Transcriptome Analysis of Newt Lens Regeneration Reveals Distinct Gradients in Gene Expression Patterns
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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. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Eif2b Is a Decameric Guanine Nucleotide Exchange Factor with a G2e2 Tetrameric Core
ARTICLE Received 19 Feb 2014 | Accepted 15 Apr 2014 | Published 23 May 2014 DOI: 10.1038/ncomms4902 OPEN eIF2B is a decameric guanine nucleotide exchange factor with a g2e2 tetrameric core Yuliya Gordiyenko1,2,*, Carla Schmidt1,*, Martin D. Jennings3, Dijana Matak-Vinkovic4, Graham D. Pavitt3 & Carol V. Robinson1 eIF2B facilitates and controls protein synthesis in eukaryotes by mediating guanine nucleotide exchange on its partner eIF2. We combined mass spectrometry (MS) with chemical cross- linking, surface accessibility measurements and homology modelling to define subunit stoichiometry and interactions within eIF2B and eIF2. Although it is generally accepted that eIF2B is a pentamer of five non-identical subunits (a–e), here we show that eIF2B is a decamer. MS and cross-linking of eIF2B complexes allows us to propose a model for the subunit arrangements within eIF2B where the subunit assembly occurs through catalytic g- and e-subunits, with regulatory subunits arranged in asymmetric trimers associated with the core. Cross-links between eIF2 and eIF2B allow modelling of interactions that contribute to nucleotide exchange and its control by eIF2 phosphorylation. Finally, we identify that GTP binds to eIF2Bg, prompting us to propose a multi-step mechanism for nucleotide exchange. 1 Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK. 2 MRC Laboratory of Molecular Biology, University of Cambridge, Francis Crick Avenue, Cambridge CB2 0QH, UK. 3 Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. 4 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. -
Cofactor Dependent Conformational Switching of Gtpases
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 1704 Biophysical Journal Volume 95 August 2008 1704–1715 Cofactor Dependent Conformational Switching of GTPases Vasili Hauryliuk,*y Sebastian Hansson,z and Ma˚ns Ehrenberg* *Department of Cell and Molecular Biology, Molecular Biology Program, Uppsala University, Uppsala, Sweden; yEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; and zLaboratoire d’Enzymologie et Biochimie Structurales, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France ABSTRACT This theoretical work covers structural and biochemical aspects of nucleotide binding and GDP/GTP exchange of GTP hydrolases belonging to the family of small GTPases. Current models of GDP/GTP exchange regulation are often based on two specific assumptions. The first is that the conformation of a GTPase is switched by the exchange of the bound nucleotide from GDP to GTP or vice versa. The second is that GDP/GTP exchange is regulated by a guanine nucleotide exchange factor, which stabilizes a GTPase conformation with low nucleotide affinity. Since, however, recent biochemical and structural data seem to contradict this view, we present a generalized scheme for GTPase action. This novel ansatz accounts for those important cases when conformational switching in addition to guanine nucleotide exchange requires the presence of cofactors, and gives a more nuanced picture of how the nucleotide exchange is regulated. The scheme is also used to discuss some problems of interpretation that may arise when guanine nucleotide exchange mechanisms are inferred from experiments with analogs of GTP, like GDPNP, GDPCP, and GDP g S. -
A Dissertation Entitled Characterization of the CXCR4
A Dissertation entitled Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer by Cory M Howard Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences ___________________________________________ Dayanidhi Raman, B.V.Sc., Ph.D., Committee Chair ___________________________________________ Amit Tiwari, Ph.D., Committee Member ___________________________________________ Ritu Chakravarti, Ph.D., Committee Member ___________________________________________ Nagalakshmi Nadiminty, Ph.D., Committee Member ___________________________________________ Saori Furuta, Ph.D., Committee Member ___________________________________________ Shi-He Liu, M.D., Committee Member ___________________________________________ Amanda C. Bryant-Friedrich, Ph.D., Dean College of Graduate Studies The University of Toledo August 2020 © 2020 Cory M. Howard This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer by Cory M. Howard Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo August 2020 Triple-negative breast cancer (TNBC) remains clinically challenging as effective targeted therapies are still lacking. In addition, patient mortality mainly results from the metastasized -
A Dissertation Entitled the Androgen Receptor
A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen. -
Nck Adapter Proteins: Functional Versatility in T Cells Marcus Lettau, Jennifer Pieper and Ottmar Janssen
Cell Communication and Signaling BioMed Central Review Open Access Nck adapter proteins: functional versatility in T cells Marcus Lettau, Jennifer Pieper and Ottmar Janssen Address: 1University Hospital Schleswig-Holstein Campus Kiel, Institute of Immunology, Molecular Immunology, Arnold-Heller-Str 3, Bldg 17, D-24105 Kiel, Germany E-mail: Marcus Lettau* - [email protected]; Jennifer Pieper - [email protected]; Ottmar Janssen - [email protected] *Corresponding author Published: 02 February 2009 Received: 2 December 2008 Cell Communication and Signaling 2009, 7:1 doi: 10.1186/1478-811X-7-1 Accepted: 2 February 2009 This article is available from: http://www.biosignaling.com/content/7/1/1 © 2009 Lettau et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Nck is a ubiquitously expressed adapter protein that is almost exclusively built of one SH2 domain and three SH3 domains. The two isoproteins of Nck are functionally redundant in many aspects and differ in only few amino acids that are mostly located in the linker regions between the interaction modules. Nck proteins connect receptor and non-receptor tyrosine kinases to the machinery of actin reorganisation. Thereby, Nck regulates activation-dependent processes during cell polarisation and migration and plays a crucial role in the signal transduction of a variety of receptors including for instance PDGF-, HGF-, VEGF- and Ephrin receptors. In most cases, the SH2 domain mediates binding to the phosphorylated receptor or associated phosphoproteins, while SH3domaininteractionsleadtotheformationoflargerproteincomplexes.InTlymphocytes,Nck plays a pivotal role in the T cell receptor (TCR)-induced reorganisation of the actin cytoskeleton and the formation of the immunological synapse. -
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A Canonical Cancer-Network Map Eugene F. Douglass Jr., Ph.D. ;<=:>&'? Cell-Surface Interactions @@@JJ; Growth Receptor Signalling Cell-ECM Growth/Motility Proliferation Cell-Cell Contact Inhibition Metabolism MMP COLONIC CRYPT IGF/IGFR-1 EGFR / ErbB WNT ! WNT ! WNT WNT Integrin WNT RAS must be held near PI3K to activate it 5 CAD-domains Signalosome R-spdn p.195 GTP RAS PTEN NF1 SOS PLC PIP3 E-cadherin SHC PIP RASGAP GRB2 2 ZNRF3 p120 p120 " p120 p120 p120 p120 FZD Akt PDK1 PH JM Src-dep Y845 STAT3 GDP GTP Y974 F-actin PI3K PTB SHC/SHP2 GRB2 LRP Assembly vincilin talin PI3K Integrin-Linked Kinase(ILK) Y981 RAS RAS LGR RNF43 NCK2 ! ! ! ARP2/3 FAK Y988 FAK 2 min PINCH SOCS3 C hevell Akt KD s e paxilin SOS i d PDK1 Src IRS1 ! ! ! d paxilin Src (PKB) internlz AP2 RSU1 Y1015 ½ HIC5 ! t PI3K Y460 SOCS1/6 Y992 PLC" Parvin Src TESK1 PI3K Y546 SHIP2 GTP p130Cas CRK CSG ubiq axin PAK1 Y1091 Y1045 CBL S46-7 RAF-1 KSR DOCK180 SOS PI3K Y608 S1057 = GSK3 PI3K Y628 Y1127 Y1068 GRB2 14-3-3 14-3-3 PI3K Y658 GRB2 Y1086 B-RAF C-RAF GSK RHEB PI3K Y690 RASGAP 9 Wtx mTOR1 Y1163 Y1101 Gab1 Apc PI3K Y727 Y1167 PI3K Y759 RASGAP Y1168 MAPK Rac GTP Y1148 SHC GRB2 p120 p120 Y815 SHIP2 RhoGEF RalGEF p70-S6K Y1215 ! ! Y1175 SOS GTP Y891 phos SHP1 Cdc42 Y903 SHIP2 Y1253 SHP2 GRB2 ! ! PTP1 MKK1/2 PI3K Y935 Wtx GTP CT ! Rho PI3K Y983 SHIP2 Y1282 GRB2 SHP2 Y1006 Y1283 RalBP1 RalA/B GTP MP1 axin PI3K Y1352 PI3K Erk1/2 GSK3 Sprouty Apc MKP1 GTP GRB2 SHP2 Y1173 Rac 1. -
Regulation of the Stability of the Protein Kinase DYRK1A: Establishing Connections with the Wnt Signaling Pathway
Regulation of the stability of the protein kinase DYRK1A: establishing connections with the Wnt signaling pathway Krisztina Arató TESI DOCTORAL UPF / 2010 Barcelona, November 2010 Regulation of the stability of the protein kinase DYRK1A: establishing connections with the Wnt signaling pathway Krisztina Arató Memòria presentada per optar al grau de Doctora per la Universitat Pompeu Fabra. Aquesta tesi ha estat realitzada sota la direcció de la Dra. Susana de la Luna al Centre de Regulació Genòmica (CRG, Barcelona), dins del Programa de Genes i Malaltia. Krisztina Arató Susana de la Luna A Pere, por haberme traído a Barcelona… Cover design by Luisa Lente (www.yoyo.es). Index Page Abstract/Resumen.................................................................................. 1 Introduction............................................................................................. 5 The protein kinase DYRK1A................................................................ 7 The DYRK family of protein ....................................................... 7 Structure and mechanism of activation of DYRK1A kinase........ 8 Regulation of DYRK1A expression ............................................ 10 Regulation of DYRK1A subcellular localization.......................... 11 Regulation of DYRK1A activity................................................... 13 DYRK1A as a regulator of signaling pathways........................... 14 The Notch signaling pathway........................................... 16 Receptor tyrosine kinase signaling................................. -
The Energy Status of Astrocytes Is the Achilles' Heel of Eif2b
cells Article The Energy Status of Astrocytes Is the Achilles’ Heel of eIF2B-Leukodystrophy Melisa Herrero 1, Maron Daw 1, Andrea Atzmon 1 and Orna Elroy-Stein 1,2,* 1 Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; [email protected] (M.H.); [email protected] (M.D.); [email protected] (A.A.) 2 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel * Correspondence: [email protected] Abstract: Translation initiation factor 2B (eIF2B) is a master regulator of global protein synthesis in all cell types. The mild genetic Eif2b5(R132H) mutation causes a slight reduction in eIF2B enzymatic activity which leads to abnormal composition of mitochondrial electron transfer chain complexes and impaired oxidative phosphorylation. Previous work using primary fibroblasts isolated from Eif2b5(R132H/R132H) mice revealed that owing to increased mitochondrial biogenesis they exhibit normal cellular ATP level. In contrast to fibroblasts, here we show that primary astrocytes isolated from Eif2b5(R132H/R132H) mice are unable to compensate for their metabolic impairment and exhibit chronic state of low ATP level regardless of extensive adaptation efforts. Mutant astrocytes are hypersensitive to oxidative stress and to further energy stress. Moreover, they show migration deficit upon exposure to glucose starvation. The mutation in Eif2b5 prompts reactive oxygen species (ROS)-mediated inferior ability to stimulate the AMP-activated protein kinase (AMPK) axis, due to a requirement to increase the mammalian target of rapamycin complex-1 (mTORC1) Citation: Herrero, M.; Daw, M.; signalling in order to enable oxidative glycolysis and generation of specific subclass of ROS-regulating Atzmon, A.; Elroy-Stein, O. -
The Eukaryotic Translation Initiation Factor 2, a Hero Turned Villain in Β Cells
The eukaryotic translation initiation factor 2, a hero turned villain in β cells By Baroj Abdulkarim Université libre de Bruxelles Faculty of Medicine ULB Center for Diabetes Research Academic year 2016-2017 Jury Members: Dr. Ingrid Langer (President) Dr. Miriam Cnop (Promoter and secretary) Dr. Mariana Igoillo Esteve (Co-Promoter) Dr. Daniel Christophe Dr. Christophe Erneux Dr. Claudine Heinrichs Dr. Amar Abderrahmani Dr. Patrick Gilon Dedicated to my daughter Elîn 2 Contents Papers constituting this thesis .................................................................................... 4 Abbreviations .............................................................................................................. 5 Abstract ...................................................................................................................... 8 Résumé ...................................................................................................................... 9 Introduction ............................................................................................................... 10 Diabetes mellitus ................................................................................................... 10 How β cells work ................................................................................................ 11 Type 2 and monogenic diabetes ........................................................................ 12 Free fatty acids and diabetes ............................................................................... -
Wellison Jarles Da Silva Diniz Identificação De Redes
UNIVERSIDADE FEDERAL DE SÃO CARLOS CENTRO DE CIÊNCIAS BIOLÓGICAS E DA SAÚDE PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA EVOLUTIVA E BIOLOGIA MOLECULAR WELLISON JARLES DA SILVA DINIZ IDENTIFICAÇÃO DE REDES GÊNICAS DE COEXPRESSÃO E DOS MECANISMOS REGULATÓRIOS ASSOCIADOS À COMPOSIÇÃO MINERAL E QUALIDADE DE CARNE EM BOVINOS SÃO CARLOS - SP 2019 WELLISON JARLES DA SILVA DINIZ IDENTIFICAÇÃO DE REDES GÊNICAS DE COEXPRESSÃO E DOS MECANISMOS REGULATÓRIOS ASSOCIADOS À COMPOSIÇÃO MINERAL E QUALIDADE DE CARNE EM BOVINOS Thesis submitted iN partial fulfillmeNt of the requiremeNts for the Doctor of Philosophy degree in EvolutioNary GeNetics aNd Molecular Biology from the GraduatioN Program of EvolutioNary GeNetics aNd Molecular Biology, CeNter for Biological aNd Health ScieNces in the Federal UNiversity of São Carlos. Advisor: Prof. Dr. LuciaNa Correia de Almeida RegitaNo São Carlos-SP 2019 This thesis is dedicated to my family for all the encouragement and support to pursue my dreams, and to my dearest wife, Priyanka, for all the love and abetting through the Ph.D. path. ACKNOWLEDGMENTS Through these four years of Ph.D. course, I was lucky to meet aNd have had the pleasure to collaborate with exceptioNal professioNals who guided me to make great persoNal aNd scieNtific achievemeNts. I am profouNdly grateful to all of those who coNtributed to my learNiNg, direct or iNdirectly, aNd uNfortuNately, I’m Not able to Name all of them here. However, be sure that you were importaNt aNd are part of this achievemeNt. I am grateful to my advisor, Prof. Dr. LuciaNa C. A. RegitaNo, for all the guidaNce, meNtoriNg, frieNdship, support, aNd trust duriNg the Ph.D.