclear soluble fraction, while in the presence of SERDs protein levels decreased drastically and the remaining ERα was largely found in a nuclear insoluble fraction. mRNA levels of ESR1 were reduced compared to untreated cells in the presence of all ligands tested, including E2. E2 and SERDs induced ERα degradation occurred in distinct nuclear foci composed of ERα and the proteasome providing a simple explanation for ERα sequestration in the nucleus. Conclusions Our results indicate that chemical structure of ligands directly affect the nuclear fate and protein turnover of the estrogen receptor alpha independently of their impact on transcription. These findings provide a molecular basis for the selection of antiestrogen compounds issue from pharmacological studies aimed at improving treatment of breast cancer.
    Keywords Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Cytology ; QH573-671
    Subject code 616
    Language English
    Publishing date 2010-12-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article: Molecular and Biochemical Analysis of the Estrogenic and Proliferative Properties of Vitamin E Compounds.

    Khallouki, Farid / de Medina, Philippe / Caze-Subra, Stéphanie / Bystricky, Kerstin / Balaguer, Patrick / Poirot, Marc / Silvente-Poirot, Sandrine

    Frontiers in oncology

    2016  Volume 5, Page(s) 287

    Abstract: Tocols are vitamin E compounds that include tocopherols (TPs) and tocotrienols (TTs). These lipophilic compounds are phenolic antioxidants and are reportedly able to modulate estrogen receptor β (ERβ). We investigated the molecular determinants that ... ...

    Abstract Tocols are vitamin E compounds that include tocopherols (TPs) and tocotrienols (TTs). These lipophilic compounds are phenolic antioxidants and are reportedly able to modulate estrogen receptor β (ERβ). We investigated the molecular determinants that control their estrogenicity and effects on the proliferation of breast cancer cells. Docking experiments highlighted the importance of the tocol phenolic groups for their interaction with the ERs. Binding experiments confirmed that they directly interact with both ERα and ERβ with their isoforms showing potencies in the following order: δ-tocols > γ-tocols > α-tocols. We also found that tocols activated the transcription of an estrogen-responsive reporter gene that had been stably transfected into cells expressing either ERα or ERβ. The role of the phenolic group in tocol-ER interaction was further established using δ-tocopherylquinone, the oxidized form of δ-TP, which had no ER affinity and did not induce ER-dependent transcriptional modulation. Tocol activity also required the AF1 transactivation domain of ER. We found that both δ-TP and δ-TT stimulated the expression of endogenous ER-dependent genes. However, whereas δ-TP induced the proliferation of ER-positive breast cancer cells but not ER-negative breast cancer cells, δ-TT inhibited the proliferation of both ER-positive and ER-negative breast cancer cells. These effects of δ-TT were found to act through the down regulation of HMG-CoA reductase (HMGR) activity, establishing that ERs are not involved in this effect. Altogether, these data show that the reduced form of δ-TP has estrogenic properties which are lost when it is oxidized, highlighting the importance of the redox status in its estrogenicity. Moreover, we have shown that δ-TT has antiproliferative effects on breast cancer cells independently of their ER status through the inhibition of HMGR. These data clearly show that TPs can be discriminated from TTs according to their structure.
    Language English
    Publishing date 2016-01-05
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2015.00287
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Ligands specify estrogen receptor alpha nuclear localization and degradation.

    Kocanova, Silvia / Mazaheri, Mahta / Caze-Subra, Stéphanie / Bystricky, Kerstin

    BMC cell biology

    2010  Volume 11, Page(s) 98

    Abstract: Background: The estrogen receptor alpha (ERα) is found predominately in the nucleus, both in hormone stimulated and untreated cells. Intracellular distribution of the ERα changes in the presence of agonists but the impact of different antiestrogens on ... ...

    Abstract Background: The estrogen receptor alpha (ERα) is found predominately in the nucleus, both in hormone stimulated and untreated cells. Intracellular distribution of the ERα changes in the presence of agonists but the impact of different antiestrogens on the fate of ERα is a matter of debate.
    Results: A MCF-7 cell line stably expressing GFP-tagged human ERα (SK19 cell line) was created to examine the localization of ligand-bound GFP-ERα. We combined digitonin-based cell fractionation analyses with fluorescence and immuno-electron microscopy to determine the intracellular distribution of ligand-bound ERα and/or GFP-ERα.Using fluorescence- and electron microscopy we demonstrate that both endogenous ERα and GFP-ERα form numerous nuclear focal accumulations upon addition of agonist, 17β-estradiol (E2), and pure antagonists (selective estrogen regulator disruptor; SERD), ICI 182,780 or RU58,668, while in the presence of partial antagonists (selective estrogen regulator modulator; SERM), 4-hydroxytamoxifen (OHT) or RU39,411, diffuse nuclear staining persisted.Digitonin based cell fractionation analyses confirmed that endogenous ERα and GFP-ERα predominantly reside in the nuclear fraction. Overall ERα protein levels were reduced after estradiol treatment. In the presence of SERMs ERα was stabilized in the nuclear soluble fraction, while in the presence of SERDs protein levels decreased drastically and the remaining ERα was largely found in a nuclear insoluble fraction. mRNA levels of ESR1 were reduced compared to untreated cells in the presence of all ligands tested, including E2. E2 and SERDs induced ERα degradation occurred in distinct nuclear foci composed of ERα and the proteasome providing a simple explanation for ERα sequestration in the nucleus.
    Conclusions: Our results indicate that chemical structure of ligands directly affect the nuclear fate and protein turnover of the estrogen receptor alpha independently of their impact on transcription. These findings provide a molecular basis for the selection of antiestrogen compounds issue from pharmacological studies aimed at improving treatment of breast cancer.
    MeSH term(s) Cell Line, Tumor ; Digitonin/chemistry ; Estradiol/analogs & derivatives ; Estradiol/pharmacology ; Estrogen Receptor alpha/analysis ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Fulvestrant ; Green Fluorescent Proteins/analysis ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Humans ; Ligands ; Microscopy, Immunoelectron ; Proteasome Endopeptidase Complex/metabolism ; RNA, Messenger/metabolism ; Recombinant Fusion Proteins/analysis ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Tamoxifen/analogs & derivatives ; Tamoxifen/pharmacology
    Chemical Substances ESR1 protein, human ; Estrogen Receptor alpha ; Ligands ; RNA, Messenger ; Recombinant Fusion Proteins ; Tamoxifen (094ZI81Y45) ; Green Fluorescent Proteins (147336-22-9) ; afimoxifene (17197F0KYM) ; Fulvestrant (22X328QOC4) ; Estradiol (4TI98Z838E) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Digitonin (KOO5CM684H)
    Language English
    Publishing date 2010-12-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1471-2121
    ISSN (online) 1471-2121
    DOI 10.1186/1471-2121-11-98
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Activation of estrogen-responsive genes does not require their nuclear co-localization.

    Kocanova, Silvia / Kerr, Elizabeth A / Rafique, Sehrish / Boyle, Shelagh / Katz, Elad / Caze-Subra, Stephanie / Bickmore, Wendy A / Bystricky, Kerstin

    PLoS genetics

    2010  Volume 6, Issue 4, Page(s) e1000922

    Abstract: The spatial organization of the genome in the nucleus plays a role in the regulation of gene expression. Whether co-regulated genes are subject to coordinated repositioning to a shared nuclear space is a matter of considerable interest and debate. We ... ...

    Abstract The spatial organization of the genome in the nucleus plays a role in the regulation of gene expression. Whether co-regulated genes are subject to coordinated repositioning to a shared nuclear space is a matter of considerable interest and debate. We investigated the nuclear organization of estrogen receptor alpha (ERalpha) target genes in human breast epithelial and cancer cell lines, before and after transcriptional activation induced with estradiol. We find that, contrary to another report, the ERalpha target genes TFF1 and GREB1 are distributed in the nucleoplasm with no particular relationship to each other. The nuclear separation between these genes, as well as between the ERalpha target genes PGR and CTSD, was unchanged by hormone addition and transcriptional activation with no evidence for co-localization between alleles. Similarly, while the volume occupied by the chromosomes increased, the relative nuclear position of the respective chromosome territories was unaffected by hormone addition. Our results demonstrate that estradiol-induced ERalpha target genes are not required to co-localize in the nucleus.
    MeSH term(s) Cell Line, Tumor ; Cell Nucleus/metabolism ; Epithelial Cells/metabolism ; Estrogen Receptor alpha/genetics ; Estrogen Receptor alpha/metabolism ; Estrogens/pharmacology ; Female ; Humans ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Trefoil Factor-1 ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Estrogen Receptor alpha ; Estrogens ; GREB1 protein, human ; Neoplasm Proteins ; TFF1 protein, human ; Trefoil Factor-1 ; Tumor Suppressor Proteins
    Language English
    Publishing date 2010-04-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1000922
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Auraptene is an inhibitor of cholesterol esterification and a modulator of estrogen receptors.

    de Medina, Philippe / Genovese, Salvatore / Paillasse, Michael R / Mazaheri, Mahta / Caze-Subra, Stephanie / Bystricky, Kerstin / Curini, Massimo / Silvente-Poirot, Sandrine / Epifano, Francesco / Poirot, Marc

    Molecular pharmacology

    2010  Volume 78, Issue 5, Page(s) 827–836

    Abstract: Auraptene is a prenyloxycoumarin from Citrus species with chemopreventive properties against colitis-related colon and breast cancers through a yet-undefined mechanism. To decipher its mechanism of action, we used a ligand-structure based approach. We ... ...

    Abstract Auraptene is a prenyloxycoumarin from Citrus species with chemopreventive properties against colitis-related colon and breast cancers through a yet-undefined mechanism. To decipher its mechanism of action, we used a ligand-structure based approach. We established that auraptene fits with a pharmacophore involved in both the inhibition of acyl-CoA:cholesterol acyl transferase (ACAT) and the modulation of estrogen receptors (ERs). We confirmed experimentally that auraptene inhibits ACAT and binds to ERs in a concentration-dependent manner and that it inhibited ACAT in rat liver microsomes and in intact cancer cells of murine and human origins, with an IC(50) value in the micromolar range. Auraptene bound to ERs with affinities of 7.8 μM for ERα and 7.9 μM for ERβ, stabilized ERs, and modulated their transcriptional activity via an ER-dependent reporter gene and endogenous genes. We further established that these effects correlated well with the control of growth and invasiveness of tumor cells. Our data shed light on the molecular mechanism underlying the anticancer and chemopreventive effects of auraptene.
    MeSH term(s) Animals ; Anticarcinogenic Agents/pharmacology ; Binding Sites ; Binding, Competitive ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Coumarins/pharmacology ; Epoxide Hydrolases/antagonists & inhibitors ; Estrogen Antagonists/metabolism ; Estrogen Receptor alpha/metabolism ; Estrogen Receptor beta/metabolism ; Gene Expression Regulation ; Genes, Reporter ; Humans ; In Vitro Techniques ; Luciferases/biosynthesis ; Luciferases/genetics ; Mice ; Microsomes, Liver/drug effects ; Microsomes, Liver/enzymology ; Models, Molecular ; Neoplasm Invasiveness ; Radioligand Assay ; Rats ; Sterol O-Acyltransferase/antagonists & inhibitors ; Transcription, Genetic/drug effects
    Chemical Substances Anticarcinogenic Agents ; Coumarins ; Estrogen Antagonists ; Estrogen Receptor alpha ; Estrogen Receptor beta ; Luciferases (EC 1.13.12.-) ; Sterol O-Acyltransferase (EC 2.3.1.26) ; Epoxide Hydrolases (EC 3.3.2.-) ; cholesterol-5 alpha,6 alpha-epoxide hydrase (EC 3.3.2.-) ; aurapten (F79I1ZEL2E)
    Language English
    Publishing date 2010-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/mol.110.065250
    Database MEDical Literature Analysis and Retrieval System OnLINE

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