DOCSLIB.ORG

Biological Models of Colorectal Cancer Metastasis and Tumor Suppression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biological Models of Colorectal Cancer Metastasis and Tumor Suppression BIOLOGICAL MODELS OF COLORECTAL CANCER METASTASIS AND TUMOR SUPPRESSION PROVIDE MECHANISTIC INSIGHTS TO GUIDE PERSONALIZED CARE OF THE COLORECTAL CANCER PATIENT By Jesse Joshua Smith Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY In Cell and Developmental Biology May, 2010 Nashville, Tennessee Approved: Professor R. Daniel Beauchamp Professor Robert J. Coffey Professor Mark deCaestecker Professor Ethan Lee Professor Steven K. Hanks Copyright 2010 by Jesse Joshua Smith All Rights Reserved To my grandparents, Gladys and A.L. Lyth and Juanda Ruth and J.E. Smith, fully supportive and never in doubt. To my amazing and enduring parents, Rebecca Lyth and Jesse E. Smith, Jr., always there for me. .my sure foundation. To Jeannine, Bill and Reagan for encouragement, patience, love, trust and a solid backing. To Granny George and Shawn for loving support and care. And To my beautiful wife, Kelly, My heart, soul and great love, Infinitely supportive, patient and graceful. ii ACKNOWLEDGEMENTS This work would not have been possible without the financial support of the Vanderbilt Medical Scientist Training Program through the Clinical and Translational Science Award (Clinical Investigator Track), the Society of University Surgeons-Ethicon Scholarship Fund and the Surgical Oncology T32 grant and the Vanderbilt Medical Center Section of Surgical Sciences and the Department of Surgical Oncology. I am especially indebted to Drs. R. Daniel Beauchamp, Chairman of the Section of Surgical Sciences, Dr. James R. Goldenring, Vice Chairman of Research of the Department of Surgery, Dr. Naji N. Abumrad, Chairman of the Department of Surgery and Dr. John L. Tarpley, Program Director and Professor of the Department of Surgery for constant support, encouragement and guidance. I would especially like to thank Mrs. Donna Putnam, Dr. Natasha G. Deane, Associate Research Professor, Department of Surgical Oncology, Dr. Nancy J. Brown, Director, Department of Clinical Pharmacology, Dr. Yu Shyr, Professor and Chief, Department of Cancer Biostatistics and Dr. Terence Dermody, Professor and Director of the Vanderbilt Medical Scientist Training Program, who have supported my career goals and who worked tirelessly to provide me with the resources, protected time and encouragement to pursue my dreams and goals. I would also like to thank two individuals who have been taken from us, Niki Carey and Dr. Neville Grant, who provided measures of heroism and inspiration during my early residency and graduate training. I am thankful to Fei Wu, M.D., Ph.D. for getting the 34-gene story off to a great start. I thank Drs. J. Chad Johnson, Carl Schmidt, Nipun B. Merchant, Steven Eschrich, Timothy J. Yeatman and Martin J. Heslin for initial efforts to organize and secure the colorectal tissues used for the microarray analysis in this work. I am grateful to all of those with whom I have had the pleasure to work during the last 4 years in the laboratory. Each of my Dissertation Committee members has provided excellent professional iii guidance and spurred me on to pursue science and research at a new level. Notably, Drs. Mark de Caestecker and Ethan Lee had tremendous roles in my development as a scientist. I am thankful for their guidance, time, patience and generosity with reagents. I would especially like to thank Dr. Bob Coffey and Dr. Steve Hanks who have exemplified a steady hand in my graduate school career and who have provided me with much wisdom and encouragement. I would like to thank my medical school mentors, Drs. Hazim J. Safi, Charles C. Miller and Anthony L. Estrera for continued support and encouragement in my studies, my life and my career. Dr. Safi has been a stalwart and was the first to introduce me to the wonderful world of medicine and science. I am forever grateful for his inspiration and encouragement. Dr. Miller taught me how to think like a clinical scientist and kept me sane during medical school. Dr. Estrera encouraged me during my pursuit of surgical residency and taught me how to round on patients as a first year medical student. I am thankful to R. Daniel Beauchamp, M.D. and Maximilian Buja, M.D. for giving me a chance. Nothing has been more important to me than my faith and my family as a bedrock of support during my training. My mom and dad, in-laws, my brother Nate and extended family have provided much grace and love to Kelly and myself. Most importantly, I wish to thank my dear wife Kelly and our yet unknown children for unending love, support and help during my training. This work was supported by the following grants from the National Institutes of Health: 1) CA69457; DK52334; CA068485; CA077839 (R. Daniel Beauchamp, M.D.); 2) TL1 RR024978; CA106183 (Institutional support for J. Joshua Smith); 3) CA46413; CA95103; CA084239 (R. J. Coffey, M.D.); 4) CA112215 (Timothy J. Yeatman, M.D.); 5) CA126588; CA128323 (Natasha G. Deane, Ph.D.); Other sources of funding: Society of University Surgeons-Ethicon Scholarship Award (J.J.S.). iv TABLE OF CONTENTS Page DEDICATION........................................................................................................................................ ii ACKNOWLEDGEMENTS .....................................................................................................................iii LIST OF TABLES................................................................................................................................. ix LIST OF FIGURES ............................................................................................................................... x LIST OF ABBREVIATIONS..................................................................................................................xii Chapter I. INTRODUCTION TO THE PROBLEM OF COLORECTAL CANCER...............................................1 Epidemiology and Pathogenesis.......................................................................................................1 Genomic Instability............................................................................................................................2 Mutational Inactivation of Tumor-Suppressor Genes........................................................................2 Oncogenic Pathway Activation..........................................................................................................3 Developmental Biology and Carcinogenesis in Intestinal Epithelial Cells .........................................5 Overview of Prominent Signaling Pathways.................................................................................5 Metastasis and Epithelial-Mesenchymal Transition (EMT): Parallels in Developmental Biology and Cancer......................................................................................................................5 Transforming Growth Factor- (TGF) Superfamily Signaling in Epithelial Biology.....................7 TGF and Smad4 in Gastrointestinal Homeostasis and Cancer.............................................9 Bone Morphogenetic Proteins in the Intestinal Tract.............................................................11 TGF Superfamily Signaling and EMT..................................................................................12 Wnt Signaling in Intestinal Growth, Differentiation and Colorectal Cancer.................................13 Adherens junctions, Wnt and EMT........................................................................................15 Tumor Biology at the Invasive Front......................................................................................17 Other Contributing Pathways in the Pathogenesis of Colorectal Cancer ........................................18 Predictive and Prognostic Markers and Molecular Detection in Colorectal Cancer.........................20 Biological Models of Colorectal Cancer...........................................................................................21 Summary.........................................................................................................................................23 II. AN EXPERIMENTALLY DERIVED METASTASIS GENE EXPRESSION PROFILE PREDICTS RECURRENCE AND DEATH IN COLON CANCER PATIENTS ................................25 Abstract...........................................................................................................................................25 Introduction .....................................................................................................................................26 Materials and Methods....................................................................................................................27 v Cell Culture and Mouse Model Overview...................................................................................27 Detailed Cell Culture and Mouse Methods............................................................................28 Human Tissue and Microarray Platforms...................................................................................30 Statistical Methods and Identification of VMC High-Risk Patients..............................................30 Clinical Outcomes and Testing of the 34-gene Based Metastasis Score...................................32 Vanderbilt Cox Model (Training Dataset) ..............................................................................32 Moffitt Cox Model (Test Dataset)...........................................................................................33
Load more

Recommended publications
  • Myosin Myth4-FERM Structures Highlight Important Principles of Convergent Evolution
    Myosin MyTH4-FERM structures highlight important principles of convergent evolution Vicente José Planelles-Herreroa,b, Florian Blanca,c, Serena Sirigua, Helena Sirkiaa, Jeffrey Clausea, Yannick Souriguesa, Daniel O. Johnsrudd, Beatrice Amiguesa, Marco Cecchinic, Susan P. Gilberte, Anne Houdussea,1,2, and Margaret A. Titusd,1,2 aStructural Motility, Institut Curie, CNRS, UMR 144, PSL Research University, F-75005 Paris, France; bUPMC Université de Paris 6, Institut de Formation Doctorale, Sorbonne Universités, 75252 Paris Cedex 05, France; cLaboratoire d’Ingénierie des Fonctions Moléculaires, Institut de Science et d’Ingénierie Supramoléculaires, UMR 7006 CNRS, Université de Strasbourg, F-67083 Strasbourg Cedex, France; dDepartment of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455; and eDepartment of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180 Edited by James A. Spudich, Stanford University School of Medicine, Stanford, CA, and approved March 31, 2016 (received for review January 15, 2016) Myosins containing MyTH4-FERM (myosin tail homology 4-band (Fig. 1). These MF myosins are widespread and likely quite an- 4.1, ezrin, radixin, moesin, or MF) domains in their tails are found cient because they are found in many different branches of the in a wide range of phylogenetically divergent organisms, such as phylogenetic tree (5, 6), including Opisthokonts (which includes humans and the social amoeba Dictyostelium (Dd). Interestingly, Metazoa, unicellular Holozoa, and Fungi), Amoebozoa, and the evolutionarily distant MF myosins have similar roles in the exten- SAR (Stramenopiles, Alveolates, and Rhizaria) (Fig. 1 A and B). sion of actin-filled membrane protrusions such as filopodia and Over the course of hundreds of millions years of parallel evolution bind to microtubules (MT), suggesting that the core functions of the MF myosins have acquired or maintained roles in the formation these MF myosins have been highly conserved over evolution.
    [Show full text]
  • Downregulation of Salivary Proteins, Protective Against Dental Caries, in Type 1 Diabetes
    proteomes Article Downregulation of Salivary Proteins, Protective against Dental Caries, in Type 1 Diabetes Eftychia Pappa 1,* , Konstantinos Vougas 2, Jerome Zoidakis 2 , William Papaioannou 3, Christos Rahiotis 1 and Heleni Vastardis 4 1 Department of Operative Dentistry, School of Dentistry, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] 2 Proteomics Laboratory, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece; [email protected] (K.V.); [email protected] (J.Z.) 3 Department of Preventive and Community Dentistry, School of Dentistry, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] 4 Department of Orthodontics, School of Dentistry, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] * Correspondence: effi[email protected] Abstract: Saliva, an essential oral secretion involved in protecting the oral cavity’s hard and soft tissues, is readily available and straightforward to collect. Recent studies have analyzed the sali- vary proteome in children and adolescents with extensive carious lesions to identify diagnostic and prognostic biomarkers. The current study aimed to investigate saliva’s diagnostic ability through proteomics to detect the potential differential expression of proteins specific for the occurrence of carious lesions. For this study, we performed bioinformatics and functional analysis of proteomic datasets, previously examined by our group, from samples of adolescents with regulated and unreg- ulated type 1 diabetes, as they compare with healthy controls. Among the differentially expressed Citation: Pappa, E.; Vougas, K.; proteins relevant to caries pathology, alpha-amylase 2B, beta-defensin 4A, BPI fold containing family Zoidakis, J.; Papaioannou, W.; Rahiotis, C.; Vastardis, H.
    [Show full text]
  • Transcriptional Regulation of RKIP in Prostate Cancer Progression
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Sciences Transcriptional Regulation of RKIP in Prostate Cancer Progression Submitted by: Sandra Marie Beach In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences Examination Committee Major Advisor: Kam Yeung, Ph.D. Academic William Maltese, Ph.D. Advisory Committee: Sonia Najjar, Ph.D. Han-Fei Ding, M.D., Ph.D. Manohar Ratnam, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: May 16, 2007 Transcriptional Regulation of RKIP in Prostate Cancer Progression Sandra Beach University of Toledo ACKNOWLDEGMENTS I thank my major advisor, Dr. Kam Yeung, for the opportunity to pursue my degree in his laboratory. I am also indebted to my advisory committee members past and present, Drs. Sonia Najjar, Han-Fei Ding, Manohar Ratnam, James Trempe, and Douglas Pittman for generously and judiciously guiding my studies and sharing reagents and equipment. I owe extended thanks to Dr. William Maltese as a committee member and chairman of my department for supporting my degree progress. The entire Department of Biochemistry and Cancer Biology has been most kind and helpful to me. Drs. Roy Collaco and Hong-Juan Cui have shared their excellent technical and practical advice with me throughout my studies. I thank members of the Yeung laboratory, Dr. Sungdae Park, Hui Hui Tang, Miranda Yeung for their support and collegiality. The data mining studies herein would not have been possible without the helpful advice of Dr. Robert Trumbly. I am also grateful for the exceptional assistance and shared microarray data of Dr.
    [Show full text]
  • Circmyo10 Promotes Osteosarcoma Progression by Regulating Mir-370
    Chen et al. Molecular Cancer (2019) 18:150 https://doi.org/10.1186/s12943-019-1076-1 RESEARCH Open Access CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/ RUVBL1 axis to enhance the transcriptional activity of β-catenin/LEF1 complex via effects on chromatin remodeling Junxin Chen1†, Gang Liu1†, Yizheng Wu1†, Jianjun Ma1†, Hongfei Wu2, Ziang Xie1, Shuai Chen1, Yute Yang1, Shengyu Wang1, Panyang Shen1, Yifan Fang3, Shunwu Fan1, Shuying Shen1* and Xiangqian Fang1* Abstract Background: CircMYO10 is a circular RNA generated by back-splicing of gene MYO10 and is upregulated in osteosarcoma cell lines, but its functional role in osteosarcoma is still unknown. This study aimed to clarify the mechanism of circMYO10 in osteosarcoma. Methods: CircMYO10 expression in 10 paired osteosarcoma and chondroma tissues was assessed by quantitative reverse transcription polymerase chain reaction (PCR). The function of circMYO10/miR-370-3p/RUVBL1 axis was assessed regarding two key characteristics: proliferation and endothelial–mesenchymal transition (EMT). Bioinformatics analysis, western blotting, real-time PCR, fluorescence in situ hybridization, immunoprecipitation, RNA pull-down assays, luciferase reporter assays, chromatin immunoprecipitation, and rescue experiments were used to evaluate the mechanism. Stably transfected MG63 cells were injected via tail vein or subcutaneously into nude mice to assess the role of circMYO10 in vivo. Results: CircMYO10 was significantly upregulated, while miR-370-3p was downregulated, in osteosarcoma cell lines and human osteosarcoma samples. Silencing circMYO10 inhibited cell proliferation and EMT in vivo and in vitro. Mechanistic investigations revealed that miR-370-3p targets RUVBL1 directly, and inhibits the interaction between RUVBL1 and β-catenin/LEF1 complex while circMYO10 showed a contrary effect via the inhibition of miR-370-3p.
    [Show full text]
  • Human Periprostatic Adipose Tissue: Secretome from Patients With
    CANCER GENOMICS & PROTEOMICS 16 : 29-58 (2019) doi:10.21873/cgp.20110 Human Periprostatic Adipose Tissue: Secretome from Patients With Prostate Cancer or Benign Prostate Hyperplasia PAULA ALEJANDRA SACCA 1, OSVALDO NÉSTOR MAZZA 2, CARLOS SCORTICATI 2, GONZALO VITAGLIANO 3, GABRIEL CASAS 4 and JUAN CARLOS CALVO 1,5 1Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina; 2Department of Urology, School of Medicine, University of Buenos Aires, Clínical Hospital “José de San Martín”, Buenos Aires, Argentina; 3Department of Urology, Deutsches Hospital, Buenos Aires, Argentina; 4Department of Pathology, Deutsches Hospital, Buenos Aires, Argentina; 5Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina Abstract. Background/Aim: Periprostatic adipose tissue Prostate cancer (PCa) is the second most common cancer in (PPAT) directs tumour behaviour. Microenvironment secretome men worldwide. While most men have indolent disease, provides information related to its biology. This study was which can be treated properly, the problem consists in performed to identify secreted proteins by PPAT, from both reliably distinguishing between indolent and aggressive prostate cancer and benign prostate hyperplasia (BPH) disease. Evidence shows that the microenvironment affects patients. Patients and Methods: Liquid chromatography-mass tumour behavior. spectrometry-based proteomic analysis was performed in Adipose tissue microenvironment is now known to direct PPAT-conditioned media (CM) from patients with prostate tumour growth, invasion and metastases (1, 2). Adipose cancer (CMs-T) (stage T3: CM-T3, stage T2: CM-T2) or tissue is adjacent to the prostate gland and the site of benign disease (CM-BPH). Results: The highest number and invasion of PCa.
    [Show full text]
  • Supplementary Table 3 Complete List of RNA-Sequencing Analysis of Gene Expression Changed by ≥ Tenfold Between Xenograft and Cells Cultured in 10%O2
    Supplementary Table 3 Complete list of RNA-Sequencing analysis of gene expression changed by ≥ tenfold between xenograft and cells cultured in 10%O2 Expr Log2 Ratio Symbol Entrez Gene Name (culture/xenograft) -7.182 PGM5 phosphoglucomutase 5 -6.883 GPBAR1 G protein-coupled bile acid receptor 1 -6.683 CPVL carboxypeptidase, vitellogenic like -6.398 MTMR9LP myotubularin related protein 9-like, pseudogene -6.131 SCN7A sodium voltage-gated channel alpha subunit 7 -6.115 POPDC2 popeye domain containing 2 -6.014 LGI1 leucine rich glioma inactivated 1 -5.86 SCN1A sodium voltage-gated channel alpha subunit 1 -5.713 C6 complement C6 -5.365 ANGPTL1 angiopoietin like 1 -5.327 TNN tenascin N -5.228 DHRS2 dehydrogenase/reductase 2 leucine rich repeat and fibronectin type III domain -5.115 LRFN2 containing 2 -5.076 FOXO6 forkhead box O6 -5.035 ETNPPL ethanolamine-phosphate phospho-lyase -4.993 MYO15A myosin XVA -4.972 IGF1 insulin like growth factor 1 -4.956 DLG2 discs large MAGUK scaffold protein 2 -4.86 SCML4 sex comb on midleg like 4 (Drosophila) Src homology 2 domain containing transforming -4.816 SHD protein D -4.764 PLP1 proteolipid protein 1 -4.764 TSPAN32 tetraspanin 32 -4.713 N4BP3 NEDD4 binding protein 3 -4.705 MYOC myocilin -4.646 CLEC3B C-type lectin domain family 3 member B -4.646 C7 complement C7 -4.62 TGM2 transglutaminase 2 -4.562 COL9A1 collagen type IX alpha 1 chain -4.55 SOSTDC1 sclerostin domain containing 1 -4.55 OGN osteoglycin -4.505 DAPL1 death associated protein like 1 -4.491 C10orf105 chromosome 10 open reading frame 105 -4.491
    [Show full text]
  • Circular RNA Hsa Circ 0005114‑Mir‑142‑3P/Mir‑590‑5P‑ Adenomatous
    ONCOLOGY LETTERS 21: 58, 2021 Circular RNA hsa_circ_0005114‑miR‑142‑3p/miR‑590‑5p‑ adenomatous polyposis coli protein axis as a potential target for treatment of glioma BO WEI1*, LE WANG2* and JINGWEI ZHAO1 1Department of Neurosurgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033; 2Department of Ophthalmology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China Received September 12, 2019; Accepted October 22, 2020 DOI: 10.3892/ol.2020.12320 Abstract. Glioma is the most common type of brain tumor APC expression with a good overall survival rate. UALCAN and is associated with a high mortality rate. Despite recent analysis using TCGA data of glioblastoma multiforme and the advances in treatment options, the overall prognosis in patients GSE25632 and GSE103229 microarray datasets showed that with glioma remains poor. Studies have suggested that circular hsa‑miR‑142‑3p/hsa‑miR‑590‑5p was upregulated and APC (circ)RNAs serve important roles in the development and was downregulated. Thus, hsa‑miR‑142‑3p/hsa‑miR‑590‑5p‑ progression of glioma and may have potential as therapeutic APC‑related circ/ceRNA axes may be important in glioma, targets. However, the expression profiles of circRNAs and their and hsa_circ_0005114 interacted with both of these miRNAs. functions in glioma have rarely been studied. The present study Functional analysis showed that hsa_circ_0005114 was aimed to screen differentially expressed circRNAs (DECs) involved in insulin secretion, while APC was associated with between glioma and normal brain tissues using sequencing the Wnt signaling pathway. In conclusion, hsa_circ_0005114‑ data collected from the Gene Expression Omnibus database miR‑142‑3p/miR‑590‑5p‑APC ceRNA axes may be potential (GSE86202 and GSE92322 datasets) and explain their mecha‑ targets for the treatment of glioma.
    [Show full text]
  • Downloaded from [266]
    Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes.
    [Show full text]
  • Cellular and Molecular Signatures in the Disease Tissue of Early
    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
    [Show full text]
  • Development of a Human Mitochondrial Oligonucleotide
    BMC Genomics BioMed Central Research article Open Access Development of a human mitochondrial oligonucleotide microarray (h-MitoArray) and gene expression analysis of fibroblast cell lines from 13 patients with isolated F1Fo ATP synthase deficiency Alena Жížková1,2,5, Viktor Stránecký1,2, Robert Ivánek1,2,4, Hana Hartmannová1,2, Lenka Nosková2, Lenka Piherová1,2, Markéta Tesařová1,3, Hana Hansíková1,3, Tomáš Honzík3, JiříZeman1,3, Petr Divina4, Andrea Potocká1,5, Jan Paul1,5, Wolfgang Sperl6, Johannes A Mayr6, Sara Seneca7, Josef Houštĕk1,5 and Stanislav Kmoch*1,2 Address: 1Center for Applied Genomics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, 2Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, 3Department of Pediatrics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, 4Institute of Molecular Genetics, Academy of Science of the Czech Republic, Prague, Czech Republic, 5Department of Bioenergetics, Institute of Physiology, Academy of Science of the Czech Republic, Prague, Czech Republic, 6Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria and 7Center of Medical Genetics, Free University Brussels, Brussels, Belgium Email: Alena Жížková - [email protected]; Viktor Stránecký - [email protected]; Robert Ivánek - [email protected]; Hana Hartmannová - [email protected]; Lenka Nosková - [email protected]; Lenka Piherová - [email protected]; Markéta Tesařová - [email protected]; Hana Hansíková -
    [Show full text]
  • KIF1A-Related Autosomal Dominant Spastic Paraplegias (SPG30) in Russian Families G
    Rudenskaya et al. BMC Neurology (2020) 20:290 https://doi.org/10.1186/s12883-020-01872-4 RESEARCH ARTICLE Open Access KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families G. E. Rudenskaya1 , V. A. Kadnikova1* , O. P. Ryzhkova1 , L. A. Bessonova1, E. L. Dadali1 , D. S. Guseva1 , T. V. Markova1 , D. N. Khmelkova2 and A. V. Polyakov1 Abstract Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population. Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel ‘spastic paraplegias’ with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole -exome sequencing. Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course.
    [Show full text]
  • Dimerization of Mammalian Kinesin-3 Motors Results in Superprocessive Motion
    Dimerization of mammalian kinesin-3 motors results in superprocessive motion Virupakshi Soppinaa,1, Stephen R. Norrisa,b, Aslan S. Dizajia, Matt Kortusa, Sarah Veatchb, Michelle Peckhamc, and Kristen J. Verheya,1 aDepartment of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109; bDepartment of Biophysics, University of Michigan, Ann Arbor, MI 48109; and cSchool of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom Edited by J. Richard McIntosh, University of Colorado, Boulder, CO, and approved March 7, 2014 (received for review January 15, 2014) The kinesin-3 family is one of the largest among the kinesin Defects in kinesin-3 transport have been implicated in a wide superfamily and its members play important roles in a wide range variety of neurodegenerative, developmental, and cancer dis- of cellular transport activities, yet the molecular mechanisms of eases (22). However, a mechanistic understanding of this im- kinesin-3 regulation and cargo transport are largely unknown. portant class of cellular transporters is currently limited. We performed a comprehensive analysis of mammalian kinesin-3 To date, mechanistic studies have focused on truncated ver- motors from three different subfamilies (KIF1, KIF13, and KIF16). sions of mammalian KIF1A and its homolog CeUNC-104, and Using Forster resonance energy transfer microscopy in live cells, these studies have yielded contradictory results (23). For exam- we show for the first time to our knowledge that KIF16B motors ple, murine KIF1A has been proposed to function as a monomer undergo cargo-mediated dimerization. The molecular mechanisms that diffuses along the microtubule surface or as a processive dimer.
    [Show full text]