Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function
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Analysis of Estrogen Receptor Isoforms and Variants in Breast Cancer Cell Lines
EXPERIMENTAL AND THERAPEUTIC MeDICINE 2: 537-544, 2011 Analysis of estrogen receptor isoforms and variants in breast cancer cell lines MAIE AL-BADER1, CHRISTOPHER FORD2, BUSHRA AL-AYADHY3 and ISSAM FRANCIS3 Departments of 1Physiology, 2Surgery, and 3Pathology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait Received November 22, 2010; Accepted February 14, 2011 DOI: 10.3892/etm.2011.226 Abstract. In the present study, the expression of estrogen domain C, the DNA binding domain; domains D/E, bearing receptor (ER)α and ERβ isoforms in ER-positive (MCF7, both the activation function-2 (AF-2) and the ligand binding T-47D and ZR-75-1) and ER-negative (MDA-MB-231, SK-BR-3, domains; and finally, domain F, the C-terminal domain (6,7). MDA-MB-453 and HCC1954) breast cancer cell lines was The actions of estrogens are mediated by binding to ERs investigated. ERα mRNA was expressed in ER-positive and (ERα and/or ERβ). These receptors, which are co-expressed some ER-negative cell lines. ERα ∆3, ∆5 and ∆7 spliced in a number of tissues, form functional homodimers or variants were present in MCF7 and T-47D cells; ERα ∆5 heterodimers. When bound to estrogens as homodimers, the and ∆7 spliced variants were detected in ZR-75-1 cells. transcription of target genes is activated (8,9), while as heterodi- MDA-MB-231 and HCC1954 cells expressed ERα ∆5 and ∆7 mers, ERβ exhibits an inhibitory action on ERα-mediated gene spliced variants. The ERβ1 variant was expressed in all of the expression and, in many instances, opposes the actions of ERα cell lines and the ERβ2 variant in all of the ER-positive and (7,9). -
Supplementary Materials: Evaluation of Cytotoxicity and Α-Glucosidase Inhibitory Activity of Amide and Polyamino-Derivatives of Lupane Triterpenoids
Supplementary Materials: Evaluation of cytotoxicity and α-glucosidase inhibitory activity of amide and polyamino-derivatives of lupane triterpenoids Oxana B. Kazakova1*, Gul'nara V. Giniyatullina1, Akhat G. Mustafin1, Denis A. Babkov2, Elena V. Sokolova2, Alexander A. Spasov2* 1Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russian Federation 2Scientific Center for Innovative Drugs, Volgograd State Medical University, Novorossiyskaya st. 39, Volgograd 400087, Russian Federation Correspondence Prof. Dr. Oxana B. Kazakova Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences 71 Prospeсt Oktyabrya Ufa, 450054 Russian Federation E-mail: [email protected] Prof. Dr. Alexander A. Spasov Scientific Center for Innovative Drugs of the Volgograd State Medical University 39 Novorossiyskaya st. Volgograd, 400087 Russian Federation E-mail: [email protected] Figure S1. 1H and 13C of compound 2. H NH N H O H O H 2 2 Figure S2. 1H and 13C of compound 4. NH2 O H O H CH3 O O H H3C O H 4 3 Figure S3. Anticancer screening data of compound 2 at single dose assay 4 Figure S4. Anticancer screening data of compound 7 at single dose assay 5 Figure S5. Anticancer screening data of compound 8 at single dose assay 6 Figure S6. Anticancer screening data of compound 9 at single dose assay 7 Figure S7. Anticancer screening data of compound 12 at single dose assay 8 Figure S8. Anticancer screening data of compound 13 at single dose assay 9 Figure S9. Anticancer screening data of compound 14 at single dose assay 10 Figure S10. -
Activated Peripheral-Blood-Derived Mononuclear Cells
Transcription factor expression in lipopolysaccharide- activated peripheral-blood-derived mononuclear cells Jared C. Roach*†, Kelly D. Smith*‡, Katie L. Strobe*, Stephanie M. Nissen*, Christian D. Haudenschild§, Daixing Zhou§, Thomas J. Vasicek¶, G. A. Heldʈ, Gustavo A. Stolovitzkyʈ, Leroy E. Hood*†, and Alan Aderem* *Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103; ‡Department of Pathology, University of Washington, Seattle, WA 98195; §Illumina, 25861 Industrial Boulevard, Hayward, CA 94545; ¶Medtronic, 710 Medtronic Parkway, Minneapolis, MN 55432; and ʈIBM Computational Biology Center, P.O. Box 218, Yorktown Heights, NY 10598 Contributed by Leroy E. Hood, August 21, 2007 (sent for review January 7, 2007) Transcription factors play a key role in integrating and modulating system. In this model system, we activated peripheral-blood-derived biological information. In this study, we comprehensively measured mononuclear cells, which can be loosely termed ‘‘macrophages,’’ the changing abundances of mRNAs over a time course of activation with lipopolysaccharide (LPS). We focused on the precise mea- of human peripheral-blood-derived mononuclear cells (‘‘macro- surement of mRNA concentrations. There is currently no high- phages’’) with lipopolysaccharide. Global and dynamic analysis of throughput technology that can precisely and sensitively measure all transcription factors in response to a physiological stimulus has yet to mRNAs in a system, although such technologies are likely to be be achieved in a human system, and our efforts significantly available in the near future. To demonstrate the potential utility of advanced this goal. We used multiple global high-throughput tech- such technologies, and to motivate their development and encour- nologies for measuring mRNA levels, including massively parallel age their use, we produced data from a combination of two distinct signature sequencing and GeneChip microarrays. -
Expression of Estrogen Receptor-Beta Isoforms in Barrett's
ANTICANCER RESEARCH 24: 2919-2924 (2004) Expression of Estrogen Receptor-Beta Isoforms in Barrett’s Metaplasia, Dysplasia and Esophageal Adenocarcinoma LIANG LIU, MINNI CHIRALA and MAMOUN YOUNES Departments of Pathology, Baylor College of Medicine and The Methodist Hospital, Houston, TX 77030, U.S.A. Abstract. We have previously shown that the majority of and beta (ER-B). ER-A is mainly expressed in female sex esophageal adenocarcinomas (EA), and its precursor Barrett’s organs, such as breast and uterus (2), whereas ER-B is metaplasia (BM), express estrogen receptor beta (ER-B). Several expressed in both sex organs and other tissues, such as isoforms of ER-B have been described and are presumed to have prostate, lung, thyroid, adrenal cortex and testis (3). Several different functions, but their distribution in BM and EA is not ER-B isoforms have been identified and characterized in known. The aim of this work was to determine which ER-B many non-gynecologic tumors including carcinomas of the isoforms are expressed in EA and BM. Sections of formalin-fixed lung (4), prostate (5), colon (6, 7) and stomach (8). and paraffin-embedded esophageal tissue from 33 esophageactomy Tamoxifen, a specific ER-B antagonist, has been successfully specimens, of which 27 had invasive EA, were stained for the ER- used in the treatment of patients with breast carcinoma B isoforms ER-B1, ER-B2, ER-B3 and ER-B5 utilizing the (9,10) and it has been shown that ER-B status is a significant immunoperoxidase method. ER-B1 was detected in 23 out of 27 predictor of survival in women with breast carcinoma treated (85%) EA compared to 3 out of 14 (21%) Barrett’s metaplasia with mastectomy and adjuvant tamoxifen (11). -
Examination of the Transcription Factors Acting in Bone Marrow
THESIS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (PHD) Examination of the transcription factors acting in bone marrow derived macrophages by Gergely Nagy Supervisor: Dr. Endre Barta UNIVERSITY OF DEBRECEN DOCTORAL SCHOOL OF MOLECULAR CELL AND IMMUNE BIOLOGY DEBRECEN, 2016 Table of contents Table of contents ........................................................................................................................ 2 1. Introduction ............................................................................................................................ 5 1.1. Transcriptional regulation ................................................................................................... 5 1.1.1. Transcriptional initiation .................................................................................................. 5 1.1.2. Co-regulators and histone modifications .......................................................................... 8 1.2. Promoter and enhancer sequences guiding transcription factors ...................................... 11 1.2.1. General transcription factors .......................................................................................... 11 1.2.2. The ETS superfamily ..................................................................................................... 17 1.2.3. The AP-1 and CREB proteins ........................................................................................ 20 1.2.4. Other promoter specific transcription factor families ................................................... -
A Molecular Switch from STAT2-IRF9 to ISGF3 Underlies Interferon-Induced Gene Transcription
ARTICLE https://doi.org/10.1038/s41467-019-10970-y OPEN A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription Ekaterini Platanitis 1, Duygu Demiroz1,5, Anja Schneller1,5, Katrin Fischer1, Christophe Capelle1, Markus Hartl 1, Thomas Gossenreiter 1, Mathias Müller2, Maria Novatchkova3,4 & Thomas Decker 1 Cells maintain the balance between homeostasis and inflammation by adapting and inte- grating the activity of intracellular signaling cascades, including the JAK-STAT pathway. Our 1234567890():,; understanding of how a tailored switch from homeostasis to a strong receptor-dependent response is coordinated remains limited. Here, we use an integrated transcriptomic and proteomic approach to analyze transcription-factor binding, gene expression and in vivo proximity-dependent labelling of proteins in living cells under homeostatic and interferon (IFN)-induced conditions. We show that interferons (IFN) switch murine macrophages from resting-state to induced gene expression by alternating subunits of transcription factor ISGF3. Whereas preformed STAT2-IRF9 complexes control basal expression of IFN-induced genes (ISG), both type I IFN and IFN-γ cause promoter binding of a complete ISGF3 complex containing STAT1, STAT2 and IRF9. In contrast to the dogmatic view of ISGF3 formation in the cytoplasm, our results suggest a model wherein the assembly of the ISGF3 complex occurs on DNA. 1 Max Perutz Labs (MPL), University of Vienna, Vienna 1030, Austria. 2 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna 1210, Austria. 3 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna 1030, Austria. 4 Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna 1030, Austria. -
Comprehensive Study of Nuclear Receptor DNA Binding Provides a Revised Framework for Understanding Receptor Specificity
ARTICLE https://doi.org/10.1038/s41467-019-10264-3 OPEN Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity Ashley Penvose 1,2,4, Jessica L. Keenan 2,3,4, David Bray2,3, Vijendra Ramlall 1,2 & Trevor Siggers 1,2,3 The type II nuclear receptors (NRs) function as heterodimeric transcription factors with the retinoid X receptor (RXR) to regulate diverse biological processes in response to endogenous 1234567890():,; ligands and therapeutic drugs. DNA-binding specificity has been proposed as a primary mechanism for NR gene regulatory specificity. Here we use protein-binding microarrays (PBMs) to comprehensively analyze the DNA binding of 12 NR:RXRα dimers. We find more promiscuous NR-DNA binding than has been reported, challenging the view that NR binding specificity is defined by half-site spacing. We show that NRs bind DNA using two distinct modes, explaining widespread NR binding to half-sites in vivo. Finally, we show that the current models of NR specificity better reflect binding-site activity rather than binding-site affinity. Our rich dataset and revised NR binding models provide a framework for under- standing NR regulatory specificity and will facilitate more accurate analyses of genomic datasets. 1 Department of Biology, Boston University, Boston, MA 02215, USA. 2 Biological Design Center, Boston University, Boston, MA 02215, USA. 3 Bioinformatics Program, Boston University, Boston, MA 02215, USA. 4These authors contributed equally: Ashley Penvose, Jessica L. Keenan. Correspondence -
IRF5 Gene Interferon Regulatory Factor 5
IRF5 gene interferon regulatory factor 5 Normal Function The protein produced from the IRF5 gene, called interferon regulatory factor 5 (IRF5), acts as a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of certain genes. When a virus is recognized in the cell, the IRF5 gene is turned on (activated), which leads to the production of IRF5 protein. The protein binds to specific regions of DNA that regulate the activity of genes that produce interferons and other cytokines. Cytokines are proteins that help fight infection by promoting inflammation and regulating the activity of immune system cells. In particular, interferons control the activity of genes that help block the replication of viruses, and they stimulate the activity of certain immune system cells known as natural killer cells. Health Conditions Related to Genetic Changes Systemic scleroderma Several normal variations in the IRF5 gene have been associated with an increased risk of developing systemic scleroderma, which is an autoimmune disorder characterized by the buildup of scar tissue (fibrosis) in the skin and internal organs. Although the IRF5 gene is known to stimulate the immune system in response to viruses, it is unknown how the gene variations contribute to the increased risk of systemic scleroderma. Researchers believe that a combination of genetic and environmental factors may play a role in development of the condition. Rheumatoid arthritis MedlinePlus Genetics provides information about Rheumatoid arthritis Systemic lupus erythematosus MedlinePlus Genetics provides information about Systemic lupus erythematosus Ulcerative colitis MedlinePlus Genetics provides information about Ulcerative colitis Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 1 Autoimmune disorders Studies have associated normal variations in the IRF5 gene with an increased risk of several autoimmune disorders. -
Inactivation of Type I IFN Jak-STAT Pathway in EBV Latency
Ning S and Wang L, J Cancer Biol Treat 2016, 3: 009 DOI: 10.24966/CBT-7546/100009 HSOA Journal of Cancer Biology and Treatment Research Article defense system, among which IRF7 is the “master” regulator of type I Inactivation of Type I IFN Interferon (IFN-I) response to pathogenic infection [4]. Robust IFN-I response during infection requires a positive feedback loop between Jak-STAT Pathway in EBV IRF7 and IFN-I [5-6]. Aberrant production of IFN-I, however, is Latency associated with autoimmune disorders and malignancies [7-9]. Thus, tight regulation of IRF7 is important in balancing the appropriate Shunbin Ning and Ling Wang* immune response to clear invading pathogens while preventing Department of Internal Medicine, Center of Excellence for Inflammation, immune-mediated pathogenesis [10]. Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, USA IFNs exert their functions through induction of IFN-Stimulated Genes (ISGs) via Jak-STAT pathways [11-13]. The IFN-I Jak-STAT pathway comprises of IFNAR1/2, Jak1, Tyk2, STAT1/2, and IRF9 [14]. Following IFN-I binding to IFNARs, signaling via protein kinases leads to tyrosine phosphorylation and activation of IFNAR1 Abstract at Y466 [15], Tyk2(Y1054/Y1055) and Jak1(Y1034/Y1035), and then to that Epstein-Barr Virus (EBV) latent infection is associated with a of STAT1(Y701) and STAT2(Y690 and S287) [16]. The phosphorylated variety of lymphomas and carcinomas. Interferon (IFN) Regulatory STAT1/2 then dimerize and associate with IRF9 to form a complex Factors (IRFs) are a family of transcription factors, among which termed interferon-stimulated gene factor 3 (ISGF3). -
Partner-Regulated Interaction of IFN Regulatory Factor 8 with Chromatin Visualized in Live Macrophages
Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages Leopoldo Laricchia-Robbio*, Tomohiko Tamura*, Tatiana Karpova†, Brian L. Sprague†, James G. McNally†, and Keiko Ozato*‡ *Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753; and †Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055 Edited by Laurie H. Glimcher, Harvard School of Public Health, Boston, MA, and approved August 18, 2005 (received for review May 17, 2005) IFN regulatory factor (IRF) 8 is a transcription factor that directs protein–protein interactions on fluorescence recovery have not macrophage differentiation. By fluorescence recovery after pho- been extensively studied. Moreover, many FRAP studies so far tobleaching, we visualized the movement of IRF8-GFP in differen- reported are qualitative, lacking quantitative insight into the tiating macrophages. Recovery data fitted to mathematical models chromatin-binding events. More recent efforts to fit FRAP data revealed two binding states for IRF8. The majority of IRF8 was to mathematical models begin to provide a clearer knowledge on highly mobile and transiently interacted with chromatin, whereas the property of FRAP mobility (16, 17). a small fraction of IRF8 bound to chromatin more stably. IRF8 IRF8, a member of the IFN regulatory factor (IRF) family, is mutants that did not stimulate macrophage differentiation a key factor that guides the development of macrophages (18). showed a faster recovery, revealing little interaction with chro- We previously established an in vitro model system where matin. A macrophage activation signal by IFN-␥͞LPS led to a global IRF8Ϫ/Ϫ myeloid progenitor cells called Tot2 differentiate into slowdown of IRF8 movement, leading to increased chromatin macrophages upon IRF8 introduction (19). -
An Immunoevasive Strategy Through Clinically-Relevant Pan-Cancer Genomic and Transcriptomic Alterations of JAK-STAT Signaling Components
bioRxiv preprint doi: https://doi.org/10.1101/576645; this version posted March 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components Wai Hoong Chang1 and Alvina G. Lai1, 1Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford, OX3 7FZ, United Kingdom Since its discovery almost three decades ago, the Janus ki- Although cytokines are responsible for inflammation in nase (JAK)-signal transducer and activator of transcription cancer, spontaneous eradication of tumors by endoge- (STAT) pathway has paved the road for understanding inflam- nous immune processes rarely occurs. Moreover, the matory and immunity processes related to a wide range of hu- dynamic interaction between tumor cells and host immu- man pathologies including cancer. Several studies have demon- nity shields tumors from immunological ablation, which strated the importance of JAK-STAT pathway components in overall limits the efficacy of immunotherapy in the clinic. regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Focusing on 133 genes involved in Cytokines can be pro- or anti-inflammatory and are inter- JAK-STAT signaling, we found that copy number alterations dependent on each other’s function to maintain immune underpin transcriptional dysregulation that differs within and homeostasis(3). -
Hepatitis C Virus As a Unique Human Model Disease to Define
viruses Review Hepatitis C Virus as a Unique Human Model Disease to Define Differences in the Transcriptional Landscape of T Cells in Acute versus Chronic Infection David Wolski and Georg M. Lauer * Liver Center at the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA * Correspondence: [email protected]; Tel.: +1-617-724-7515 Received: 27 June 2019; Accepted: 23 July 2019; Published: 26 July 2019 Abstract: The hepatitis C virus is unique among chronic viral infections in that an acute outcome with complete viral elimination is observed in a minority of infected patients. This unique feature allows direct comparison of successful immune responses with those that fail in the setting of the same human infection. Here we review how this scenario can be used to achieve better understanding of transcriptional regulation of T-cell differentiation. Specifically, we discuss results from a study comparing transcriptional profiles of hepatitis C virus (HCV)-specific CD8 T-cells during early HCV infection between patients that do and do not control and eliminate HCV. Identification of early gene expression differences in key T-cell differentiation molecules as well as clearly distinct transcriptional networks related to cell metabolism and nucleosomal regulation reveal novel insights into the development of exhausted and memory T-cells. With additional transcriptional studies of HCV-specific CD4 and CD8 T-cells in different stages of infection currently underway, we expect HCV infection to become a valuable model disease to study human immunity to viruses. Keywords: viral hepatitis; hepatitis C virus; T cells; transcriptional regulation; transcription factors; metabolism; nucleosome 1.