Transcriptional and Progesterone Receptor Binding Profiles of the Human
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Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine
Published OnlineFirst September 14, 2016; DOI: 10.1158/2159-8290.CD-16-0263 RESEARCH BRIEF Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition Mary T. Scott 1 , 2 , Koorosh Korfi 1 , 2 , Peter Saffrey 1 , Lisa E.M. Hopcroft 2 , Ross Kinstrie 1 , Francesca Pellicano 2 , Carla Guenther 1 , 2 , Paolo Gallipoli 2 , Michelle Cruz 1 , Karen Dunn 2 , Heather G. Jorgensen 2 , Jennifer E. Cassels 2 , Ashley Hamilton 2 , Andrew Crossan 1 , Amy Sinclair 2 , Tessa L. Holyoake 2 , and David Vetrie 1 ABSTRACT A major obstacle to curing chronic myeloid leukemia (CML) is residual disease main- tained by tyrosine kinase inhibitor (TKI)–persistent leukemic stem cells (LSC). These are BCR–ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensi- tizing them to apoptosis upon treatment with an EZH2-specifi c inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused signifi cant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in signifi cant loss of LSCs compared to TKI alone, in vitro , and in long-term bone marrow murine xenografts. Our fi ndings point to a promising epigenetic-based thera- peutic strategy to more effectively target LSCs in patients with CML receiving TKIs. SIGNIFICANCE: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a signifi cant unmet clinical need. -
Breast Cancer Res 7
Available online http://breast-cancer-research.com/content/7/5/R753 ResearchVol 7 No 5 article Open Access Phosphorylation of estrogen receptor α serine 167 is predictive of response to endocrine therapy and increases postrelapse survival in metastatic breast cancer Hiroko Yamashita1, Mariko Nishio2, Shunzo Kobayashi3, Yoshiaki Ando1, Hiroshi Sugiura1, Zhenhuan Zhang2, Maho Hamaguchi1, Keiko Mita1, Yoshitaka Fujii1 and Hirotaka Iwase2 1Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 2Oncology and Endocrinology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 3Josai Municipal Hospital of Nagoya, Nagoya, Japan Corresponding author: Hiroko Yamashita, [email protected] Received: 29 Jan 2005 Revisions requested: 15 Apr 2005 Revisions received: 12 Jun 2005 Accepted: 28 Jun 2005 Published: 27 Jul 2005 Breast Cancer Research 2005, 7:R753-R764 (DOI 10.1186/bcr1285) This article is online at: http://breast-cancer-research.com/content/7/5/R753 © 2005 Yamashita et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ 2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Introduction Endocrine therapy is the most important treatment Results Phosphorylation of ER-α Ser118, but not Ser167, was option for women with hormone-receptor-positive breast positively associated with overexpression of HER2, and HER2- cancer. The potential mechanisms for endocrine resistance positive tumors showed resistance to endocrine therapy. The involve estrogen receptor (ER)-coregulatory proteins and present study has shown for the first time that phosphorylation crosstalk between ER and other growth factor signaling of ER-α Ser167, but not Ser118, and expression of PRA and networks. -
BCL2L10 Antibody
Efficient Professional Protein and Antibody Platforms BCL2L10 Antibody Basic information: Catalog No.: UMA21342 Source: Mouse Size: 50ul/100ul Clonality: Monoclonal 8A11G12 Concentration: 1mg/ml Isotype: Mouse IgG2a Purification: The antibody was purified by immunogen affinity chromatography. Useful Information: WB:1:500 - 1:2000 Applications: FCM:1:200 - 1:400 ELISA:1:10000 Reactivity: Human Specificity: This antibody recognizes BCL2L10 protein. Purified recombinant fragment of human BCL2L10 (AA: 31-186) expressed Immunogen: in E. Coli. The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activi- ties. The protein encoded by this gene contains conserved BH4, BH1 and BH2 domains. This protein can interact with other members of BCL-2 pro- tein family including BCL2, BCL2L1/BCL-X(L), and BAX. Overexpression of Description: this gene has been shown to suppress cell apoptosis possibly through the prevention of cytochrome C release from the mitochondria, and thus acti- vating caspase-3 activation. The mouse counterpart of this protein is found to interact with Apaf1 and forms a protein complex with Caspase 9, which suggests the involvement of this protein in APAF1 and CASPASE 9 related apoptotic pathway. Uniprot: Q9HD36 BiowMW: 22kDa Buffer: Purified antibody in PBS with 0.05% sodium azide Storage: Store at 4°C short term and -20°C long term. Avoid freeze-thaw cycles. Note: For research use only, not for use in diagnostic procedure. Data: Gene Universal Technology Co. Ltd www.universalbiol.com Tel: 0550-3121009 E-mail: [email protected] Efficient Professional Protein and Antibody Platforms Figure 1:Black line: Control Antigen (100 ng);Purple line: Antigen (10ng); Blue line: Antigen (50 ng); Red line:Antigen (100 ng) Figure 2:Western blot analysis using BCL2L10 mAb against human BCL2L10 (AA: 31-186) re- combinant protein. -
Bcl2l10 Mediates the Proliferation, Invasion and Migration of Ovarian Cancer Cells
INTERNATIONAL JOURNAL OF ONCOLOGY 56: 618-629, 2020 Bcl2l10 mediates the proliferation, invasion and migration of ovarian cancer cells SU-YEON LEE, JINIE KWON, JI HYE WOO, KYEOUNG-HWA KIM and KYUNG-AH LEE Department of Biomedical Sciences, College of Life Sciences, CHA University, Seongnam-si, Gyeonggi-do 13488, Republic of Korea Received July 18, 2019; Accepted December 2, 2019 DOI: 10.3892/ijo.2019.4949 Abstract. Bcl2l10, also known as Diva, Bcl-b and Boo, is a homology (BH) domains (1,3). These proteins are grouped member of the Bcl2 family of proteins, which are involved in into 3 categories: i) Anti-apoptotic proteins, including Bcl-2, signaling pathways that regulate cell apoptosis and autophagy. Bcl-xL, Bcl-w, NR-13, A1 and Mcl-1; ii) multi-domain Previously, it was demonstrated that Bcl2l10 plays a crucial role pro-apoptotic proteins, such as Bax, and Bak; and iii) BH3 in the completion of oocyte meiosis and is a key regulator of domain-only proteins, such as Bad, Bim, Bid and Bik (1,4). Aurora kinase A (Aurka) expression and activity in oocytes. Interactions between pro-apoptotic and anti-apoptotic Bcl-2 Aurka is overexpressed in several types of solid tumors and family proteins play important roles in controlling and has been considered a target of cancer therapy. Based on these promoting apoptosis (1,3). However, Bcl2l10 reportedly previous results, in the present study, the authors aimed to has contradictory functions in different apoptotic cells or investigate the regulatory role of Bcl2l10 in A2780 and SKOV3 tissues and is recognized for its both pro-apoptotic (5-7) and human ovarian cancer cells. -
The Novel Progesterone Receptor
0013-7227/99/$03.00/0 Vol. 140, No. 3 Endocrinology Printed in U.S.A. Copyright © 1999 by The Endocrine Society The Novel Progesterone Receptor Antagonists RTI 3021– 012 and RTI 3021–022 Exhibit Complex Glucocorticoid Receptor Antagonist Activities: Implications for the Development of Dissociated Antiprogestins* B. L. WAGNER†, G. POLLIO, P. GIANGRANDE‡, J. C. WEBSTER, M. BRESLIN, D. E. MAIS, C. E. COOK, W. V. VEDECKIS, J. A. CIDLOWSKI, AND D. P. MCDONNELL Department of Pharmacology and Cancer Biology (B.L.W., G.P., P.G., D.P.M.), Duke University Medical Center, Durham, North Carolina 27710; Molecular Endocrinology Group (J.C.W., J.A.C.), NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709; Department of Biochemistry and Molecular Biology (M.B., W.V.V.), Louisiana State University Medical School, New Orleans, Louisiana 70112; Ligand Pharmaceuticals, Inc. (D.E.M.), San Diego, California 92121; Research Triangle Institute (C.E.C.), Chemistry and Life Sciences, Research Triangle Park, North Carolina 27709 ABSTRACT by agonists for DNA response elements within target gene promoters. We have identified two novel compounds (RTI 3021–012 and RTI Accordingly, we observed that RU486, RTI 3021–012, and RTI 3021– 3021–022) that demonstrate similar affinities for human progeste- 022, when assayed for PR antagonist activity, accomplished both of rone receptor (PR) and display equivalent antiprogestenic activity. As these steps. Thus, all three compounds are “active antagonists” of PR with most antiprogestins, such as RU486, RTI 3021–012, and RTI function. When assayed on GR, however, RU486 alone functioned as 3021–022 also bind to the glucocorticoid receptor (GR) with high an active antagonist. -
Alterations of the Interactome of Bcl-2 Proteins in Breast Cancer at the Transcriptional, Mutational and Structural Level
RESEARCH ARTICLE Alterations of the interactome of Bcl-2 proteins in breast cancer at the transcriptional, mutational and structural level Simon Mathis Kønig1, Vendela Rissler1, Thilde Terkelsen1, Matteo Lambrughi1, 1,2 Elena PapaleoID * 1 Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen, Denmark, a1111111111 2 Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark a1111111111 a1111111111 * [email protected] a1111111111 a1111111111 Abstract Apoptosis is an essential defensive mechanism against tumorigenesis. Proteins of the B- OPEN ACCESS cell lymphoma-2 (Bcl-2) family regulate programmed cell death by the mitochondrial apopto- sis pathway. In response to intracellular stress, the apoptotic balance is governed by inter- Citation: Kønig SM, Rissler V, Terkelsen T, Lambrughi M, Papaleo E (2019) Alterations of the actions of three distinct subgroups of proteins; the activator/sensitizer BH3 (Bcl-2 homology interactome of Bcl-2 proteins in breast cancer at 3)-only proteins, the pro-survival, and the pro-apoptotic executioner proteins. Changes in the transcriptional, mutational and structural level. expression levels, stability, and functional impairment of pro-survival proteins can lead to an PLoS Comput Biol 15(12): e1007485. https://doi. imbalance in tissue homeostasis. Their overexpression or hyperactivation can result in org/10.1371/journal.pcbi.1007485 oncogenic effects. Pro-survival Bcl-2 family members carry out their function by binding the Editor: Igor N. Berezovsky, A�STAR Singapore, BH3 short linear motif of pro-apoptotic proteins in a modular way, creating a complex net- SINGAPORE work of protein-protein interactions. Their dysfunction enables cancer cells to evade cell Received: July 8, 2019 death. -
BCL2L10 Is Frequently Silenced by Promoter Hypermethylation in Gastric Cancer
1701-1708.qxd 23/4/2010 11:02 Ì ™ÂÏ›‰·1701 ONCOLOGY REPORTS 23: 1701-1708, 2010 BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer RINTARO MIKATA1, KENICHI FUKAI1, FUMIO IMAZEKI1, MAKOTO ARAI1, KEIICHI FUJIWARA1, YUTAKA YONEMITSU1, KAIYU ZHANG1, YOSHIHIRO NABEYA2, TAKENORI OCHIAI2 and OSAMU YOKOSUKA1 Departments of 1Medicine and Clinical Oncology, and 2Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo Ward, Chiba 260-8670, Japan Received November 12, 2009; Accepted February 9, 2010 DOI: 10.3892/or_00000814 Abstract. In gastric cancer, several tumor suppressor and Introduction tumor-related genes are silenced by aberrant methylation. Previously, we demonstrated that BCL2L10, which belongs Transcriptional silencing of tumor suppressor genes by to the pro-apoptotic Bcl-2 family, was transcriptionally promoter hypermethylation is a common feature of human repressed by promoter hypermethylation and that its cancer. In gastric cancer, several tumor suppressor and overexpression caused apoptosis and growth inhibition of tumor-related genes, including CDKN2A (p16) (1), RUNX3 gastric cancer cells. In this study, we investigated the (2) and hMLH1 (3), have been reported to be silenced by methylation status of BCL2L10 and its expression in 21 aberrant methylation. Recently, the number of genes known gastric cancer tissues and corresponding non-neoplastic to be inactivated by DNA methylation in gastric cancer, such mucosae along with the methylation status of p16, RUNX3, as genes related to cell cycle control (4), cell proliferation (5) and hMLH1 genes by using methylation specific PCR. and apoptosis (6), have accumulated. We previously In addition, we examined the association between the analyzed the genes induced by the demethylating agent 5- methylation status of each gene and the expression of EZH2, aza-2'-deoxycytidine (DAC) in gastric cancer cell lines using which was associated with DNA methylation of its target a cDNA microarray containing 30,000 genes. -
Nuclear Progesterone Receptor Isoforms and Their Functions in the Female Reproductive Tract
Polish Journal of Veterinary Sciences Vol. 14, No. 1 (2011), 149-158 DOI 10.2478/v10181-011-0024-9 Review Nuclear progesterone receptor isoforms and their functions in the female reproductive tract R. Rękawiecki, M.K. Kowalik, J. Kotwica Institute of Animal Reproduction and Food Research of Polish Academy of Science, Tuwima 10, 10-747 Olsztyn, Poland Abstract Progesterone (P4), which is produced by the corpus luteum (CL), creates proper conditions for the embryo implantation, its development, and ensures proper conditions for the duration of preg- nancy. Besides the non-genomic activity of P4 on target cells, its main physiological effect is caused through genomic action by the progesterone nuclear receptor (PGR). This nuclear progesterone receptor occurs in two specific isoforms, PGRA and PGRB. PGRA isoform acts as an inhibitor of transcriptional action of PGRB. The inactive receptor is connected with chaperone proteins and attachment of P4 causes disconnection of chaperones and unveiling of DNA binding domain (DBD). After receptor dimerization in the cells’ nucleus and interaction with hormone response element (HRE), the receptor coactivators are connected and transcription is initiated. The ratio of these isoforms changes during the estrous cycle and reflects the different levels of P4 effect on the repro- ductive system. Both isoforms, PGRA and PGRB, also show a different response to the P4 receptor antagonist activity. Connection of the antagonist to PGRA can block PGRB, but acting through the PGRB isoform, P4 receptor antagonist may undergo conversion to a strongly receptor agonist. A third isoform, PGRC, has also been revealed. This isoform is the shortest and does not have transcriptional activity. -
Progesterone Receptors
SCUOLA DI DOTTORATO Medicina Sperimentale e Biotecnologie Mediche XXIX Ciclo DIPARTIMENTO Biotecnologie Mediche e Medicina Traslazionale TESI DI DOTTORATO DI RICERCA Effects of 3-ketodesogestrel and all-trans retinoic acid on PHOX2A and PHOX2B expression: a common strategy as new therapeutic perspective in Congenital Central Hypoventilation Syndrome (CCHS) and Neuroblastoma (NB) treatment. settore scientifico disciplinare: Bio/14 NOME DEL DOTTORANDO Debora Belperio NOME E COGNOME DEL TUTOR Prof. Diego Fornasari NOME E COGNOME DEL COORDINATORE DEL DOTTORATO Prof. Massimo Locati A.A. 2016/2017 1 Contents Abbreviations: ............................................................................................................................................... 4 Abstract ......................................................................................................................................................... 5 CHAPTER 1 ..................................................................................................................................... 7 General introduction .................................................................................................................................. 7 1.1 Phox2 proteins in nervous system development .................................................................................... 8 1.2 Phox2b and the brainstem respiratory circuit ...................................................................................... 12 1.3 PHOX2 proteins in normal condition: structure -
Role of BCL2L10 Methylation and TET2 Mutations in Higher Risk Myelodysplastic Syndromes Treated with 5-Azacytidine
Letters to the Editor 1910 4 Department of Biomedical Engineering, Institute for 9 Carter H, Chen S, Isik L, Tyekucheva S, Velculescu VE, Kinzler KW Computational Medicine, Johns Hopkins University, et al. Cancer-specific high-throughput annotation of somatic Baltimore, MD, USA mutations: computational prediction of driver missense mutations. E-mail: [email protected] Cancer Res 2009; 69: 6660–6667. 5These authors contributed equally to this work. 10 Carter H, Samayoa J, Hruban RH, Karchin R. Prioritization of driver mutations in pancreatic cancer using cancer-specific high-throughput annotation of somatic mutations (CHASM). References Cancer biol ther 2010; 10: 582–587. 11 Amit YaG D. Shape quantization and recognition with random 1 Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. trees. Neural Comput 1997; 9: 1545–1588. N Engl J Med 2005; 352: 804–815. 12 Breiman L. Random Forest. Machine Learning 2001; 45: 5–32. 2 Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger 13 Forbes SA, Tang G, Bindal N, Bamford S, Dawson E, Cole C et al. L et al. Genomic aberrations and survival in chronic lymphocytic COSMIC (the Catalogue of Somatic Mutations in Cancer): a leukemia. N Engl J Med 2000; 343: 1910–1916. resource to investigate acquired mutations in human cancer. 3 Brown JR, Levine RL, Thompson C, Basile G, Gilliland DG, Nucleic Acids Res 2010; 38 (Database issue): D652–D657. Freedman AS. Systematic genomic screen for tyrosine kinase 14 Backert S, Gelos M, Kobalz U, Hanski ML, Bohm C, Mann B et al. mutations in CLL. Leukemia 2008; 22: 1966–1969. -
Thirty Years of BCL-2: Translating Cell Death Discoveries Into Novel Cancer
PERSPECTIVES normal physiology and cancer remains TIMELINE unclear, and is beyond the scope of this article (for a review on these topics, see Thirty years of BCL-2: translating REF. 10). This Timeline article focuses on key advances in our understanding of the function of the BCL-2 protein family in cell death discoveries into novel cell death, in the development of cancer, cancer therapies and as targets in cancer therapy. Early studies on apoptosis Alex R. D. Delbridge, Stephanie Grabow, Andreas Strasser and David L. Vaux In their 1972 paper that adopted the word ‘apoptosis’ to describe a physiological Abstract | The ‘hallmarks of cancer’ are generally accepted as a set of genetic and process of cellular suicide, Kerr and epigenetic alterations that a normal cell must accrue to transform into a fully colleagues11 recognized the presence malignant cancer. It follows that therapies designed to counter these alterations of apoptotic cells in tissue sections of miht e effective as anti-cancer strateies ver the past 3 years, research on certain human cancers. Accordingly, the BCL-2-regulated apoptotic pathway has led to the development of they proposed that increasing the rate of apoptosis of neoplastic cells relative to their small-molecule compounds, nown as BH3-mimetics, that ind to pro-survival rate of production could potentially be BCL-2 proteins to directly activate apoptosis of malignant cells. This Timeline therapeutic. However, interest in cell death article focuses on the discovery and study of BCL-2, the wider BCL-2 protein family and its role in cancer languished until the and, specifically, its roles in cancer development and therapy late 1980s, when genetic abnormalities that prevented cell death were directly linked to malignancy in humans. -
Datasheet (Pdf)
Recombinant Human BCL2 Like 10 Protein Datasheet Catalog Number: PR27251 Product Type: Recombinant Protein Source: E. Coli Amino Acid Sequence: MGSSHHHHHH SSGLVPRGSH MGSMVDQLRE RTTMADPLRE RTELLLADYL GYCAREPGTP EPAPSTPEAA VLRSAAARLR QIHRSFFSAY LGYPGNRFEL VALMADSVLS DSPGPTWGRV VTLVTFAGTL LERGPLVTAR WKKWGFQPRL KEQEGDVARD CQRLVALLSS RLMGQHRAWL QAQGGWDGFC HFFRT. Description/Molecular BCL2 Like 10 (BCL2L10) is a member of the BCL-2 protein family. BCL2 family members form hetero Mass: or homodimers and serve as anti or pro-apoptotic regulators which are involved in a wide variety of cellular activities. BCL2L10 includes the conserved BH4, BH1 and BH2 domains. BCL2L10 interacts with other members of BCL2 protein family including BCL2, BCL2L1/BCL-X(L), and BAX. BCL2L10 overexpression suppresses cell apoptosis possibly through the prevention of cytochrome C release from the mitochondria, and consequently activating caspase-3 activation. BCL2L10 Human Recombinant produced in E.Coli is a single, non-glycosylated polypeptide chain containing 195 amino acids (1-172 a.a.) and having a molecular mass of 21.8kDa. BCL2L10 is fused to a 23 amino acid His-tag at N-terminus & purified by proprietary chromatographic techniques. Purity: Greater than 90.0% as determined by: (a) Analysis by SDS-PAGE. Format: BCL2L10 protein solution (0.5mg/ml) containing 20mM Tris-HCl buffer (pH 8.0), 0.15M NaCl, 20% glycerol and 1mM DTT. Storage: Store at 4°C if entire vial will be used within 2-4 weeks. Store, frozen at -20°C for longer periods of time. For long term storage it is recommended to add a carrier protein (0.1% HSA or BSA). Avoid multiple freeze-thaw cycles.