The Function of BARD1 in Centrosome Regulation in Cooperation with BRCA1/OLA1/RACK1
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Parameter IV Dose (1 Mg/Kg) Oral Dose (10 Mg/Kg)
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations Katharine Yen, Jeremy Travins, Fang Wang, Muriel D. David, Erin Artin, Kimberly Straley, Anil Padyana, Stefan Gross, Byron DeLaBarre, Erica Tobin, Yue Chen, Raj Nagaraja, Sung Choe, Lei Jin, Zenon Konteatis, Giovanni Cianchetta, Jeffrey O. Saunders, Francesco G. Salituro, Cyril Quivoron, Paule Opolon, Olivia Bawa, Véronique Saada, Angélo Paci, Sophie Broutin, Olivier Bernard, Stéphane de Botton, Benoît S. Marteyn, Monika Pilichowska, YingXia Xu, Cheng Fang, Fan Jiang, Wentao Wei, Shengfang Jin, Lee Silverman, Wei Liu, Hua Yang, Lenny Dang, Marion Dorsch, Virginie Penard-Lacronique, Scott A. Biller, Shin-San Michael Su SUPPLEMENTARY TABLES Supplementary Table 1. Drug metabolism and pharmacokinetic attributes of AG-221 Parameter IV dose (1 mg/kg) Oral dose (10 mg/kg) CL (l/h/kg) 0.83 ± 0.10 NA Vss (l/kg) 5.5 ± 1.6 NA AUC (h.ng/ml) 1,200 ± 130 5,000 ± 610 t1/2 (h) 5.4 ± 1.8 5.4 ± 1.2 F (%) NA 41 ± 5.0 IV and oral pharmacokinetic parameters of AG-221 in male Sprague-Dawley rats (mean ± s.d., n = 3). AUC, area under plasma concentration curve; CL, clearance; F, absolute oral bioavailability; IV, intravenous; NA, not applicable; t1/2, terminal half-life; Vss, volume of distribution at steady state. Page 1 of 12 Supplementary Table 2. Selectivity of AG-221 confirmed by testing against a panel of kinases Enzyme IC50 of AG-221 IC50 of reference Reference (nM) (nM) P13K >10,000 9.1 PI 103 JNK2 >10,000 5741.2 Staurosporine AKT1 >10,000 9.8 Staurosporine -
Loss of BCL-3 Sensitises Colorectal Cancer Cells to DNA Damage, Revealing A
bioRxiv preprint doi: https://doi.org/10.1101/2021.08.03.454995; this version posted August 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title: Loss of BCL-3 sensitises colorectal cancer cells to DNA damage, revealing a role for BCL-3 in double strand break repair by homologous recombination Authors: Christopher Parker*1, Adam C Chambers*1, Dustin Flanagan2, Tracey J Collard1, Greg Ngo3, Duncan M Baird3, Penny Timms1, Rhys G Morgan4, Owen Sansom2 and Ann C Williams1. *Joint first authors. Author affiliations: 1. Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University Walk, University of Bristol, Bristol, BS8 1TD, UK 2. Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden Glasgow, G61 1BD UK 3. Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN UK 4. School of Life Sciences, University of Sussex, Sussex House, Falmer, Brighton, BN1 9RH UK 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.03.454995; this version posted August 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract (250 words) Objective: The proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC) and increased expression of the gene correlates with poor patient prognosis. The aim is to investigate whether inhibiting BCL-3 can increase the response to DNA damage in CRC. -
Identification and Characterization of Missense Alterations in the BRCA1
633 ORIGINAL ARTICLE Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer M K Sauer, I L Andrulis ............................................................................................................................... J Med Genet 2005;42:633–638. doi: 10.1136/jmg.2004.030049 Background: BRCA1 associated RING domain protein (BARD1) was originally identified due to its interaction with the RING domain of BRCA1. BARD1 is required for S phase progression, contact inhibition and normal nuclear division, as well as for BRCA1 independent, p53 dependent apoptosis. See end of article for Methods: To investigate whether alterations in BARD1 are involved in human breast and ovarian cancer, authors’ affiliations ....................... we used single strand conformation polymorphism analysis and sequencing on 35 breast tumours and cancer cell lines and on 21 ovarian tumours. Correspondence to: Results: Along with the G2355C (S761N) missense mutation previously identified in a uterine cancer, we Dr M K Sauer, Samuel Lunenfeld Research found two other variants in breast cancers, T2006C (C645R) and A2286G (I738V). The T2006C (C645R) Institute, Mount Sinai mutation was also found in one ovarian tumour. A variant of uncertain consequence, G1743C (C557S), Hospital, 600 University was found to be homozygous or hemizygous in an ovarian tumour. Eleven variants of BARD1 were Ave, Toronto, Ontario, M5G 1X5, Canada; characterised with respect to known functions of BARD1. None of the variants appears to affect [email protected] localisation or interaction with BRCA1; however, putative disease associated alleles appear to affect the stability of p53. These same mutations also appear to abrogate the growth suppressive and apoptotic Received activities of BARD1. -
NPM1-ALK (Human) Recombinant Gene Summary: the 2;5 Chromosomal Translocation Is Protein Frequently Associated with Anaplastic Large Cell Lymphomas (Alcls)
NPM1-ALK (Human) Recombinant Gene Summary: The 2;5 chromosomal translocation is Protein frequently associated with anaplastic large cell lymphomas (ALCLs). The translocation creates a fusion Catalog Number: P5782 gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' Regulation Status: For research use only (RUO) half of ALK, derived from chromosome 2, is fused to the 5' portion of NPM from chromosome 5. A recent study Product Description: Human NPM1-ALK (BAA08343.1, shows that the product of the NPM-ALK fusion gene is 1 a.a. - 680 a.a.) partial recombinant protein with GST oncogenic. The deduced amino acid sequences reveal tag expressed in Baculovirus infected Sf21 cells. that ALK is a novel receptor protein-tyrosine kinase having a putative transmembrane domain and an Host: Insect extracellular domain. These sequences are absent in the product of the transforming NPM-ALK gene. ALK shows Theoretical MW (kDa): 103 the greatest sequence similarity to LTK (leukocyte tyrosine kinase). ALK plays an important role in the Applications: Func, SDS-PAGE development of the brain and exerts its effects on (See our web site product page for detailed applications specific neurons in the nervous system. [provided by information) RefSeq] Protocols: See our web site at http://www.abnova.com/support/protocols.asp or product page for detailed protocols Form: Liquid Preparation Method: Baculovirus infected insect cell (Sf21) expression system Purification: Glutathione sepharose chromatography Purity: 81 % by SDS-PAGE/CBB staining Activity: The activity was measured by off-chip mobility shift assay. The enzyme was incubated with fluorescence-labeled substrate and Mg (or Mn)/ATP. -
Functional Characterization of Full-Length BARD1 Strengthens Its
Journal of Cancer 2020, Vol. 11 1495 Ivyspring International Publisher Journal of Cancer 2020; 11(6): 1495-1504. doi: 10.7150/jca.36164 Research Paper Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma Flora Cimmino1,2, Marianna Avitabile1,2, Vito Alessandro Lasorsa1,2, Lucia Pezone1, Antonella Cardinale1, Annalaura Montella2, Sueva Cantalupo3, Achille Iolascon1,2, Mario Capasso1,2,3 1. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, Naples, Italy 2. CEINGE Biotecnologie Avanzate, Naples, Italy 3. IRCCS SDN, Naples, Italy Corresponding author: Flora Cimmino, phD, University of Naples Federico II, Department of Molecular Medicine and Medical Biotechnology, CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore, 486, 80145 Napoli Italy. Lab: +39 0813737736; Fax: +39 0813737804; Email: [email protected] © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2019.04.29; Accepted: 2019.11.12; Published: 2020.01.14 Abstract BARD1 is associated with the development of high-risk neuroblastoma patients. Particularly, the expression of full length (FL) isoform, FL BARD1, correlates to high-risk neuroblastoma development and its inhibition is sufficient to induce neuroblastoma cells towards a worst phenotype. Here we have investigated the mechanisms of FL BARD1 in neuroblastoma cell lines depleted for FL BARD1 expression. We have shown that FL BARD1 expression protects the cells from spontaneous DNA damage and from damage accumulated after irradiation. We demonstrated a role for FL BARD1 as tumor suppressor to prevent unscheduled mitotic entry of DNA damaged cells and to lead to death cells that have bypassed cell cycle checkpoints. -
Increased Expression of NPM1 Suppresses P27kip1 Function in Cancer Cells
cancers Article Increased Expression of NPM1 Suppresses p27Kip1 Function in Cancer Cells Tatsuya Kometani, Takuya Arai and Taku Chibazakura * Department of Bioscience, Tokyo University of Agriculture 1-1-1, Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan; [email protected] (T.K.); [email protected] (T.A.) * Correspondence: [email protected] Received: 4 August 2020; Accepted: 5 October 2020; Published: 8 October 2020 Simple Summary: Cancer malignancy frequently correlates with a low expression of p27Kip1, a major cyclin-dependent kinase inhibitor, and the p27 protein level has been reportedly responsible for its antiproliferative function. However, we found the function of overexpressed p27 is suppressed in some cancer cells, suggesting that p27 function is also regulated independently of its protein level. The aim of this study was to clarify this unknown p27 regulatory mechanism and its impact on cancer proliferation. We isolated nucleophosmin isoform 1 (NPM1), which is highly expressed in variety of cancers, as a novel p27-interacting protein. Overexpressing NPM1 in normal cells suppressed and silencing NPM1 in cancer cells rescued the p27 function, respectively, in vitro. Moreover, NPM1 silencing and p27 induction in cancer cells significantly suppressed their proliferation in mouse xenografts. Our findings reveal that NPM1 is a novel p27 functional suppressor and a potential anti-cancer target, especially in cancers with normal p27 expression. Abstract: p27Kip1, a major cyclin-dependent kinase inhibitor, is frequently expressed at low levels in cancers, which correlates with their malignancy. However, in this study, we found a qualitative suppression of p27 overexpressed in some cancer cells. By proteomic screening for factors interacting with p27, we identified nucleophosmin isoform 1 (NPM1) as a novel p27-interacting factor and observed that NPM1 protein was expressed at high levels in some cancer cells. -
Centrosome Positioning in Vertebrate Development
Commentary 4951 Centrosome positioning in vertebrate development Nan Tang1,2,*,` and Wallace F. Marshall2,` 1Department of Anatomy, Cardiovascular Research Institute, The University of California, San Francisco, USA 2Department Biochemistry and Biophysics, The University of California, San Francisco, USA *Present address: National Institute of Biological Science, Beijing, China `Authors for correspondence ([email protected]; [email protected]) Journal of Cell Science 125, 4951–4961 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.038083 Summary The centrosome, a major organizer of microtubules, has important functions in regulating cell shape, polarity, cilia formation and intracellular transport as well as the position of cellular structures, including the mitotic spindle. By means of these activities, centrosomes have important roles during animal development by regulating polarized cell behaviors, such as cell migration or neurite outgrowth, as well as mitotic spindle orientation. In recent years, the pace of discovery regarding the structure and composition of centrosomes has continuously accelerated. At the same time, functional studies have revealed the importance of centrosomes in controlling both morphogenesis and cell fate decision during tissue and organ development. Here, we review examples of centrosome and centriole positioning with a particular emphasis on vertebrate developmental systems, and discuss the roles of centrosome positioning, the cues that determine positioning and the mechanisms by which centrosomes respond to these cues. The studies reviewed here suggest that centrosome functions extend to the development of tissues and organs in vertebrates. Key words: Centrosome, Development, Mitotic spindle orientation Introduction radiating out to the cell cortex (Fig. 2A). In some cases, the The centrosome of animal cells (Fig. -
Centrosome Impairment Causes DNA Replication Stress Through MLK3
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.09.898684; this version posted January 10, 2020. 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 4.0 International license. Centrosome impairment causes DNA replication stress through MLK3/MK2 signaling and R-loop formation Zainab Tayeh 1, Kim Stegmann 1, Antonia Kleeberg 1, Mascha Friedrich 1, Josephine Ann Mun Yee Choo 1, Bernd Wollnik 2, and Matthias Dobbelstein 1* 1) Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany 2) Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany *Lead Contact. Correspondence and requests for materials should be addressed to M. D. (e-mail: [email protected]; ORCID 0000-0001-5052-3967) Running title: Centrosome integrity supports DNA replication Key words: Centrosome, CEP152, CCP110, SASS6, CEP152, Polo-like kinase 4 (PLK4), DNA replication, DNA fiber assays, R-loops, MLK3, MK2 alias MAPKAPK2, Seckel syndrome, microcephaly. Highlights: • Centrosome defects cause replication stress independent of mitosis. • MLK3, p38 and MK2 (alias MAPKAPK2) are signalling between centrosome defects and DNA replication stress through R-loop formation. • Patient-derived cells with defective centrosomes display replication stress, whereas inhibition of MK2 restores their DNA replication fork progression and proliferation. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.01.09.898684; this version posted January 10, 2020. 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. -
Core Transcription Factors, Oct4, Sox2 and Nanog, Individually Form Complexes with Nucleophosmin (Npm1) to Control Embryonic Stem
www.impactaging.com AGING, November 2010, Vol 2 N 11 Research Paper Core transcription factors, Oct4, Sox2 and Nanog, individually form complexes with nucleophosmin (Npm1) to control embryonic stem (ES) cell fate determination Helena Johansson and Stina Simonsson Department of Medical Biochemistry and Cell Biology; Institute of Biomedicine; University of Gothenburg, box 440, 405 30 Gothenburg, Västra Götaland; Sweden Key words: Npm1, Oct4, Sox2, Nanog, ES cells, Tpt1 Received: 10/25/10; accepted: 11/10/10; published on line: 11/12/10 Corresponding author: Stina Simonsson, PhD; E‐mail: [email protected] Copyright: © Johansson and Simonsson. This is an open‐access article distributed under the terms of the Creative Commons A ttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Abstract: Embryonic stem (ES) cells have therapeutic potential in regenerative medicine, although the molecular mechanism controlling their pluripotency is not completely understood. Depending on interaction partners most proteins can be involved in several different cellular mechanisms. We screened for novel protein‐protein interactions using in situ proximity ligation assays together with specific antibodies directed against known important ES cell proteins. We found that all three core transcription factors, namely Oct4, Sox2 and Nanog, individually formed complexes with nucleophosmin (Npm1). We showed that the Npm1/Sox2 complex was sustained when cells were induced to differentiate by retinoic acid, while decreased in the other differentiation pathways. Moreover, Oct4 also formed individual complexes with translationally controlled tumor protein (Tpt1). Downregulation of Npm1 or Tpt1 increased mRNA levels for genes involved in mesoderm and ectoderm differentiation pathways, respectively, indicative of their involvement in ES cell maintenance. -
Next Generation Gene Sequencing -Solid Tumor
Cancer‐related Mutaon Analysis Next Generaon Gene Sequencing for Solid Tumors Assay Summary IU Health Molecular Pathology Laboratory now offers high throughput sequencing for hot spot mutations found in clinically relevant cancer genes. In addition to a general panel of 48 genes, selected panels have been developed for a more tailored application in specific cancers. Comparing to single gene assay, these panels offer a more comprehensive and economic way to assess prognosis and/or treatment options for cancer patients at the initial diagnosis or at the relapse. Orderable Name: Use IU Health Molecular Pathology requisition; Call 317.491.6417 for requisition. Panels include: Lung cancer panel AKT1, ALK, BRAF, EGFR, KRAS, MET, NRAS, PIK3CA, PTEN Colon cancer panel APC, AKT1, BRAF, KRAS, NRAS, PIK3CA, PTEN, SMAD4 Gastrointestinal stromal tumor (GIST) panel BRAF, KIT, PDGFRA Melanoma panel BRAF, CTNNB1, GNA11, GNAQ, KIT, NRAS Ovarian cancer panel BRAF, KRAS, PIK3CA, PTEN Thyroid cancer panel KIT, BRAF, RET Breast cancer panel AKT1, ERBB2, PIK3CA Oncology sequencing panel ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53, VHL Clinical Utility: This test is useful for the assessment of prognosis and/or treatment options for individuals with cancers at initial diagnosis or at replase1. Clinical Information: The Oncology Sequencing Solid Tumor Panel is a highly multiplexed targeted resequencing assay for detecting somatic mutations across hundreds of mutational hotspots in cancer genomes. -
BRCA1–BARD1 Regulates Axon Regeneration in Concert with the Gqα–DAG Signaling Network
Research Articles: Cellular/Molecular BRCA1–BARD1 regulates axon regeneration in concert with the Gqα–DAG signaling network https://doi.org/10.1523/JNEUROSCI.1806-20.2021 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.1806-20.2021 Received: 13 July 2020 Revised: 20 January 2021 Accepted: 5 February 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Sakai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Sakai et al., 1 1 BRCA1–BARD1 regulates axon regeneration in 2 concert with the GqD–DAG signaling network 3 4 Abbreviated Title: BRCA1–BARD1 regulates axon regeneration 5 6 Yoshiki Sakai, Hiroshi Hanafusa, Tatsuhiro Shimizu, Strahil Iv. 7 Pastuhov, Naoki Hisamoto, and Kunihiro Matsumoto 8 9 Division of Biological Science, Graduate School of Science, Nagoya University, 10 Chikusa-ku, Nagoya 464-8602, Japan 11 12 To whom correspondence should be addressed: 13 Kunihiro Matsumoto and Naoki Hisamoto 14 Division of Biological Science, Graduate School of Science, 15 Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. 16 E-mail address: [email protected] (K. -
BARD1 in Cell Life and Death
Role of BARD1 in cell life and death Irmgard Irminger-Finger Biology of Aging Laboratory Department of Geriatrics University of Geneva Switzerland Age is the biggest risk factor for cancer DePinho, 2000 Cancer Risks for Men prostate From1950 1990 Cancer Risks for Women breast From1950 1990 Cancers of old age are different from young age cancers Cancer in old age has a different face than cancer in young age BCC Basal cell carcinoma SCC Squamous cell carcinoma DePinho, 2000 What could link epithelial cell derived cancers to aging? BARD1, not just another cancer predisposition gene Common pathways for cancer and aging? Accumulation of damage DNA damage DNA damage proliferation- DNA damage arrest repair senescence proliferation cancer elimination apoptosis Cellular aging BARD1 Summary • BARD1 structure • BARD1 repression studies • BARD1 overexpression studies • BARD1 dynamic localization • BARD1 induced upon stress • Non-correlated expression of BARD1 and BRCA1 • Role in spermatogenesis • BARD1 upregulation upon stress • Role in tumorigenesis • BARD1 a tumor antigen • BARD1 in cancer vaccine and genetherapy Conserved structures in BARD1 and BRCA1 Q>H RING ANK BRCT BARD1 66 95 53 97 77 91 conservation RING BRCT BRCA1 C>G No one like BARD1 RING ANK BRCT BARD1 BRCA1 Arabidopsis 2 hypoth.p. Arabidopsis CAC05430 C. elegans 3 hypoth. p. C. elegans 6 hypoth. p. C. elegans T15564 C. elegans T15566 Xenopus BARD1 Joukov, Livingston, PNAS, 2001 BRCA1 BARD1- BRCA1 heterodimer Rad51 PCNA ? RNA-Pol II p53 BAP1 Nuclear localization BACH1 RHA signals Granin BRCA2 motif BARD1 interaction Ankyrin repeats BRCT BRCA1 domain interaction Ubiquitin-ligase Polyadenylation activity A B C D BARD1 BRCA1 BARD1 BRCA1 BARD1 Bcl-3 Pol II/Holo CstF-50 NF-kB Replication? S-phase dots Transcription: mRNA Regulation of Pol II/Holo Interaction Processing? transcription? [Scully et al.