DOCSLIB.ORG

MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-0909 RESEARCH ARTICLE MACROD2 Haploinsuffi ciency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors Anuratha Sakthianandeswaren 1 , 2 , Marie J. Parsons 1 , 3 , Dmitri Mouradov 1 , 2 , Ruth N. MacKinnon 4 , 5 , Bruno Catimel1 , 2 , Sheng Liu 1 , 2 , Michelle Palmieri 1 , 2 , Christopher Love 6 , Robert N. Jorissen 1 , 2 , Shan Li 1 , Lachlan Whitehead1 , 2 , Tracy L. Putoczki 2 , 7 , Adele Preaudet 7 , Cary Tsui 8 , Cameron J. Nowell 9 , Robyn L. Ward10 , Nicholas J. Hawkins 11 , Jayesh Desai 1 , 2 , 12 , Peter Gibbs 1 , 2 , 12 , Matthias Ernst 13 , 14 , Ian Street1 , 2 , 15 , Michael Buchert 13 , 14 , and Oliver M. Sieber 1 , 2 , 3 , 16 ABSTRACT ADP-ribosylation is an important posttranslational protein modifi cation that regu- lates diverse biological processes, controlled by dedicated transferases and hydro- lases. Here, we show that frequent deletions (∼30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage– dependent manner. MACROD2 haploinsuffi ciency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in Apc Min/+ mice and the growth of human colorectal cancer xenografts. MACROD2 dele- tion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploin- suffi cient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution. SIGNIFICANCE: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsuffi ciency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov; 8(8); 988–1005. ©2018 AACR. See related commentary by Jin and Burkard, p. 921. 1 Systems Biology and Personalised Medicine Division, The Walter and Australia. 13 Olivia Newton-John Cancer Research Institute, Olivia Newton- Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. John Cancer & Wellness Centre, Heidelberg, Victoria, Australia. 14 School 2 Department of Medical Biology, The University of Melbourne, Parkville, of Cancer Medicine, LaTrobe University, Heidelberg, Victoria, Australia. Victoria, Australia. 3 Department of Surgery, The University of Melbourne, 15 Cancer Therapeutics Cooperative Research Centre, Parkville, Victoria, Parkville, Victoria, Australia. 4 Victorian Cancer Cytogenetics Service, St Australia. 16 Department of Biochemistry & Molecular Biology, Monash Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia. 5 Department University, Clayton, Victoria, Australia. of Medicine, The University of Melbourne (St Vincent’s Hospital), Fitzroy, Note: Supplementary data for this article are available at Cancer Discovery 6 Victoria, Australia. Department of Pathology, Peter MacCallum Cancer Online (http://cancerdiscovery.aacrjournals.org/). Centre, Parkville, Victoria, Australia. 7 Infl ammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. A. Sakthianandeswaren, M.J. Parsons, and D. Mouradov contributed equally 8 Histology Facility, The Walter and Eliza Hall Institute of Medical Research, to this article. Parkville, Victoria, Australia. 9 Drug Discovery Biology, The Monash Insti- Corresponding Author: Oliver M. Sieber, The Walter and Eliza Hall Institute tute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia. Australia. 10 Offi ce of the Deputy Vice-Chancellor (Research), The Univer- Phone: 613-9345-2885. E-mail: [email protected] 11 sity of Queensland, Brisbane, Queensland, Australia. Faculty of Medicine, doi: 10.1158/2159-8290.CD-17-0909 The University of Queensland, Brisbane, Queensland, Australia. 12 Depart- ment of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, ©2018 American Association for Cancer Research. 988 | CANCER DISCOVERY AUGUST 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-0909 INTRODUCTION establishes and amplifies the DNA-damage signal, recruiting repair factors and activating effector proteins involved in the ADP-ribosylation is a widespread posttranslational pro- DNA-damage response, including master regulators such tein modification at DNA lesions, which is governed by the as ATM, ATR, and DNA-dependent protein kinase (8). PAR activities of specific transferases and hydrolases. This modifi- synthesis is reversed by degradation by poly(ADP-ribose) cation regulates various biological processes, including DNA- glycohydrolase; however, removal of the terminal autoinhibi- damage response, chromatin reorganization, transcriptional tory mono-ADP-ribose from PARP1 to cause reactivation regulation, apoptosis, and mitosis (1–3). Genome-wide DNA requires MACROD2 recruitment and enzymatic activity (7). copy-number analyses across human cancers have revealed MACROD2 phosphorylation by ATM acts as a negative feed- common focal deletions of the MACROD2 mono-ADP- back loop, triggering MACROD2 nuclear export upon DNA ribosylhydrolase locus on chromosome 20p12.1 in multiple damage, thus temporally restricting its recruitment to DNA malignancies, including gastric and colorectal cancers (4, 5). lesions (9). However, the locus is considered a tissue-specific fragile site MACROD2 has further been implicated as a regulator of (6), and whether MACROD2 aberrations contribute to car- glycogen synthase kinase 3-beta (GSK3β), indicating a role in cinogenesis is unknown. the modulation of WNT signaling (10). MACROD2 reverses Recent studies have identified MACROD2 as a regulator PARP10-catalyzed mono-ADP-ribose-mediated inhibition of of PARP1, a principal sensor of DNA single-strand breaks GSK3β, activating GSK3β to phosphorylate β-catenin in the (SSB) and double-strand breaks (DSB; ref. 7). Following context of a protein complex with adenomatous polyposis coli binding to sites of DNA nicks or breaks, PARP1 polymer- (APC), axin, and other components. Phosphorylation targets izes PAR chains onto histones and other proteins, includ- β-catenin for ubiquitination and proteasomal degradation, ing itself. This auto- and substrate-PARylation by PARP1 preventing its translocation to the nucleus and interaction AUGUST 2018 CANCER DISCOVERY | 989 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-0909 RESEARCH ARTICLE Sakthianandeswaren et al. with members of the T-cell factor/lymphoid enhancer factor microdeletions also exhibited aberrant MACROD2 tran- (TCF/LEF) transcription factor family to activate expression scripts lacking one or more exons, indicating pathogenicity of WNT target genes (11). in these cases. In five cell lines with multiple heterozygous These observations raise the possibility that somatic exonic or intronic MACROD2 aberrations, no wild-type tran- genomic aberrations in MACROD2 contribute to cancer devel- script was detected consistent with deletions affecting both opment through impairing the DNA-damage response or alleles. Aberrant transcripts were predicted to result in pre- promoting aberrant WNT signaling. Here, we present genetic, mature MACROD2 protein truncation in 28% (7 of 26) of biochemical, and functional data that reveal MACROD2 as cases, or in-frame exonic deletions involving the catalytic a caretaker tumor suppressor gene essential for the mainte- macrodomain of the protein in 72% (19 of 26) of cases (Sup- nance of cancer genome integrity. plementary Table S4). MACROD2 Somatic Mutation Burden in Human RESULTS Colorectal Cancer Focal Deletions at Chromosome 20p12.1 Target We next examined the contribution of somatic mutations MACROD2 in Human Colorectal Cancer to the burden of MACROD2 aberrations in colorectal cancer. To comprehensively characterize the human cancer types We sequenced all exons of MACROD2 in 102 sporadic colorec- in which the MACROD2 locus is subject to focal deletions tal cancers and 53 colorectal cancer cell lines. Detected vari- at chromosome 20p12.1, we analyzed The Cancer Genome ants were verified to not correspond to known SNPs, and for Atlas (TCGA)–derived DNA copy-number data from 10,575 primary tumors were confirmed to be somatically acquired by tumors representing 32 malignancies using Genomic Iden- sequencing of matched normal tissue. Results were combined tification of Significant Targets in Cancer (GISTIC; ref. with TCGA-derived mutation data for colorectal cancer (n = 12). Colorectal adenocarcinoma (COAD/READ) exhibited 536; Supplementary Table S5). the strongest evidence for recurrent focal DNA copy-num- Somatic MACROD2 mutations were found to be of low ber loss at MACROD2 (q = 5.89E−78), but targeting was prevalence, with 14 missense mutations detected in a total also observed in stomach adenocarcinoma (STAD), cervical of 691 cases. MACROD2 missense mutations were localized squamous cell carcinoma
Load more

Recommended publications
  • Astrin-SKAP Complex Reconstitution Reveals Its Kinetochore
    RESEARCH ARTICLE Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80 David M Kern1,2, Julie K Monda1,2†, Kuan-Chung Su1†, Elizabeth M Wilson-Kubalek3, Iain M Cheeseman1,2* 1Whitehead Institute for Biomedical Research, Cambridge, United States; 2Department of Biology, Massachusetts Institute of Technology, Cambridge, United States; 3Department of Cell Biology, The Scripps Research Institute, La Jolla, United States Abstract Chromosome segregation requires robust interactions between the macromolecular kinetochore structure and dynamic microtubule polymers. A key outstanding question is how kinetochore-microtubule attachments are modulated to ensure that bi-oriented attachments are selectively stabilized and maintained. The Astrin-SKAP complex localizes preferentially to properly bi-oriented sister kinetochores, representing the final outer kinetochore component recruited prior to anaphase onset. Here, we reconstitute the 4-subunit Astrin-SKAP complex, including a novel MYCBP subunit. Our work demonstrates that the Astrin-SKAP complex contains separable kinetochore localization and microtubule binding domains. In addition, through cross-linking analysis in human cells and biochemical reconstitution, we show that the Astrin-SKAP complex binds synergistically to microtubules with the Ndc80 complex to form an integrated interface. We propose a model in which the Astrin-SKAP complex acts together with the Ndc80 complex to stabilize correctly formed kinetochore-microtubule interactions. *For correspondence: DOI: https://doi.org/10.7554/eLife.26866.001 [email protected] †These authors contributed equally to this work Introduction Competing interests: The The macromolecular kinetochore complex links chromosomes to dynamic microtubule polymers and authors declare that no harnesses the forces generated by microtubule growth and depolymerization to facilitate accurate competing interests exist.
    [Show full text]
  • CD56+ T-Cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients
    CD56+ T-cells in Relation to Cytomegalovirus in Healthy Subjects and Kidney Transplant Patients Institute of Infection and Global Health Department of Clinical Infection, Microbiology and Immunology Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Mazen Mohammed Almehmadi December 2014 - 1 - Abstract Human T cells expressing CD56 are capable of tumour cell lysis following activation with interleukin-2 but their role in viral immunity has been less well studied. The work described in this thesis aimed to investigate CD56+ T-cells in relation to cytomegalovirus infection in healthy subjects and kidney transplant patients (KTPs). Proportions of CD56+ T cells were found to be highly significantly increased in healthy cytomegalovirus-seropositive (CMV+) compared to cytomegalovirus-seronegative (CMV-) subjects (8.38% ± 0.33 versus 3.29%± 0.33; P < 0.0001). In donor CMV-/recipient CMV- (D-/R-)- KTPs levels of CD56+ T cells were 1.9% ±0.35 versus 5.42% ±1.01 in D+/R- patients and 5.11% ±0.69 in R+ patients (P 0.0247 and < 0.0001 respectively). CD56+ T cells in both healthy CMV+ subjects and KTPs expressed markers of effector memory- RA T-cells (TEMRA) while in healthy CMV- subjects and D-/R- KTPs the phenotype was predominantly that of naïve T-cells. Other surface markers, CD8, CD4, CD58, CD57, CD94 and NKG2C were expressed by a significantly higher proportion of CD56+ T-cells in healthy CMV+ than CMV- subjects. Functional studies showed levels of pro-inflammatory cytokines IFN-γ and TNF-α, as well as granzyme B and CD107a were significantly higher in CD56+ T-cells from CMV+ than CMV- subjects following stimulation with CMV antigens.
    [Show full text]
  • Produktinformation
    Produktinformation Diagnostik & molekulare Diagnostik Laborgeräte & Service Zellkultur & Verbrauchsmaterial Forschungsprodukte & Biochemikalien Weitere Information auf den folgenden Seiten! See the following pages for more information! Lieferung & Zahlungsart Lieferung: frei Haus Bestellung auf Rechnung SZABO-SCANDIC Lieferung: € 10,- HandelsgmbH & Co KG Erstbestellung Vorauskassa Quellenstraße 110, A-1100 Wien T. +43(0)1 489 3961-0 Zuschläge F. +43(0)1 489 3961-7 [email protected] • Mindermengenzuschlag www.szabo-scandic.com • Trockeneiszuschlag • Gefahrgutzuschlag linkedin.com/company/szaboscandic • Expressversand facebook.com/szaboscandic MYCBP monoclonal antibody (M13), clone 1B12 Catalog # : H00026292-M13 規格 : [ 100 ug ] List All Specification Application Image Product Mouse monoclonal antibody raised against a partial recombinant Western Blot (Transfected lysate) Description: MYCBP. Immunogen: MYCBP (NP_036465.2, 34 a.a. ~ 103 a.a) partial recombinant protein with GST tag. MW of the GST tag alone is 26 KDa. Sequence: LYEEPEKPNSALDFLKHHLGAATPENPEIELLRLELAEMKEKYEAIVEENK KLKAKLAQYEPPQEEKRAE enlarge Host: Mouse Western Blot (Recombinant protein) Reactivity: Human Sandwich ELISA (Recombinant Isotype: IgG2a Kappa protein) Quality Control Antibody Reactive Against Recombinant Protein. Testing: enlarge ELISA Western Blot detection against Immunogen (33.44 KDa) . Storage Buffer: In 1x PBS, pH 7.4 Storage Store at -20°C or lower. Aliquot to avoid repeated freezing and thawing. Instruction: MSDS: Download Datasheet: Download Applications Western Blot (Transfected lysate) Page 1 of 3 2016/5/23 Western Blot analysis of MYCBP expression in transfected 293T cell line by MYCBP monoclonal antibody (M13), clone 1B12. Lane 1: MYCBP transfected lysate(12 KDa). Lane 2: Non-transfected lysate. Protocol Download Western Blot (Recombinant protein) Protocol Download Sandwich ELISA (Recombinant protein) Detection limit for recombinant GST tagged MYCBP is 0.1 ng/ml as a capture antibody.
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Structural Capacitance in Protein Evolution and Human Diseases
    Structural Capacitance in Protein Evolution and Human Diseases Adrian Woolfson, Ashley Buckle, Natalie Borg, Geoffrey Webb, Itamar Kass, Malcolm Buckle, Jiangning Song, Chen Li, Liah Clark, Rory Zhang, et al. To cite this version: Adrian Woolfson, Ashley Buckle, Natalie Borg, Geoffrey Webb, Itamar Kass, et al.. Structural Ca- pacitance in Protein Evolution and Human Diseases. Journal of Molecular Biology, Elsevier, 2018, 10.1016/j.jmb.2018.06.051. hal-02368321 HAL Id: hal-02368321 https://hal.archives-ouvertes.fr/hal-02368321 Submitted on 20 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Structural Capacitance in Protein Evolution and Human Diseases Chen Li, Liah Clark, Rory Zhang, Benjamin Porebski, Julia Mccoey, Natalie Borg, Geoffrey Webb, Itamar Kass, Malcolm Buckle, Jiangning Song, etal. To cite this version: Chen Li, Liah Clark, Rory Zhang, Benjamin Porebski, Julia Mccoey, et al.. Structural Capaci- tance in Protein Evolution and Human Diseases. Journal of Molecular Biology, Elsevier, 2018, 10.1016/j.jmb.2018.06.051. hal-02368321 HAL Id: hal-02368321 https://hal.archives-ouvertes.fr/hal-02368321 Submitted on 20 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not.
    [Show full text]
  • Lncrna LUNAR1 Accelerates Colorectal Cancer Progression by Targeting the Mir‑495‑3P/MYCBP Axis
    INTERNATIONAL JOURNAL OF ONCOLOGY 57: 1157-1168, 2020 lncRNA LUNAR1 accelerates colorectal cancer progression by targeting the miR‑495‑3p/MYCBP axis JIAJIE QIAN1, ALOK GARG2, FUQIANG LI3, QIANYUN SHEN1 and KE XIAO4 1Department of Gastrointestinal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China; 2Department of Surgery, City Hospital Braunschweig, D-38118 Braunschweig, Germany; 3Department of Thyroid Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China; 4Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, D-30625 Hannover, Lower Saxony, Germany Received April 16, 2020; Accepted September 14, 2020 DOI: 10.3892/ijo.2020.5128 Abstract. Colorectal cancer (CRC) is a tumor type and functional research showed that LUNAR1 accelerated characterized by high patient morbidity and mortality. It has CRC progression via the miR-495-3p/MYCBP axis. In been reported that long non-coding (lncRNA) LUNAR1 conclusion, LUNAR1 accelerates CRC progression via the (LUNAR1) participates in the regulation of tumor progression, miR-495-3p/MYCBP axis, indicating that LUNAR1 may such as diffuse large B-cell lymphoma. However, its role and serve as a prognostic biomarker for CRC patients. underlying mechanisms in CRC progression have not been elucidated. The present study was designed to investigate Introduction the underlying mechanisms by which LUNAR1 regulates CRC progression. RT-qPCR and Pearson's correlation Colorectal cancer (CRC) is a tumor type characterized by analysis revealed that LUNAR1 was highly expressed and high patient morbidity and mortality (1). At present, surgery, was negatively associated with the overall survival of CRC radiotherapy and chemotherapy are the primary strategies for patients.
    [Show full text]
  • DNA Damage Sensitization of Breast Cancer Cells with PARP10/ARTD10 Inhibitor Mikko Hukkanen
    Pro gradu DNA damage sensitization of breast cancer cells with PARP10/ARTD10 inhibitor Mikko Hukkanen University of Oulu Faculty of Biochemistry and Molecular Medicine 2019 This thesis was completed at the Faculty of Biochemistry and Molecular Medicine, University of Oulu. Oulu, Finland Supervisors: Professor Lari Lehtiö, Dr. Jarkko Koivunen and MSc Sudarshan Murthy Acknowledgements The work of this thesis was made in Faculty of Biochemistry and Molecular Medicine (FBMM) of University of Oulu. Firstly, I would like to thank Professor Lari Lehtiö for the opportunity working in his group, and the advice I received for my thesis. My gratitude is expressed also to my other supervisors, Jarkko Koivunen, for all the guidance I received in the cell culture, and Sudarshan Murthy, for the guidance to express and purify protein, and to conclude IC50 analysis. I would also thank all the personnel in LL group for all the advice I received in laboratory. I would especially thank Sven Sowa who made the Mantis run for IC50 analysis possible. Abbreviations 5-FU – 5-fluorouracil aa – Aminoacid ADP – Adenosine diphosphate ADPr – ADP-ribosylation AEC – Anion-exchange chromatography AIF – Apoptosis inducing factor AIM – Auto-induction medium Arg – Arginine ART – ADP-ribosyltransferase ARTD – Diphtheria toxin –like ADP-ribosyltransferase Asp – Aspartate BRCA – Breast cancer gene BRCT – BRCA1 C terminus CPT – Camptothecin CRC – Colorectal cancer CRM1 – Chromosome region maintenance 1 Cys – Cysteine DDR – DNA damage response dH2O – Distilled water DMEM – Dulbecco’s
    [Show full text]
  • Novel Gene Discovery in Primary Ciliary Dyskinesia
    Novel Gene Discovery in Primary Ciliary Dyskinesia Mahmoud Raafat Fassad Genetics and Genomic Medicine Programme Great Ormond Street Institute of Child Health University College London A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy University College London 1 Declaration I, Mahmoud Raafat Fassad, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Primary Ciliary Dyskinesia (PCD) is one of the ‘ciliopathies’, genetic disorders affecting either cilia structure or function. PCD is a rare recessive disease caused by defective motile cilia. Affected individuals manifest with neonatal respiratory distress, chronic wet cough, upper respiratory tract problems, progressive lung disease resulting in bronchiectasis, laterality problems including heart defects and adult infertility. Early diagnosis and management are essential for better respiratory disease prognosis. PCD is a highly genetically heterogeneous disorder with causal mutations identified in 36 genes that account for the disease in about 70% of PCD cases, suggesting that additional genes remain to be discovered. Targeted next generation sequencing was used for genetic screening of a cohort of patients with confirmed or suggestive PCD diagnosis. The use of multi-gene panel sequencing yielded a high diagnostic output (> 70%) with mutations identified in known PCD genes. Over half of these mutations were novel alleles, expanding the mutation spectrum in PCD genes. The inclusion of patients from various ethnic backgrounds revealed a striking impact of ethnicity on the composition of disease alleles uncovering a significant genetic stratification of PCD in different populations.
    [Show full text]
  • ALK Is a Critical Regulator of the MYC-Signaling Axis in ALK Positive Lung Cancer
    Henry Ford Health System Henry Ford Health System Scholarly Commons Hematology Oncology Articles Hematology-Oncology 2-6-2018 ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer Amanda B. Pilling Henry Ford Health System, [email protected] Jihye Kim Adriana Estrada-Bernal Qiong Zhou Anh T. Le See next page for additional authors Follow this and additional works at: https://scholarlycommons.henryford.com/ hematologyoncology_articles Recommended Citation Pilling AB, Kim J, Estrada-Bernal A, Zhou Q, Le AT, Singleton KR, Heasley LE, Tan AC, DeGregori J, and Doebele RC. ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. Oncotarget 2018; 9(10):8823-8835. This Article is brought to you for free and open access by the Hematology-Oncology at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Hematology Oncology Articles by an authorized administrator of Henry Ford Health System Scholarly Commons. Authors Amanda B. Pilling, Jihye Kim, Adriana Estrada-Bernal, Qiong Zhou, Anh T. Le, Katherine R. Singleton, Lynn E. Heasley, Aik C. Tan, James DeGregori, and Robert C. Doebele This article is available at Henry Ford Health System Scholarly Commons: https://scholarlycommons.henryford.com/ hematologyoncology_articles/14 www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 10), pp: 8823-8835 Priority Research Paper ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer Amanda B. Pilling1,2, Jihye Kim1, Adriana Estrada-Bernal1, Qiong Zhou1, Anh T. Le1, Katherine R. Singleton1, Lynn E. Heasley1, Aik Choon Tan1, James DeGregori1 and Robert C.
    [Show full text]
  • Differential Expression of Skin Cancer and Hair-Follicle Cycle Regulated Genes in Tumor Susceptible K14-Agouti Mice
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 8-2006 Differential Expression of Skin Cancer and Hair-Follicle Cycle Regulated Genes in Tumor Susceptible K14-Agouti Mice Yesim Aydin Son University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Son, Yesim Aydin, "Differential Expression of Skin Cancer and Hair-Follicle Cycle Regulated Genes in Tumor Susceptible K14-Agouti Mice. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1636 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yesim Aydin Son entitled "Differential Expression of Skin Cancer and Hair-Follicle Cycle Regulated Genes in Tumor Susceptible K14-Agouti Mice." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Life Sciences. Edward J. Michaud, Major Professor We have read this dissertation and recommend its acceptance: Cymbeline T. Culiat, Mitchel
    [Show full text]
  • Downloaded Per Proteome Cohort Via the Web- Site Links of Table 1, Also Providing Information on the Deposited Spectral Datasets
    www.nature.com/scientificreports OPEN Assessment of a complete and classifed platelet proteome from genome‑wide transcripts of human platelets and megakaryocytes covering platelet functions Jingnan Huang1,2*, Frauke Swieringa1,2,9, Fiorella A. Solari2,9, Isabella Provenzale1, Luigi Grassi3, Ilaria De Simone1, Constance C. F. M. J. Baaten1,4, Rachel Cavill5, Albert Sickmann2,6,7,9, Mattia Frontini3,8,9 & Johan W. M. Heemskerk1,9* Novel platelet and megakaryocyte transcriptome analysis allows prediction of the full or theoretical proteome of a representative human platelet. Here, we integrated the established platelet proteomes from six cohorts of healthy subjects, encompassing 5.2 k proteins, with two novel genome‑wide transcriptomes (57.8 k mRNAs). For 14.8 k protein‑coding transcripts, we assigned the proteins to 21 UniProt‑based classes, based on their preferential intracellular localization and presumed function. This classifed transcriptome‑proteome profle of platelets revealed: (i) Absence of 37.2 k genome‑ wide transcripts. (ii) High quantitative similarity of platelet and megakaryocyte transcriptomes (R = 0.75) for 14.8 k protein‑coding genes, but not for 3.8 k RNA genes or 1.9 k pseudogenes (R = 0.43–0.54), suggesting redistribution of mRNAs upon platelet shedding from megakaryocytes. (iii) Copy numbers of 3.5 k proteins that were restricted in size by the corresponding transcript levels (iv) Near complete coverage of identifed proteins in the relevant transcriptome (log2fpkm > 0.20) except for plasma‑derived secretory proteins, pointing to adhesion and uptake of such proteins. (v) Underrepresentation in the identifed proteome of nuclear‑related, membrane and signaling proteins, as well proteins with low‑level transcripts.
    [Show full text]
  • Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase
    BASIC RESEARCH www.jasn.org Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase † ‡ Yifei Zhong,* Edward Y. Chen, § Ruijie Liu,*¶ Peter Y. Chuang,* Sandeep K. Mallipattu,* ‡ ‡ † | ‡ Christopher M. Tan, § Neil R. Clark, § Yueyi Deng, Paul E. Klotman, Avi Ma’ayan, § and ‡ John Cijiang He* ¶ *Department of Medicine, Mount Sinai School of Medicine, New York, New York; †Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; ‡Department of Pharmacology and Systems Therapeutics and §Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York; |Baylor College of Medicine, Houston, Texas; and ¶Renal Section, James J. Peters Veterans Affairs Medical Center, New York, New York ABSTRACT The Connectivity Map database contains microarray signatures of gene expression derived from approximately 6000 experiments that examined the effects of approximately 1300 single drugs on several human cancer cell lines. We used these data to prioritize pairs of drugs expected to reverse the changes in gene expression observed in the kidneys of a mouse model of HIV-associated nephropathy (Tg26 mice). We predicted that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a histone deacetylase inhibitor would maximally reverse the disease-associated expression of genes in the kidneys of these mice. Testing the combination of these inhibitors in Tg26 mice revealed an additive renoprotective effect, as suggested by reduction of proteinuria, improvement of renal function, and attenuation of kidney injury. Furthermore, we observed the predicted treatment-associated changes in the expression of selected genes and pathway components. In summary, these data suggest that the combination of an ACE inhibitor and a histone deacetylase inhibitor could have therapeutic potential for various kidney diseases.
    [Show full text]