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The Nuclear Receptor Co Activator 5 Is A Potential New Co Regulator Of The Estrogen Related Receptor Alpha In Breast Cancer
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Book Synopsis The Nuclear Receptor Co-Activator 5 is a Potential New Co-regulator of the Estrogen Related Receptor [alpha] in Breast Cancer by : Amandine Laffitte
Download or read book The Nuclear Receptor Co-Activator 5 is a Potential New Co-regulator of the Estrogen Related Receptor [alpha] in Breast Cancer written by Amandine Laffitte and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Nuclear receptors are transcriptional factors that are essential for a wide range of biological processes. They are partly regulated through their interaction with co-regulatory proteins. Here, we focus on the orphan nuclear receptor ERRa and its potential new co-activator protein NCOA5. Using NCOA5 knockdown or overexpression via a lentiviral system, we investigated the role of NCOA5 in ERRa regulation in Her2-positive breast cancer cells and its effect on known targets of ERRa in this context, such as the ERBB2 amplicon transcription. We show that NCOA5 and ERRa can regulate each other, yet the precise mechanism remains to be elucidated. NCOA5 protein level affects ERR[alpha] transcription and protein level, also affecting the transcription of ERRa targets from the ERBB2 amplicon including the Her2 receptor itself. Modulation of NCOA5 levels leads to variation in cell proliferation and metabolism, thus revealing that NCOA5 is an important factor in the ERBB2 amplicon regulation." --
Book Synopsis The Nuclear Receptor Co-Activator 5 is a Potential New Co-regulator of the Estrogen Related Receptor Α in Breast Cancer by : Amandine Laffitte
Download or read book The Nuclear Receptor Co-Activator 5 is a Potential New Co-regulator of the Estrogen Related Receptor Α in Breast Cancer written by Amandine Laffitte and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis An Estrogen Receptor-Selective Coactivator: A Potential Regulator of Tamoxifen Effectiveness in Breast Cancer Treatment and Prevention by :
Download or read book An Estrogen Receptor-Selective Coactivator: A Potential Regulator of Tamoxifen Effectiveness in Breast Cancer Treatment and Prevention written by and published by . This book was released on 2002 with total page 17 pages. Available in PDF, EPUB and Kindle. Book excerpt: The estrogen receptor (ER) is involved in breast cancer development and progression. We have isolated a novel 97 kDa DEAD box RNA helicase (DP97) that interacts with the estrogen receptor alpha (ERa) in the presence of either estradiol or trans-hydroxytamoxifen. DP97 represses the transcriptonal activity of the estradiol-occupied estrogen receptor and this repression can be relieved with Trichostatin A(TSA), a selective histone deacetylase inhibitor. DP97 represses the activity of a constitutive SV4O promoter when it is recruited as a Gal-4 DNA binding domain fusion protein. DP97 also interacts with, and represses the activity of, other nucelar receptors such as the progesterone receptor b, glucocorticoid receptor, and retionic acid receptor a. However, DP97 does not repress the activity of either p53 or VP16. We show that the N- terminal helicase region of DP97 is dispensible for its activity as a transcriptional repressor. Furthermore, a BLAST homology search of the remaining sequence of p97 reveales that this protein has a small region of homology with the SMRTe(NCoR2) corepressor protein. This small region is also able to repress a constitutively active SV4O promoter when it is recmited to it as a Gal-4 DNA binding domain fusion protein. Therefore, DP97 functions as a RNA helicase, a nuclear receptor interacting protein, and as a transcriptional coregulator.
Book Synopsis Estrogen-Related Receptor Alpha (ERRa)-Coactivator Interactions as Targets for Discovery of New Anti-Breast Cancer Therapeutics by :
Download or read book Estrogen-Related Receptor Alpha (ERRa)-Coactivator Interactions as Targets for Discovery of New Anti-Breast Cancer Therapeutics written by and published by . This book was released on 2006 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: The nuclear receptor estrogen receptor alpha (ERalpha) is a primary focus of the therapy of breast cancers. ERalpha-positive breast cancers have traditionally been treated with the anti-estrogen tamoxifen, or with inhibitors of aromatase. ERalpha-negative breast cancers do not respond to anti-estrogen treatment; instead, current therapeutics, such as Herceptin, have focused on the transmembrane tyrosine kinase receptor ErbB2 (HER2) because it is often overexpressed in ERalpha-negative tumors and correlates with a poor prognosis. Estrogen-related receptor alpha (ERRalpha) has sequence similarity to ERalpha, but ERRalpha does not bind estrogens. In some cases ERRalpha is constitutively active, which is likely determined not only by its interaction with coactivators, but also in part by post-translational modifications occurring via the ErbB2 (HER2) signaling pathways. Thus, ERRalpha probably plays a key role in the etiology and progression of a subset of breast cancers. We believe that the ERRalpha-coactivator interaction is a promising target for new chemotherapeutic drug development. We have generated and characterized a set of murine monoclonal antibodies for use in studying the biology of ERRalpha. We are now using some of those antibodies in gentle immunoaffinity chromatography to determine ERRalpha-associated proteins. Using in vitro assays, we will study the binding properties of ERRalpha with known coactivators like transcriptional intermediary factor 2 (TIF2), as well as any ERRalpha-associated proteins we may find during immunopurification. In the future, using a luminescence resonance energy transfer-based high-throughput screen previously developed in our laboratory, we hope to identify small molecules that interfere with the binding of ERRalpha with these coactivators.
Book Synopsis Nuclear Receptors as Drug Targets by : Eckhard Ottow
Download or read book Nuclear Receptors as Drug Targets written by Eckhard Ottow and published by Wiley-VCH. This book was released on 2008-10-13 with total page 522 pages. Available in PDF, EPUB and Kindle. Book excerpt: Edited by two experts working at the pioneering pharmaceutical company and major global player in hormone-derived drugs, this handbook and reference systematically treats the drug development aspects of all human nuclear receptors, including recently characterized receptors such as PPAR, FXR and LXR. Authors from leading pharmaceutical companies around the world present examples and real-life data from their own work.
Book Synopsis Placat angaaende Oprettelsen af en Direction for Universitetet og de lærde Skoler i Danmark og Norge by :
Download or read book Placat angaaende Oprettelsen af en Direction for Universitetet og de lærde Skoler i Danmark og Norge written by and published by . This book was released on 1950 with total page 2 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Inhibition of Estrogen Receptor Coactivator Expression by Antisense Oligodeoxynucleotides and Effect on Breast Cancer Cell Proliferation and Gene Expression by :
Download or read book Inhibition of Estrogen Receptor Coactivator Expression by Antisense Oligodeoxynucleotides and Effect on Breast Cancer Cell Proliferation and Gene Expression written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Coactivators are nuclear proteins that interact with steroid receptors, such as estrogen receptor-alpha (ERalpha), and are required for the ability of receptors to stimulate the expression of target genes. Antiestrogen ligand are commonly utilized in the treatment of breast cancer to negatively regulate the activity of steroid receptors. However, tumors often can develop resistance to antiestrogen therapy. Therefore, as an alternative approach to inhibiting ERalpha function in breast cancer cells, we have developed antisense oligonucleotides against three of the major ERalpha coactivator proteins. These oligonucleotides decrease the expression of coactivator mRNA and protein, and in so doing, decrease the ability of ERalpha to stimulate gene expression. These oligonucleotides also decrease the proliferation of MCF-7 breast cancer cells in response to estrogen treatment. Taken together, anti sense oligonucleotide technology has the potential to regulate ERalpha action at a level that circumvents ligand control, and therefore represents a novel mechanism by which to inhibit breast cancer gene expression and proliferation, and potentially to regulate the growth of breast cancer.
Book Synopsis Estrogen Nuclear Receptor Coactivators in Pathogenesis of Breast Cancer by :
Download or read book Estrogen Nuclear Receptor Coactivators in Pathogenesis of Breast Cancer written by and published by . This book was released on 1998 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This project focuses on the role of nuclear receptor coactivators in steroid dependent regulation of cell growth in pathogenesis of breast cancer. A novel nuclear receptor coactivator of transcription, p300 and CBP associated factor (p/CAF) has been shown to be required for estrogen, thyroid hormone, and retinoic acid-dependent gene expression. The histone acetyltransferase activity of p/CAF was demonstrated to play essential role in nuclear receptor dependent gene expression and it appeared to be transcription factor specific. The ligand-dependent association of p/CAF with nuclear receptor depends upon nuclear receptor corepressor (NCoR) dismissal. These data suggest that p/CAF complex plays a central role in nuclear receptor dependent gene regulation, a key element in steroid dependent cancer development.
Book Synopsis Estrogen Receptor Alpha Protein Interactions with Nuclear Components in Breast Cancer Cells by : Amy L. Weinberg
Download or read book Estrogen Receptor Alpha Protein Interactions with Nuclear Components in Breast Cancer Cells written by Amy L. Weinberg and published by . This book was released on 2007 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors by : Brian J. Bennion
Download or read book Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors written by Brian J. Bennion and published by . This book was released on 2005 with total page 52 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here we describe our work with the human estrogen receptor alpha (hERa) and the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We found that PhIP, in contrast to the other heterocyclic amines, increased cell-proliferation in MCF-7 human breast cancer cells and activated the hERa receptor. We show mechanistic data supporting this activation both computationally by homology modeling and docking, and by NMR confirmation that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ER activation presumably by binding into another cavity on the LBD. Moreover, molecular dynamics simulations of inhibitory heterocyclic amines reveal a disruption of the surface of the receptor protein involved with protein-protein signaling. We therefore propose that the mechanism for the tissue specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.
Book Synopsis Coactivator Requirements for Serm Action by :
Download or read book Coactivator Requirements for Serm Action written by and published by . This book was released on 2005 with total page 24 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor alpha- (ER(alpha)) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ER(alpha) activity and has been used in breast cancer therapy. The molecular determinants of tamoxifen action are not completely understood, but the availability of ER coregulators is thought to play a role. Tamoxifen-bound ER(alpha) associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. To determine if these corepressors are required for tamoxifen- mediated repression, their expression levels were reduced by RNA interference and the effects on tamoxifen action in breast cancer cells were measured. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the 0-myc, cyclin Dl, or SDF-1 genes, which play a role in estrogen-induced cell growth. By contrast, expression of X-box binding protein 1 (XBP-1) was markedly elevated upon silencing N-CoR and SMRT and treating with tamoxifen. These results indicate that N-CoR and SMRT may influence tamoxifen action on a subset of genes involved in ER(alpha) function and cell proliferation. These findings help to further elucidate mechanisms underlying tamoxifen action that may be relevant to understanding tamoxifen-stimulated tumor growth.
Book Synopsis Design and Synthesis of Estrogen Receptor Coactivator Binding Inhibitors by :
Download or read book Design and Synthesis of Estrogen Receptor Coactivator Binding Inhibitors written by and published by . This book was released on 2004 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Targeting of the Nuclear Receptor Coactivator Isoform DELTA3AIB1 in Breast Cancer by :
Download or read book Targeting of the Nuclear Receptor Coactivator Isoform DELTA3AIB1 in Breast Cancer written by and published by . This book was released on 2007 with total page 19 pages. Available in PDF, EPUB and Kindle. Book excerpt: AIB1 which stands for Amplified in Breast Cancer, codes for a protein that is a member of the steroid receptor coactivator (SRC) family. AIB1 is amplified in approximately 5-10% of breast cancers and the mRNA and protein overexpressed in>30% of breast cancers. AIB1 interacts with a superfamily of ligand activated nuclear receptors to potentiate transcriptional activity leading to upregulation of downstream target gene expression. An important finding was that an isoform of AIB1 (Delta3AIB1) is a significantly more effective coactivator of the estrogen receptor than AIB1 and is highly overexpressed in human breast cancer. Prior work in our lab showed that the downregulation of overall levels of AIB1 plus DELTA3AIB1, using a regulatable AIB1 directed ribozyme, resulted in reduced tumor growth in vivo. Overall, these data indicate a major role for AIB1 and its isoform DELTA3AIB1 in breast cancer development and growth. However the relative roles of AIB1 versus the more highly active DELTA3AIB1 in phenotypic changes in the breast has not been determined. In this investigation, we are developing a method to use siRNA directed at DELTA3AIB1 in order investigate its role in breast cancer and as a possible future therapeutic approach to breast cancer.
Book Synopsis The Role of Steroid Receptor Coactivator-1 in Breast Cancer by : Neil J. McKenna
Download or read book The Role of Steroid Receptor Coactivator-1 in Breast Cancer written by Neil J. McKenna and published by . This book was released on 2001 with total page 33 pages. Available in PDF, EPUB and Kindle. Book excerpt: The role of steroid receptor coactivator-1 (SRC-1) in breast cancer is primarily a function of (i) the expression patterns of nuclear receptors (NRs) and SRC family members in the tumor, and (ii) their inherent interaction affinities. An outstanding question is the extent to which SRC/NR pathways in breast cancer are uncoupled by administration of selective estrogen receptor modulator (SERM) regimens such as 4-hydroxytamoxifen. An appreciation of the role of SRC-1 and other SRCs in the selective recruitment of NRs during the development of breast cancer is a prerequisite for the design of novel SRMs for treatment of breast cancer. We used BlAcore analysis to monitor interactions between SRCs and His-tagged NRs. Distinct affinities were noted for different NR-coactivator interactions, indicating an interaction preference spectrum for estrogen receptor-alpha (ERalpha) of SRC-3>SRC-1>SRC-2. The interaction of ERalpha with SRC family members was differentially influenced by different SERMs. In all cases, the interaction between ERalpha and SRCs was promoted by 17beta-estradiol and inhibited by 4-hydroxytamoxifen, raloxifene and ICI 182, 780. The interaction kinetics of SRC family members with liganded NRs are consistent with a bipartite model involving a transitional intermediate. By providing accurate measurements of the modulation by SRMs of the interaction between NRs and SRC family members, we have created a model system within which rational design of SERMs for breast cancer treatment can be evaluated in a functional context.
Book Synopsis Nuclear Hormone Receptors by : Malcolm G. Parker
Download or read book Nuclear Hormone Receptors written by Malcolm G. Parker and published by . This book was released on 1991 with total page 434 pages. Available in PDF, EPUB and Kindle. Book excerpt: An overview of the supergene family made up of those nuclear hormone receptors which recognize thyroid and steroid hormones, vitamen D and retinoic acid and which are characterized by their ability to bind both ligands and the genes which respond to them.
Book Synopsis EGF Regulation of Nuclear Co-Activator AIB1 Function in Breast Cancer by :
Download or read book EGF Regulation of Nuclear Co-Activator AIB1 Function in Breast Cancer written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Various growth factor receptor pathways promote human breast tumorigenesis of hormone-independent tumors. The nuclear receptor coactivator AIBi (amplified in breast cancer 1) can be phosphorylated and regulated by growth factor-induced signaling pathways such as MAP kinase and IkB kinase. Our lab has found a splice variant of AIBl, called delta exon3 AIBl, which has a higher co-activating ability than the full-length protein. This study determined the ability of delta exon3 splice variant compared with AIBi in potentiating growth factor signaling and to determine the mechanism of this potentiation using a growth factor responsive promoter.
Book Synopsis Targeting of the Nuclear Receptor Coactivator Isoform Delta3Air in Breast Cancer by :
Download or read book Targeting of the Nuclear Receptor Coactivator Isoform Delta3Air in Breast Cancer written by and published by . This book was released on 2005 with total page 21 pages. Available in PDF, EPUB and Kindle. Book excerpt: Of particular interest to breast cancer was the discovery that an area of chromosome 20q, known to be frequently amplified in breast cancer, harbored the gene for AIB1. AIB1 which stands for "Amplified in Breast cancer" codes for a protein which is a member of the steroid receptor coactivator (SRC) family. AIB1 is amplified in approximately 5-10% of breast cancers and the mRNA and protein overexpressed in>30% of breast cancers. AIB1 interacts with a superfamily of ligand activated nuclear receptors including the estrogen receptor (ER) and progesterone receptor (PR) to potentiate transcriptional activity leading to upregulation of downstream target gene expression. An important finding was that an isoform of AIB1 (delta3AIB1) is a significantly more effective coactivator of the estrogen receptor than AIB1 and is highly overexpressed in human breast cancer. Prior work in our lab showed that the downregulation of overall levels of AIB1 plus delta3AIB1, using a regulatable AIB1 directed ribozyme, resulted in reduced tumor growth in vivo. Overall, these data indicate a major role for AIB1 and its isoform delta3AIB1 in breast cancer development and growth. However the relative roles of AIB1 versus the more highly active delta3AIB1 in phenotypic changes in the breast has not been determined.
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