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Isyte: Integrated Systems Tool for Eye Gene Discovery
Lens iSyTE: Integrated Systems Tool for Eye Gene Discovery Salil A. Lachke,1,2,3,4 Joshua W. K. Ho,1,4,5 Gregory V. Kryukov,1,4,6 Daniel J. O’Connell,1 Anton Aboukhalil,1,7 Martha L. Bulyk,1,8,9 Peter J. Park,1,5,10 and Richard L. Maas1 PURPOSE. To facilitate the identification of genes associated ther investigation. Extension of this approach to other ocular with cataract and other ocular defects, the authors developed tissue components will facilitate eye disease gene discovery. and validated a computational tool termed iSyTE (integrated (Invest Ophthalmol Vis Sci. 2012;53:1617–1627) DOI: Systems Tool for Eye gene discovery; http://bioinformatics. 10.1167/iovs.11-8839 udel.edu/Research/iSyTE). iSyTE uses a mouse embryonic lens gene expression data set as a bioinformatics filter to select candidate genes from human or mouse genomic regions impli- ven with the advent of high-throughput sequencing, the cated in disease and to prioritize them for further mutational Ediscovery of genes associated with congenital birth defects and functional analyses. such as eye defects remains a challenge. We sought to develop METHODS. Microarray gene expression profiles were obtained a straightforward experimental approach that could facilitate for microdissected embryonic mouse lens at three key devel- the identification of candidate genes for developmental disor- opmental time points in the transition from the embryonic day ders, and, as proof-of-principle, we chose defects involving the (E)10.5 stage of lens placode invagination to E12.5 lens primary ocular lens. Opacification of the lens results in cataract, a leading cause of blindness that affects 77 million persons and fiber cell differentiation. -
Prevalence and Functional Analysis of Sequence Variants in the ATR Checkpoint Mediator Claspin
Published OnlineFirst September 8, 2009; DOI: 10.1158/1541-7786.MCR-09-0033 Prevalence and Functional Analysis of Sequence Variants in the ATR Checkpoint Mediator Claspin Jianmin Zhang,1 Young-Han Song,1 Brian W. Brannigan,1 Doke C.R. Wahrer,1 Taryn A. Schiripo,1 Patricia L. Harris,1 Sara M. Haserlat,1 Lindsey E. Ulkus,1 Kristen M. Shannon,1 Judy E. Garber,2 Matthew L. Freedman,3 Brian E. Henderson,4 Lee Zou,1 Dennis C. Sgroi,1 Daniel A. Haber,1 and Daphne W. Bell1 1Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts; 2Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; 3Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, and Broad Institute for Biomedical Research, Boston, Massachusetts; and 4Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California Abstract mutation, was defective in its ability to mediate CHK1 Mutational inactivation of genes controlling the phosphorylation followingDNA damageand was unable to DNA-damage response contributes to cancer susceptibility rescue sensitivity to replicative stress in CLSPN-depleted within families and within the general population as well as cells. Taken together, these observations raise the to sporadic tumorigenesis. Claspin (CLSPN) encodes a possibility that CLSPN may encode a component of the recently recognized mediator protein essential for the ATR DNA-damage response pathway that is targeted by and CHK1-dependent checkpoint elicited by replicative mutations in human cancers, suggesting the need for larger stress or the presence of ssDNA. Here, we describe a study population-based studies to investigate whether CLSPN to determine whether mutational disruption of CLSPN variants contribute to cancer susceptibility. -
ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency
Published OnlineFirst March 24, 2014; DOI: 10.1158/0008-5472.CAN-13-3229 Cancer Therapeutics, Targets, and Chemical Biology Research ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency Kareem N. Mohni, Gina M. Kavanaugh, and David Cortez Abstract The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions, with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase cyclin E. Here, we report a systematic screen to identify synthetic lethal interactions with ATR pathway–targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure-specific endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1- deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells were arrested in S-phase and failed to complete cell-cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non–small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR pathway–targeted drugs. Overall, we concluded that ATR pathway–targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. Cancer Res; 74(10); 1–11. Ó2014 AACR. Introduction repair pathway such as homologous recombination or post- – Replicating DNA is sensitive to a wide array of endogenous replicative repair to remove the PARP DNA complexes (7). -
Proteome Analysis of the HIV-1 Gag Interactome
Virology 460-461 (2014) 194–206 Contents lists available at ScienceDirect Virology journal homepage: www.elsevier.com/locate/yviro Proteome analysis of the HIV-1 Gag interactome Christine E. Engeland a, Nigel P. Brown b, Kathleen Börner a,b, Michael Schümann c, Eberhard Krause c, Lars Kaderali d, Gerd A. Müller e, Hans-Georg Kräusslich a,n a Department of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany b Bioquant, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany c Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, D-13125 Berlin, Germany d Institute for Medical Informatics and Biometry (IMB), Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, D-01307 Dresden, Germany e Molecular Oncology, Medical School, University of Leipzig, Semmelweisstraße 14, D-04103 Leipzig, Germany article info abstract Article history: Human immunodeficiency virus Gag drives assembly of virions in infected cells and interacts with host Received 20 January 2014 factors which facilitate or restrict viral replication. Although several Gag-binding proteins have been Returned to author for revisions characterized, understanding of virus–host interactions remains incomplete. In a series of six affinity 6 February 2014 purification screens, we have identified protein candidates for interaction with HIV-1 Gag. Proteins Accepted 19 April 2014 previously found in virions or identified in siRNA screens for host factors influencing HIV-1 replication Available online 10 June 2014 were recovered. Helicases, translation factors, cytoskeletal and motor proteins, factors involved in RNA Keywords: degradation and RNA interference were enriched in the interaction data. Cellular networks of HIV Gag cytoskeleton, SR proteins and tRNA synthetases were identified. -
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. -
Análise Correlacional Entre a Expressão Dos Fatores De Splicing E a Ocorrência De Splicing Alternativo Em Tecidos Humanos E De Camundongos
ANÁLISE CORRELACIONAL ENTRE A EXPRESSÃO DOS FATORES DE SPLICING E A OCORRÊNCIA DE SPLICING ALTERNATIVO EM TECIDOS HUMANOS E DE CAMUNDONGOS JULIO CÉSAR NUNES Dissertação apresentada à Fundação Antônio Prudente para a obtenção do título de Mestre em Ciências Área de Concentração: Oncologia Orientador: Dr. Sandro José de Souza São Paulo 2008 Livros Grátis http://www.livrosgratis.com.br Milhares de livros grátis para download. FICHA CATALOGRÁFICA Preparada pela Biblioteca da Fundação Antônio Prudente Nunes, Julio César Análise correlacional entre a expressão dos fatores de splicing e a ocorrência de splicing alternativo em tecidos humanos e de camundongos / Julio César Nunes – São Paulo, 2008. 79p. Dissertação (Mestrado) - Fundação Antônio Prudente. Curso de Pós-Graduação em Ciências - Área de concentração: Oncologia. Orientador: Sandro José Souza Descritores: 1. SPLICING ALTERNATIVO 2. BIOLOGIA MOLECULAR COMPUTACIONAL 3. CÂNCER 4. GENOMICA. AGRADECIMENTOS Agradeço à FAPESP e CAPES pela bolsa de Mestrado. Ao Sandro José de Souza agradeço toda orientação e conhecimento oferecido. Meus especiais agradecimentos ao Pedro Alexandre Favoretto Galante que dedicou atenção a minha formação no processo de Pós-Graduação na Fundação Antônio Prudente, bem como pela sua oficiosa co-orientação ao projeto de pesquisa. À grande família e amigos pela dedicação e incentivo a minha formação acadêmica. À Fundação Antônio Prudente, Hospital do Câncer e Instituto Ludwig de Pesquisa sobre o Câncer dedico os meus nobres agradecimentos finais. RESUMO Nunes JC. Análise correlacional entre a expressão dos fatores de splicing e a ocorrência de splicing alternativo em tecidos humanos e de camundongos. São Paulo; 2007. [Dissertacão de Mestrado - Fundação Antônio Prudente] Splicing alternativo desempenha uma significante função no aumento da complexidade genômica, produzindo um extenso número de mRNA e isoformas protéicas. -
Curcumin Alters Gene Expression-Associated DNA Damage, Cell Cycle, Cell Survival and Cell Migration and Invasion in NCI-H460 Human Lung Cancer Cells in Vitro
ONCOLOGY REPORTS 34: 1853-1874, 2015 Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro I-TSANG CHIANG1,2, WEI-SHU WANG3, HSIN-CHUNG LIU4, SU-TSO YANG5, NOU-YING TANG6 and JING-GUNG CHUNG4,7 1Department of Radiation Oncology, National Yang‑Ming University Hospital, Yilan 260; 2Department of Radiological Technology, Central Taiwan University of Science and Technology, Taichung 40601; 3Department of Internal Medicine, National Yang‑Ming University Hospital, Yilan 260; 4Department of Biological Science and Technology, China Medical University, Taichung 404; 5Department of Radiology, China Medical University Hospital, Taichung 404; 6Graduate Institute of Chinese Medicine, China Medical University, Taichung 404; 7Department of Biotechnology, Asia University, Taichung 404, Taiwan, R.O.C. Received March 31, 2015; Accepted June 26, 2015 DOI: 10.3892/or.2015.4159 Abstract. Lung cancer is the most common cause of cancer CARD6, ID1 and ID2 genes, associated with cell survival and mortality and new cases are on the increase worldwide. the BRMS1L, associated with cell migration and invasion. However, the treatment of lung cancer remains unsatisfactory. Additionally, 59 downregulated genes exhibited a >4-fold Curcumin has been shown to induce cell death in many human change, including the DDIT3 gene, associated with DNA cancer cells, including human lung cancer cells. However, the damage; while 97 genes had a >3- to 4-fold change including the effects of curcumin on genetic mechanisms associated with DDIT4 gene, associated with DNA damage; the CCPG1 gene, these actions remain unclear. Curcumin (2 µM) was added associated with cell cycle and 321 genes with a >2- to 3-fold to NCI-H460 human lung cancer cells and the cells were including the GADD45A and CGREF1 genes, associated with incubated for 24 h. -
Clinicopathological Significance of Claspin Overexpression and Its
Human Pathology (2019) 84,8–17 www.elsevier.com/locate/humpath Original contribution Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer☆,☆☆ Go Kobayashi MBBS a,b,KazuhiroSentaniMD,PhDa,⁎, Takuya Hattori MD, PhD a, Yuji Yamamoto MD a, Takeharu Imai MD c, Naoya Sakamoto MD, PhD a, Kazuya Kuraoka MD, PhD d, Naohide Oue MD, PhD a, Naomi Sasaki MD, PhD b, Kiyomi Taniyama MD, PhD d,WataruYasuiMD,PhDa aDepartment of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551 Japan bDepartment of Pathology, Kure-Kyosai Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Hiroshima, 737-8505 Japan cDepartment of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, 501-1194 Japan dDepartment of Pathology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure-City, Hiroshima, 737-0023 Japan Received 27 May 2018; revised 31 August 2018; accepted 6 September 2018 Keywords: Summary Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Spheroid colony Cancer stem cell; formation is a useful method to identify cancer stem cells (CSCs). The aim of this study was to identify a novel CD44; prognostic marker or therapeutic target for GC using a method to identify CSCs. We analyzed the microarray Claspin; data in spheroid body–forming and parental cells and focused on the CLSPN gene because it is overexpressed Gastric cancer; in the spheroid body–forming cells in both the GC cell lines MKN-45 and MKN-74. Quantitative reverse- Spheroid transcription polymerase chain reaction analysis revealed that CLSPN messenger RNA expression was up- regulated in GC cell lines MKN-45, MKN-74, and TMK-1. -
A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection
CLINICAL RESEARCH www.jasn.org A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection Weijia Zhang,1 Zhengzi Yi,1 Karen L. Keung,2 Huimin Shang,3 Chengguo Wei,1 Paolo Cravedi,1 Zeguo Sun,1 Caixia Xi,1 Christopher Woytovich,1 Samira Farouk,1 Weiqing Huang,1 Khadija Banu,1 Lorenzo Gallon,4 Ciara N. Magee,5 Nader Najafian,5 Milagros Samaniego,6 Arjang Djamali ,7 Stephen I. Alexander,2 Ivy A. Rosales,8 Rex Neal Smith,8 Jenny Xiang,3 Evelyne Lerut,9 Dirk Kuypers,10,11 Maarten Naesens ,10,11 Philip J. O’Connell,2 Robert Colvin,8 Madhav C. Menon,1 and Barbara Murphy1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. Methods We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 indi- viduals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. -
In This Table Protein Name, Uniprot Code, Gene Name P-Value
Supplementary Table S1: In this table protein name, uniprot code, gene name p-value and Fold change (FC) for each comparison are shown, for 299 of the 301 significantly regulated proteins found in both comparisons (p-value<0.01, fold change (FC) >+/-0.37) ALS versus control and FTLD-U versus control. Two uncharacterized proteins have been excluded from this list Protein name Uniprot Gene name p value FC FTLD-U p value FC ALS FTLD-U ALS Cytochrome b-c1 complex P14927 UQCRB 1.534E-03 -1.591E+00 6.005E-04 -1.639E+00 subunit 7 NADH dehydrogenase O95182 NDUFA7 4.127E-04 -9.471E-01 3.467E-05 -1.643E+00 [ubiquinone] 1 alpha subcomplex subunit 7 NADH dehydrogenase O43678 NDUFA2 3.230E-04 -9.145E-01 2.113E-04 -1.450E+00 [ubiquinone] 1 alpha subcomplex subunit 2 NADH dehydrogenase O43920 NDUFS5 1.769E-04 -8.829E-01 3.235E-05 -1.007E+00 [ubiquinone] iron-sulfur protein 5 ARF GTPase-activating A0A0C4DGN6 GIT1 1.306E-03 -8.810E-01 1.115E-03 -7.228E-01 protein GIT1 Methylglutaconyl-CoA Q13825 AUH 6.097E-04 -7.666E-01 5.619E-06 -1.178E+00 hydratase, mitochondrial ADP/ATP translocase 1 P12235 SLC25A4 6.068E-03 -6.095E-01 3.595E-04 -1.011E+00 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 Protein kinase C and casein Q9BY11 PACSIN1 3.837E-03 -5.863E-01 3.680E-06 -1.824E+00 kinase substrate in neurons protein 1 Tubulin polymerization- O94811 TPPP 6.466E-03 -5.755E-01 6.943E-06 -1.169E+00 promoting protein MIC C9JRZ6 CHCHD3 2.912E-02 -6.187E-01 2.195E-03 -9.781E-01 Mitochondrial 2- -
A Systems-Wide Screen Identifies Substrates of the SCF Ubiquitin Ligase
RESEARCH RESOURCE PROTEOMICS A systems-wide screen identifies substrates of the SCFbTrCP ubiquitin ligase Teck Yew Low,1,2 Mao Peng,1,2* Roberto Magliozzi,3* Shabaz Mohammed,1,2† Daniele Guardavaccaro,3 Albert J. R. Heck1,2‡ Cellular proteins are degraded by the ubiquitin-proteasome system (UPS) in a precise and timely fashion. Such precision is conferred by the high substrate specificity of ubiquitin ligases. Identification of substrates of ubiquitin ligases is crucial not only to unravel the molecular mechanisms by which the UPS controls protein degradation but also for drug discovery purposes because many established UPS substrates are implicated in disease. We developed a combined bioinformatics and affinity purification– mass spectrometry (AP-MS) workflow for the system-wide identification of substrates of SCFbTrCP,a member of the SCF family of ubiquitin ligases. These ubiquitin ligases are characterized by a multi- subunit architecture typically consisting of the invariable subunits Rbx1, Cul1, and Skp1, and one of 69 F-box proteins. The F-box protein of this member of the family is bTrCP. SCFbTrCP binds, through the WD40 b repeats of TrCP, to the DpSGXX(X)pS diphosphorylated motif in its substrates. We recovered 27 pre- Downloaded from viously reported SCFbTrCP substrates, of which 22 were verified by two independent statistical proto- cols, thereby confirming the reliability of this approach. In addition to known substrates, we identified 221 proteins that contained the DpSGXX(X)pS motif and also interacted specifically with the WD40 repeats of bTrCP. Thus, with SCFbTrCP, as the example, we showed that integration of structural infor- mation, AP-MS, and degron motif mining constitutes an effective method to screen for substrates of ubiquitin ligases. -
PRMT1-Dependent Regulation of RNA Metabolism and DNA Damage Response Sustains Pancreatic Ductal Adenocarcinoma ✉ Virginia Giuliani 1 , Meredith A
ARTICLE https://doi.org/10.1038/s41467-021-24798-y OPEN PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma ✉ Virginia Giuliani 1 , Meredith A. Miller1,17, Chiu-Yi Liu1,17, Stella R. Hartono 2,17, Caleb A. Class 3,13, Christopher A. Bristow1, Erika Suzuki1, Lionel A. Sanz2, Guang Gao1, Jason P. Gay1, Ningping Feng1, Johnathon L. Rose4, Hideo Tomihara4,14, Joseph R. Daniele1, Michael D. Peoples1, Jennifer P. Bardenhagen5, Mary K. Geck Do5, Qing E. Chang6, Bhavatarini Vangamudi1,15, Christopher Vellano1, Haoqiang Ying 7, Angela K. Deem1, Kim-Anh Do3, Giannicola Genovese4,8, Joseph R. Marszalek1, Jeffrey J. Kovacs1, Michael Kim9, 1234567890():,; Jason B. Fleming9,16, Ernesto Guccione10, Andrea Viale4, Anirban Maitra 11, M. Emilia Di Francesco5, Timothy A. Yap 12, Philip Jones 5, Giulio Draetta 1,4,5, Alessandro Carugo 1, Frederic Chedin 2 & ✉ Timothy P. Heffernan 1 Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clini- cally challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative poly- adenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth.