Pathogenic Impact of Transcript Isoform Switching in 1,209 Cancer
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PPP2R3C Gene Variants Cause Syndromic 46,XY Gonadal
5 180 T Guran and others PPP2R3C in testis developmentQ1 180:5 291–309 Clinical Study and spermatogenesis PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans Tulay Guran1, Gozde Yesil2, Serap Turan1, Zeynep Atay3, Emine Bozkurtlar4, AghaRza Aghayev5, Sinem Gul6, Ilker Tinay7, Basak Aru8, Sema Arslan9, M Kutay Koroglu10, Feriha Ercan10, Gulderen Y Demirel8, Funda S Eren4, Betul Karademir9 and Abdullah Bereket1 1Department of Paediatric Endocrinology and Diabetes, Marmara University, 2Department of Genetics, Bezm-i Alem University, 3Department of Paediatric Endocrinology and Diabetes, Medipol University, 4Department of Pathology, Marmara University, School of Medicine, Istanbul, Turkey, 5Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey, 6Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, Turkey, 7Department of Urology, Marmara University, School of Medicine, Istanbul, Turkey, 8Department of Immunology, Yeditepe Correspondence University, Faculty of Medicine, Istanbul, Turkey, 9Department of Biochemistry, Genetic and Metabolic Diseases should be addressed Research and Investigation Center, and 10Department of Histology and Embryology, Marmara University, School of to T Guran Medicine, Istanbul, Turkey Email [email protected] Abstract Context: Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. -
Identification of Key Candidate Genes for Colorectal Cancer by Bioinformatics Analysis
ONCOLOGY LETTERS 18: 6583-6593, 2019 Identification of key candidate genes for colorectal cancer by bioinformatics analysis ZHIHUA CHEN1*, YILIN LIN1*, JI GAO2*, SUYONG LIN1, YAN ZHENG1, YISU LIU1 and SHAO QIN CHEN1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Fujian Medical University; 2School of Nursing, Fujian Medical University, Fuzhou, Fujian 350004, P.R. China Received December 27, 2018; Accepted August 16, 2019 DOI: 10.3892/ol.2019.10996 Abstract. Colorectal cancer (CRC) is one of the most Introduction common cancers of the digestive tract. Although numerous studies have been conducted to elucidate the cause of CRC, Colorectal cancer (CRC) ranks third (13.5%) and second the exact mechanism of CRC development remains to be (9.5%) among the incidence of malignancies worldwide determined. To identify candidate genes that may be involved in male and female patients, respectively, and is a serious in CRC development and progression, the microarray datasets hazard to human health (1). Previous studies have demon- GSE41657, GSE77953 and GSE113513 were downloaded from strated that the molecular pathogenesis of CRC is mostly the Gene Expression Omnibus database. Gene Ontology and caused by genetic mutations (2,3). Numerous studies over Kyoto Encyclopedia of Genes and Genomes were used for the past two decades have reported that genetic mutations functional enrichment analysis of differentially expressed are associated with the prognosis and treatment of CRC, and genes (DEGs). A protein-protein interaction network was targeted therapies have been developed (4-7). The progres- constructed, and the hub genes were subjected to module sion of CRC is usually accompanied by the activation of the analysis and identification using Search Tool for the Retrieval KRAS and BRAF genes and the inhibition of the p53 tumour of Interacting Genes/Proteins and Cytoscape. -
Allele-Specific Expression of Ribosomal Protein Genes in Interspecific Hybrid Catfish
Allele-specific Expression of Ribosomal Protein Genes in Interspecific Hybrid Catfish by Ailu Chen A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama August 1, 2015 Keywords: catfish, interspecific hybrids, allele-specific expression, ribosomal protein Copyright 2015 by Ailu Chen Approved by Zhanjiang Liu, Chair, Professor, School of Fisheries, Aquaculture and Aquatic Sciences Nannan Liu, Professor, Entomology and Plant Pathology Eric Peatman, Associate Professor, School of Fisheries, Aquaculture and Aquatic Sciences Aaron M. Rashotte, Associate Professor, Biological Sciences Abstract Interspecific hybridization results in a vast reservoir of allelic variations, which may potentially contribute to phenotypical enhancement in the hybrids. Whether the allelic variations are related to the downstream phenotypic differences of interspecific hybrid is still an open question. The recently developed genome-wide allele-specific approaches that harness high- throughput sequencing technology allow direct quantification of allelic variations and gene expression patterns. In this work, I investigated allele-specific expression (ASE) pattern using RNA-Seq datasets generated from interspecific catfish hybrids. The objective of the study is to determine the ASE genes and pathways in which they are involved. Specifically, my study investigated ASE-SNPs, ASE-genes, parent-of-origins of ASE allele and how ASE would possibly contribute to heterosis. My data showed that ASE was operating in the interspecific catfish system. Of the 66,251 and 177,841 SNPs identified from the datasets of the liver and gill, 5,420 (8.2%) and 13,390 (7.5%) SNPs were identified as significant ASE-SNPs, respectively. -
Role of Mitochondrial Ribosomal Protein S18-2 in Cancerogenesis and in Regulation of Stemness and Differentiation
From THE DEPARTMENT OF MICROBIOLOGY TUMOR AND CELL BIOLOGY (MTC) Karolinska Institutet, Stockholm, Sweden ROLE OF MITOCHONDRIAL RIBOSOMAL PROTEIN S18-2 IN CANCEROGENESIS AND IN REGULATION OF STEMNESS AND DIFFERENTIATION Muhammad Mushtaq Stockholm 2017 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by E-Print AB 2017 © Muhammad Mushtaq, 2017 ISBN 978-91-7676-697-2 Role of Mitochondrial Ribosomal Protein S18-2 in Cancerogenesis and in Regulation of Stemness and Differentiation THESIS FOR DOCTORAL DEGREE (Ph.D.) By Muhammad Mushtaq Principal Supervisor: Faculty Opponent: Associate Professor Elena Kashuba Professor Pramod Kumar Srivastava Karolinska Institutet University of Connecticut Department of Microbiology Tumor and Cell Center for Immunotherapy of Cancer and Biology (MTC) Infectious Diseases Co-supervisor(s): Examination Board: Professor Sonia Lain Professor Ola Söderberg Karolinska Institutet Uppsala University Department of Microbiology Tumor and Cell Department of Immunology, Genetics and Biology (MTC) Pathology (IGP) Professor George Klein Professor Boris Zhivotovsky Karolinska Institutet Karolinska Institutet Department of Microbiology Tumor and Cell Institute of Environmental Medicine (IMM) Biology (MTC) Professor Lars-Gunnar Larsson Karolinska Institutet Department of Microbiology Tumor and Cell Biology (MTC) Dedicated to my parents ABSTRACT Mitochondria carry their own ribosomes (mitoribosomes) for the translation of mRNA encoded by mitochondrial DNA. The architecture of mitoribosomes is mainly composed of mitochondrial ribosomal proteins (MRPs), which are encoded by nuclear genomic DNA. Emerging experimental evidences reveal that several MRPs are multifunctional and they exhibit important extra-mitochondrial functions, such as involvement in apoptosis, protein biosynthesis and signal transduction. Dysregulations of the MRPs are associated with severe pathological conditions, including cancer. -
1 AGING Supplementary Table 2
SUPPLEMENTARY TABLES Supplementary Table 1. Details of the eight domain chains of KIAA0101. Serial IDENTITY MAX IN COMP- INTERFACE ID POSITION RESOLUTION EXPERIMENT TYPE number START STOP SCORE IDENTITY LEX WITH CAVITY A 4D2G_D 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ B 4D2G_E 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ C 6EHT_D 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ D 6EHT_E 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ E 6GWS_D 41-72 41 72 100 100 3.2Å PCNA X-RAY DIFFRACTION √ F 6GWS_E 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ G 6GWS_F 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ H 6IIW_B 2-11 2 11 100 100 1.699Å UHRF1 X-RAY DIFFRACTION √ www.aging-us.com 1 AGING Supplementary Table 2. Significantly enriched gene ontology (GO) annotations (cellular components) of KIAA0101 in lung adenocarcinoma (LinkedOmics). Leading Description FDR Leading Edge Gene EdgeNum RAD51, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, CENPW, HJURP, NDC80, CDCA5, NCAPH, BUB1, ZWILCH, CENPK, KIF2C, AURKA, CENPN, TOP2A, CENPM, PLK1, ERCC6L, CDT1, CHEK1, SPAG5, CENPH, condensed 66 0 SPC24, NUP37, BLM, CENPE, BUB3, CDK2, FANCD2, CENPO, CENPF, BRCA1, DSN1, chromosome MKI67, NCAPG2, H2AFX, HMGB2, SUV39H1, CBX3, TUBG1, KNTC1, PPP1CC, SMC2, BANF1, NCAPD2, SKA2, NUP107, BRCA2, NUP85, ITGB3BP, SYCE2, TOPBP1, DMC1, SMC4, INCENP. RAD51, OIP5, CDK1, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, ESCO2, CENPW, HJURP, TTK, NDC80, CDCA5, BUB1, ZWILCH, CENPK, KIF2C, AURKA, DSCC1, CENPN, CDCA8, CENPM, PLK1, MCM6, ERCC6L, CDT1, HELLS, CHEK1, SPAG5, CENPH, PCNA, SPC24, CENPI, NUP37, FEN1, chromosomal 94 0 CENPL, BLM, KIF18A, CENPE, MCM4, BUB3, SUV39H2, MCM2, CDK2, PIF1, DNA2, region CENPO, CENPF, CHEK2, DSN1, H2AFX, MCM7, SUV39H1, MTBP, CBX3, RECQL4, KNTC1, PPP1CC, CENPP, CENPQ, PTGES3, NCAPD2, DYNLL1, SKA2, HAT1, NUP107, MCM5, MCM3, MSH2, BRCA2, NUP85, SSB, ITGB3BP, DMC1, INCENP, THOC3, XPO1, APEX1, XRCC5, KIF22, DCLRE1A, SEH1L, XRCC3, NSMCE2, RAD21. -
A Combined Algorithm for Genome- Wide Prediction of Protein Function
letters to nature cluster for the synthesis of a class of cell wall lipids unique to pathogenic mycobacteria. J. Biol. Chem. tionally related yeast proteins. Links between characterized and 272, 16741±16745 (1997). uncharacterized proteins allow a general function to be assigned 9. Mathur, M. & Kolattukudy, P. E. Molecular cloning and sequencing of the gene for mycocerosic acid synthase, a novel fatty acid elongating multifunctional enzyme, from Mycobacterium tuberculosis var. to more than half of the 2,557 previously uncharacterized yeast bovis Bacillus Calmette-Guerin. J. Biol. Chem. 267, 19388±19395 (1992). proteins. Examples of functional links are given for a protein 10. Azad, A. K., Sirakova, T. D., Rogers, L. M. & Kolattukudy, P. E. Targeted replacement of the family of previously unknown function, a protein whose human mycocerosic acid synthase gene in Mycobacterium bovis BCG produces a mutant that lacks mycosides. homologues are implicated in colon cancer and the yeast prion Proc. Natl Acad. Sci. USA 93, 4787±4792 (1996). 11. Cole, S. T. et al. Deciphering the biology of Mycobactrium tuberculosis from the complete genome Sup35. sequence [see comments]. Nature 393, 537±544 (1998). The historical method of ®nding the function of a protein 12. Fitzmaurice, A. M. & Kolattukudy, P. E. An acyl-CoA synthase (acoas) gene adjacent to the involves extensive genetic and biochemical analyses, unless the mycocerosic acid synthase (mas) locus is necessary for mycocerosyl lipid synthesis in Mycobacterium tuberculosis var. bovis. BCG. J. Biol. Chem. 273, 8033±8039 (1998). amino-acid sequence of the protein resembles another whose 13. Fitzmaurice, A. M. & Kolattukudy, P. E. -
PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: a Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder
International Journal of Molecular Sciences Review PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder Dayita Biswas 1, Whitney Cary 2,3,* and Jan A. Nolta 1,2,3,* 1 SPARK Program Scholar, Institute for Regenerative Cures, University of California, Sacramento, CA 95817, USA; [email protected] 2 Stem Cell Program, UC Davis School of Medicine, The University of California, Sacramento, CA 95817, USA 3 UC Davis Gene Therapy Program, University of California, Sacramento, CA 95817, USA * Correspondence: [email protected] (W.C.); [email protected] (J.A.N.) Received: 11 December 2019; Accepted: 10 February 2020; Published: 14 February 2020 Abstract: Protein Phosphatase 2 Regulatory Subunit B0 Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer’s disease, and Parkinson’s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. -
Association of PPP2R1A with Alzheimer's Disease and Specific
Neurobiology of Aging 81 (2019) 234e243 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Association of PPP2R1A with Alzheimer’s disease and specific cognitive domains Justin Miron a,b,c, Cynthia Picard a,b,c, Anne Labonté a,b, Daniel Auld d, John Breitner a,b,c, Judes Poirier a,b,c,*, for the United Kingdom Brain Expression Consortium, for the PREVENT-AD research group a Douglas Hospital Research Centre, Montréal, Canada b Centre for the Studies on the Prevention of Alzheimer’s Disease, Montréal, Canada c McGill University, Montréal, Canada d McGill University and Génome Québec Innovation Centre, Montréal, Canada article info abstract Article history: In an attempt to identify novel genetic variants associated with sporadic Alzheimer’s disease (AD), a Received 26 February 2019 genome-wide association study was performed on a population isolate from Eastern Canada, referred to Received in revised form 19 June 2019 as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 Accepted 23 June 2019 is associated with higher AD risk and younger age at AD onset in APOE4À individuals. After surveying the Available online 2 July 2019 region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A Keywords: mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when Alzheimer’s disease Genome-wide association study compared with age-matched controls. Using an independent cohort of cognitively normal individuals fi Quebec Founder Population with a parental history of AD, we found that the rs10406151 C variant is signi cantly associated with APOE4 lower visuospatial and constructional performances. -
Proteomic Analysis of Exosome-Like Vesicles Derived from Breast Cancer Cells
ANTICANCER RESEARCH 32: 847-860 (2012) Proteomic Analysis of Exosome-like Vesicles Derived from Breast Cancer Cells GEMMA PALAZZOLO1, NADIA NINFA ALBANESE2,3, GIANLUCA DI CARA3, DANIEL GYGAX4, MARIA LETIZIA VITTORELLI3 and IDA PUCCI-MINAFRA3 1Institute for Biomedical Engineering, Laboratory of Biosensors and Bioelectronics, ETH Zurich, Switzerland; 2Department of Physics, University of Palermo, Palermo, Italy; 3Centro di Oncobiologia Sperimentale (C.OB.S.), Oncology Department La Maddalena, Palermo, Italy; 4Institute of Chemistry and Bioanalytics, University of Applied Sciences Northwestern Switzerland FHNW, Muttenz, Switzerland Abstract. Background/Aim: The phenomenon of membrane that vesicle production allows neoplastic cells to exert different vesicle-release by neoplastic cells is a growing field of interest effects, according to the possible acceptor targets. For instance, in cancer research, due to their potential role in carrying a vesicles could potentiate the malignant properties of adjacent large array of tumor antigens when secreted into the neoplastic cells or activate non-tumoral cells. Moreover, vesicles extracellular medium. In particular, experimental evidence show could convey signals to immune cells and surrounding stroma that at least some of the tumor markers detected in the blood cells. The present study may significantly contribute to the circulation of mammary carcinoma patients are carried by knowledge of the vesiculation phenomenon, which is a critical membrane-bound vesicles. Thus, biomarker research in breast device for trans cellular communication in cancer. cancer can gain great benefits from vesicle characterization. Materials and Methods: Conditioned medium was collected The phenomenon of membrane release in the extracellular from serum starved MDA-MB-231 sub-confluent cell cultures medium has long been known and was firstly described by and exosome-like vesicles (ELVs) were isolated by Paul H. -
Anglemetry of Neural Axis Cell Differentiation Genes by Structural Pressurotopy of DNA Loop Strand Segment Tropy in Reference to Tissue Macro-Compliance Hemant Sarin
Sarin Translational Medicine Communications (2019) 4:13 Translational Medicine https://doi.org/10.1186/s41231-019-0045-4 Communications RESEARCH Open Access Anglemetry of neural axis cell differentiation genes by structural pressurotopy of DNA loop strand segment tropy in reference to tissue macro-compliance Hemant Sarin Abstract Background: Even as the eukaryotic stranded DNA is known to heterochromatinize at the nuclear envelope in response to mechanical strain, the precise mechanistic basis for alterations in chromatin gene transcription in differentiating cell lineages has been difficult to determine due to limited spatial resolution for detection of shifts in reference to a specific gene in vitro. In this study, heterochromatin shift during euchromatin gene transcription has been studied by parallel determinations of DNA strand loop segmentation tropy nano-compliance (esebssiwaagoTQ units, linear nl), gene positioning angulation in linear normal two- 0 dimensional (2-D) z, y-vertical plane (anglemetry, ), horizontal alignment to the z, x-plane (vectormetry; mA, mM,a.u.),andby pressuromodulation mapping of differentiated neuron cell sub-class operating range for neuroaxis gene expression in reference to tissue macro-compliance (Peff). Methods: The esebssiwaagoTQ effectivepressureunit(Peff) maxima and minima for horizontal gene intergene base segment tropy loop alignment were determined (n = 224); the Peff esebssiwaagoTQ quotient were determined (n =28)foranalysisof gene intergene base loop segment tropy structure nano-compliance (n = 28; n = 188); and gene positioning anglemetry and vectormetry was performed (n = 42). The sebs intercept-to-sebssiwa intercept quotient for linear normalization was determined (bsebs/bsebssiwa) by exponential plotting of sub-episode block sum (sebs) (x1, y1; x2, y2) and sub-episode block sum split integrated weighted average (sebssiwa) functions was performed, and the sebs – sebssiwa function residuals were determined. -
Temporal Proteomic Analysis of HIV Infection Reveals Remodelling of The
1 1 Temporal proteomic analysis of HIV infection reveals 2 remodelling of the host phosphoproteome 3 by lentiviral Vif variants 4 5 Edward JD Greenwood 1,2,*, Nicholas J Matheson1,2,*, Kim Wals1, Dick JH van den Boomen1, 6 Robin Antrobus1, James C Williamson1, Paul J Lehner1,* 7 1. Cambridge Institute for Medical Research, Department of Medicine, University of 8 Cambridge, Cambridge, CB2 0XY, UK. 9 2. These authors contributed equally to this work. 10 *Correspondence: [email protected]; [email protected]; [email protected] 11 12 Abstract 13 Viruses manipulate host factors to enhance their replication and evade cellular restriction. 14 We used multiplex tandem mass tag (TMT)-based whole cell proteomics to perform a 15 comprehensive time course analysis of >6,500 viral and cellular proteins during HIV 16 infection. To enable specific functional predictions, we categorized cellular proteins regulated 17 by HIV according to their patterns of temporal expression. We focussed on proteins depleted 18 with similar kinetics to APOBEC3C, and found the viral accessory protein Vif to be 19 necessary and sufficient for CUL5-dependent proteasomal degradation of all members of the 20 B56 family of regulatory subunits of the key cellular phosphatase PP2A (PPP2R5A-E). 21 Quantitative phosphoproteomic analysis of HIV-infected cells confirmed Vif-dependent 22 hyperphosphorylation of >200 cellular proteins, particularly substrates of the aurora kinases. 23 The ability of Vif to target PPP2R5 subunits is found in primate and non-primate lentiviral 2 24 lineages, and remodeling of the cellular phosphoproteome is therefore a second ancient and 25 conserved Vif function. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing