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Formin Proteins in Normal Tissues and Cancer
FORMIN PROTEINS IN NORMAL TISSUES AND CANCER Maria Gardberg TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS Sarja - ser. D osa - tom. 1163 | Medica - Odontologica | Turku 2015 University of Turku Faculty of Medicine Institute of Biomedicine Department of Pathology National Graduate School of Clinical Investigation (CLIGS) Doctoral Programme of Clinical Investigation (CLIDP) University of Turku and Turku University Hospital Supervised by Professor Olli Carpén Department of Pathology Turku University Hospital and University of Turku, Turku, Finland Reviewed by Docent Maria Vartiainen Professor Veli-Pekka Lehto Institute of Biotechnology Department of Pathology University of Helsinki, Helsinki, Finland University of Helsinki, Helsinki, Finland Opponent Professor Robert Grosse Institute of Pharmacology University of Marburg, Marburg, Germany The originality of this thesis has been checked in accordance with the University of Turku quality assurance system using the Turnitin OriginalityCheck service. ISBN 978-951-29-6044-6 (PRINT) ISBN 978-951-29-6045-3 (PDF) ISSN 0355-9483 Painosalama Oy – Turku, Finland 2015 To my family 4 Abstract ABSTRACT Maria Gardberg Formin proteins in normal tissues and cancer Department of Pathology, University of Turku, Turku, Finland (2015) The actin cytoskeleton is a dynamic structure that determines cell shape. Actin turnover is mandatory for migration in normal and malignant cells. In epithelial cancers invasion is frequently accompanied by epithelial to mesenchymal transition (EMT). In EMT, cancer cells acquire a migratory phenotype through transcriptional reprogramming. EMT requires substantial re-organization of actin. During the past decade, new actin regulating proteins have been discovered. Among these are members of the formin family. To study formin expression in tissues and cells, antibodies for detection of formin proteins FMNL1 (Formin-like protein 1), FMNL2 (Formin-like protein 2) and FHOD1 (Formin homology 2 domain containing protein 1) were used. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
MUC4/MUC16/Muc20high Signature As a Marker of Poor Prognostic for Pancreatic, Colon and Stomach Cancers
Jonckheere and Van Seuningen J Transl Med (2018) 16:259 https://doi.org/10.1186/s12967-018-1632-2 Journal of Translational Medicine RESEARCH Open Access Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large‑scale genomic databases: MUC4/MUC16/ MUC20 signature is associated with poor survival in human carcinomas Nicolas Jonckheere* and Isabelle Van Seuningen* Abstract Background: MUC4 is a membrane-bound mucin that promotes carcinogenetic progression and is often proposed as a promising biomarker for various carcinomas. In this manuscript, we analyzed large scale genomic datasets in order to evaluate MUC4 expression, identify genes that are correlated with MUC4 and propose new signatures as a prognostic marker of epithelial cancers. Methods: Using cBioportal or SurvExpress tools, we studied MUC4 expression in large-scale genomic public datasets of human cancer (the cancer genome atlas, TCGA) and cancer cell line encyclopedia (CCLE). Results: We identifed 187 co-expressed genes for which the expression is correlated with MUC4 expression. Gene ontology analysis showed they are notably involved in cell adhesion, cell–cell junctions, glycosylation and cell signal- ing. In addition, we showed that MUC4 expression is correlated with MUC16 and MUC20, two other membrane-bound mucins. We showed that MUC4 expression is associated with a poorer overall survival in TCGA cancers with diferent localizations including pancreatic cancer, bladder cancer, colon cancer, lung adenocarcinoma, lung squamous adeno- carcinoma, skin cancer and stomach cancer. We showed that the combination of MUC4, MUC16 and MUC20 signature is associated with statistically signifcant reduced overall survival and increased hazard ratio in pancreatic, colon and stomach cancer. -
Bundling of Cytoskeletal Actin by the Formin FMNL1 Contributes to Celladhesion and Migration
Bundling of cytoskeletal actin by the formin FMNL1 contributes to celladhesion and migration Item Type Dissertation Authors Miller, Eric Rights Attribution-NonCommercial-NoDerivatives 4.0 International Download date 27/09/2021 05:11:17 Item License http://creativecommons.org/licenses/by-nc-nd/4.0/ Link to Item http://hdl.handle.net/20.500.12648/1760 Bundling of cytoskeletal actin by the formin FMNL1 contributes to cell adhesion and migration Eric W. Miller A Dissertation in the Department of Cell and Developmental Biology Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Graduate Studies of State University of New York, Upstate Medical University Approved ______________________ Dr. Scott D. Blystone Date______________________ i Table of Contents Title Page-------------------------------------------------------------------------------------------------------i Table of Contents-------------------------------------------------------------------------------------------ii List of Tables and Figures------------------------------------------------------------------------------vi Abbreviations----------------------------------------------------------------------------------------------viii Acknowledgements--------------------------------------------------------------------------------------xiii Thesis Abstract-------------------------------------------------------------------------------------------xvi Chapter 1: General Introduction-----------------------------------------------------------------------1 -
Targeting PH Domain Proteins for Cancer Therapy
The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2018 Targeting PH domain proteins for cancer therapy Zhi Tan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Bioinformatics Commons, Medicinal Chemistry and Pharmaceutics Commons, Neoplasms Commons, and the Pharmacology Commons Recommended Citation Tan, Zhi, "Targeting PH domain proteins for cancer therapy" (2018). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 910. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/910 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TARGETING PH DOMAIN PROTEINS FOR CANCER THERAPY by Zhi Tan Approval page APPROVED: _____________________________________________ Advisory Professor, Shuxing Zhang, Ph.D. _____________________________________________ -
UCLA Previously Published Works
UCLA UCLA Previously Published Works Title Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Permalink https://escholarship.org/uc/item/01s4f9gr Journal Nature communications, 4(1) ISSN 2041-1723 Authors Permuth-Wey, Jennifer Lawrenson, Kate Shen, Howard C et al. Publication Date 2013 DOI 10.1038/ncomms2613 Peer reviewed eScholarship.org Powered by the California Digital Library University of California HHS Public Access Author manuscript Author Manuscript Author ManuscriptNat Commun Author Manuscript. Author manuscript; Author Manuscript available in PMC 2013 July 12. Published in final edited form as: Nat Commun. 2013 ; 4: 1627. doi:10.1038/ncomms2613. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31 A full list of authors and affiliations appears at the end of the article. Abstract Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA) binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA binding site single nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (OR=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 associates with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. -
Formin Mdia1, a Downstream Molecule of FMNL1, Regulates Profilin1 for Actin Assembly and Spindle Organization During Mouse Oocyte Meiosis☆
Biochimica et Biophysica Acta 1853 (2015) 317–327 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Formin mDia1, a downstream molecule of FMNL1, regulates Profilin1 for actin assembly and spindle organization during mouse oocyte meiosis☆ Yu Zhang a,FeiWanga,Ying-JieNiua,Hong-LinLiua,RongRuib, Xiang-Shun Cui c, Nam-Hyung Kim c, Shao-Chen Sun a,⁎ a College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China b College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China c Department of Animal Sciences, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea article info abstract Article history: Mammalian diaphanous1 (mDia1) is a homologue of Drosophila diaphanous and belongs to the Formin- Received 26 August 2014 homology family of proteins that catalyze actin nucleation and polymerization. Although Formin family proteins, Received in revised form 6 October 2014 such as Drosophila diaphanous, have been shown to be essential for cytokinesis, whether and how mDia1 Accepted 4 November 2014 functions during meiosis remain uncertain. In this study, we explored possible roles and the signaling pathway Available online 15 November 2014 involved for mDia1 using a mouse oocyte model. mDia1 depletion reduced polar body extrusion, which may have been due to reduced cortical actin assembly. mDia1 and Profilin1 had similar localization patterns in Keywords: fi mDia1 mouse oocytes and mDia1 knockdown resulted in reduced Pro lin1 expression. Depleting FMNL1, another Profilin1 Formin family member, resulted in reduced mDia1 expression, while RhoA inhibition did not alter mDia1 expres- Actin sion, which indicated that there was a FMNL1-mDia1-Profilin1 signaling pathway in mouse oocytes. -
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 -
Rho Activation of Mdia Formins Is Modulated by an Interaction with Inverted Formin 2 (INF2)
Rho activation of mDia formins is modulated by an interaction with inverted formin 2 (INF2) Hua Suna,b,c, Johannes S. Schlondorffb,c, Elizabeth J. Brownc,d, Henry N. Higgse, and Martin R. Pollakb,c,1 aNephrology Division, Department of Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; bNephrology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; cDepartment of Medicine, Harvard Medical School, Boston, MA 02115; dDivision of Nephrology, Department of Medicine, Children’s Hospital, Boston, MA 02115; and eDepartment of Biochemistry, Dartmouth Medical School, Hanover, NH 03755 Edited by Christine E. Seidman, Harvard Medical School, Boston, MA, and approved December 30, 2010 (received for review November 12, 2010) Inverted formin 2 (INF2) encodes a member of the diaphanous glomerular slit diaphragm (11–13). The importance of the actin subfamily of formin proteins. Mutations in INF2 cause human cytoskeleton in maintaining the glomerular filtration barrier is kidney disease characterized by focal and segmental glomerulo- supported by the fact that mutations in α-actinin-4, an actin cross- sclerosis. Disease-causing mutations occur only in the diaphanous linking protein, cause a similar form of autosomal-dominant FSGS inhibitory domain (DID), suggesting specific roles for this domain in (14). Numerous lines of evidence support the notion that podo- the pathogenesis of disease. In a yeast two-hybrid screen, we cytes are highly sensitive to perturbations in their actin cytoskel- identified the diaphanous autoregulatory domains (DADs) of the eton (15). Consistent with this, FSGS-associated mutant forms of mammalian diaphanous-related formins (mDias) mDia1, mDia2, INF2 induce distinct patterns of actin polymerization in cultured and mDia 3 as INF2_DID-interacting partners. -
Genetic Overlap Between Alzheimer&Rsquo
Molecular Psychiatry (2015) 20, 1588–1595 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp ORIGINAL ARTICLE Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus RS Desikan1, AJ Schork2, Y Wang3,4, A Witoelar4, M Sharma5,6, LK McEvoy1, D Holland3, JB Brewer1,3, C-H Chen1,7, WK Thompson7, D Harold8, J Williams8, MJ Owen8,MCO’Donovan8, MA Pericak-Vance9, R Mayeux10, JL Haines11, LA Farrer12, GD Schellenberg13, P Heutink14, AB Singleton15, A Brice16, NW Wood17, J Hardy18, M Martinez19, SH Choi20, A DeStefano20,21, MA Ikram22, JC Bis23, A Smith24, AL Fitzpatrick25, L Launer26, C van Duijn22, S Seshadri21,27, ID Ulstein28, D Aarsland29,30,31, T Fladby32,33, S Djurovic4, BT Hyman34, J Snaedal35, H Stefansson36, K Stefansson36,37, T Gasser5, OA Andreassen4,7, AM Dale1,2,3,7for the ADNI38ADGC, GERAD, CHARGE and IPDGC Investigators39 We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n = 89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts = 1.65 × 10− 7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. -
Mouse Arhgap27 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Arhgap27 Knockout Project (CRISPR/Cas9) Objective: To create a Arhgap27 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Arhgap27 gene (NCBI Reference Sequence: NM_001205236.1 ; Ensembl: ENSMUSG00000034255 ) is located on Mouse chromosome 11. 16 exons are identified, with the ATG start codon in exon 1 and the TGA stop codon in exon 16 (Transcript: ENSMUST00000107024). Exon 4~10 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Exon 4 starts from about 48.25% of the coding region. Exon 4~10 covers 24.32% of the coding region. The size of effective KO region: ~2282 bp. The KO region does not have any other known gene. Page 1 of 9 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 4 5 6 7 8 9 10 11 16 Legends Exon of mouse Arhgap27 Knockout region Page 2 of 9 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 178 bp section upstream of Exon 4 is aligned with itself to determine if there are tandem repeats. No significant tandem repeat is found in the dot plot matrix. So this region is suitable for PCR screening or sequencing analysis. Overview of the Dot Plot (down) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 124 bp section downstream of Exon 10 is aligned with itself to determine if there are tandem repeats. -
The Genetic Case for Cardiorespiratory Fitness As a Clinical Vital Sign and the Routine
medRxiv preprint doi: https://doi.org/10.1101/2020.12.08.20243337; this version posted December 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . UKB cardiorespiratory fitness and physical activity 1 The genetic case for cardiorespiratory fitness as a clinical vital sign and the routine 2 prescription of physical activity in healthcare 3 4 Ken B. Hanscombe1, 4, Elodie Persyn1, Matthew Traylor2, Kylie P. Glanville4, Mark Hamer 3, Jonathan R. I. Coleman4, 5 Cathryn M. Lewis1, 4 6 7 1Department of Medical & Molecular Genetics, King's College London, London, United Kingdom, 2Queen Mary 8 University of London, London, United Kingdom, 3Institute of Sport Exercise & Health, Division of Surgery and 9 Interventional Science, University College London, London, United Kingdom, 4Social, Genetic and Developmental 10 Psychiatry Centre, King's College London, London, United Kingdom 11 12 Ken B. Hanscombe [email protected] (corresponding author) 13 Elodie Persyn [email protected] 14 Matthew Traylor [email protected] 15 Kylie P. Glanville [email protected] 16 Mark Hamer [email protected] 17 Jonathan R. I. Coleman [email protected] 18 Cathryn M. Lewis [email protected] 19 20 21 Abstract 22 23 Background: Cardiorespiratory fitness (CRF) and physical activity (PA) are well-established predictors of morbidity and 24 all-cause mortality. However, CRF is not routinely measured and PA not routinely prescribed as part of standard 25 healthcare.