DOCSLIB.ORG

Aberrant Expression of FBXO2 Disrupts Glucose Homeostasis Through

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Aberrant Expression of FBXO2 Disrupts Glucose Homeostasis Through Page 1 of 48 Diabetes 1 Aberrant expression of FBXO2 disrupts glucose homeostasis through ubiquitin-mediated degradation of insulin receptor in obese mice Bin Liu1 *, Han Lu2 *, Duanzhuo Li1, Xuelian Xiong3, Lu Gao4, 5, Zhixiang Wu6, and Yan Lu1, 3 1 Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Cental Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, Hubei 435003, PR China. 2 Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai 200025, PR China. 3 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China. 4 College of Life Sciences, Northeast Agricultural University, No.59 Mucai street, Harbin 150030, Heilongjiang, PR China. 5 Department of Pathology, University of Maryland School of Medicine, 655W. Baltimore Street, Baltimore, MD, 21202-1192,USA. 6 Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), Shanghai 200092, PR China. * Co-first author 1 Diabetes Publish Ahead of Print, published online December 8, 2016 Diabetes Page 2 of 48 2 Corresponding authors Dr. Lu Gao, College of Life Sciences, Northeast Agricultural University, No.59 Mucai street, Harbin 150030, Heilongjiang, PR China. Tel: +86-045155191257 Fax: +86-045155191257 E-mail: [email protected] Dr. Zhixiang Wu, Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine (SJTU-SM), 1665 Kongjiang Road, Shanghai 200092, PR China. Tel: +86-21-25078413, Fax: +86-21-65791316, E-mail: [email protected] Dr. Yan Lu, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, PR China. Tel: +86-21-64041990 Fax: +86-21-64041990 E-mail: [email protected] 2 Page 3 of 48 Diabetes 3 Abstract Insulin resistance is a critical factor in the development of metabolic disorders, including type 2 diabetes (T2DM). However, its molecular mechanisms remain incompletely understood. In the present study, we found that F-box only protein 2 (FBXO2), a substrate recognition component of SKP1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, were up-regulated in livers of obese mice. Furthermore, using a protein purification approach combined with high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS), we carried out a system-wide screening of FBXO2 substrates, in which insulin receptor (IR) was identified as a substrate for FBXO2. SCFFBXO2 acts as an E3 ligase targeting the IR for ubiquitin-dependent degradation to regulate insulin signaling integrity. As a result, adenovirus-mediated overexpression of FBXO2 in healthy mice led to hyperglycemia, glucose intolerance and insulin resistance, while ablation of FBXO2 alleviated diabetic phenotypes in obese mice. Therefore, our results identify SCFFBXO2 as an E3 ligase for IR in the liver, which might provide a novel therapeutic target for treating T2DM and related metabolic disorders. Key Words: Type 2 diabetes, Insulin resistance, Insulin signaling, 3 Diabetes Page 4 of 48 4 Ubiquitination, Protein degradation, Type 2 diabetes mellitus (T2DM), characterized by high blood glucose levels, has become a pandemic problem worldwide. Usually, hyperglycemia is caused by deficiency of insulin secretion and/or reduced insulin sensitivity. In peripheral tissues, including liver, skeletal muscle and adipose tissue, insulin binds to its receptor (IR), which then phosphorylates and recruits insulin receptor substrates (IRS) to further activate downstream signaling pathways (1). In the liver, the major node of insulin signaling is activation of phosphoinositide-3-kinase (PI3K)/AKT, which in turn inhibits the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key gluconeogenic enzymes (2). As a result, hepatic insulin resistance is characterized by excessive hepatic glucose production, contributing to fasting hyperglycemia in T2DM (3). Therefore, identification of novel molecules involved in regulating the hepatic insulin signaling pathway will advance our understanding of the pathogenesis that leads to T2DM. Polyubiquitination is the formation of an ubiquitin chain on a single lysine residue on the substrate protein, leading to protein degradation (4). It is carried out by a three-step cascade of ubiquitin-transfer 4 Page 5 of 48 Diabetes 5 reactions: activation, conjugation, and ligation, performed by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), respectively (5). The largest subfamily of E3s in mammalian is the Skp1-Cul1-F box protein ubiquitin ligases (SCFs), which consist of Skp1, Cul1, Rbx1, and one of F box proteins (FBPs) (6). Recent studies have shown that FBPs play a crucial role in many biological events, such as inflammation, cell-cycle progression and tumorigenesis, through ubiquitin-mediated degradation of cellular regulatory proteins (7; 8). Besides, their dysregulation has been implicated in several pathologies (6-8), suggesting that insights into SCF-mediated biology may provide potential strategies to treat human diseases. However, until now, whether FBPs play a role in the metabolic diseases, especially insulin resistance and T2DM, remains poorly understood. Research design and Methods Animal experiments Male C57BL/6 and db/db mice aged 8-10 weeks were purchased from the Shanghai Laboratory Animal Company (SLAC) and Nanjing Biomedical Research Institute of Nanjing University, respectively. JNK1 knockout 5 Diabetes Page 6 of 48 6 mice were obtained from Jackson Laboratories and backcrossed to C57BL/6 background for 6 generations. All mice were housed at 21°C ± 1°C with humidity of 55% ± 10% and a 12-hour light/12-hour dark cycle. HFD-induced obese mice were maintained with free access to high-fat chow (D12492; Research Diets) containing 60% kcal from fat, 20% kcal from carbohydrate, and 20% kcal from protein. For the depletion of Kupffer cells, C57BL/6 mice were fed with a high-fat-diet for 12 weeks and then injected with gadolinium chloride (GdCl3, 10 mg/kg, twice each week) or sodium chloride (NaCl) by tail vein for another 2 weeks. All study protocols comply with guidelines and institutional policies prepared by the Animal Care Committee of Shanghai Jiao Tong University School of Medicine. Immuoprecipitation (IP) and in-solution digestion The standard IP purification procedure has been previously described (9). In brief, HEK293T cells stably expressing Flag-tagged wild-type or mutant FBXO2 were lysed in 5 mL lysis buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.5% Nonidet P40, and 100mM PMSF) for 20 min with gentle rocking at 4 °C. Lysates were cleared and subjected to IP with 50 μL of anti-FLAG M2 beads overnight at 4 °C. Beads containing immune 6 Page 7 of 48 Diabetes 7 complexes were washed with 1 mL ice cold lysis buffer. Proteins were eluted with 100 μL 3 × Flag-peptide (Sigma-Aldrich, St. Louis, MO, USA) in TBS for 30 min and precipitated with cold acetone. The precipitated proteins were in-solution digested with trypsin, and the tryptic peptides were vacuum centrifuged to dryness for further analysis. HPLC/MS/MS analysis Nanoflow LC-MS/MS was performed by coupling an Easy nLC 1000 (Thermo Fisher Scientific, Waltham, MA) to an Orbitrap Fusion mass spectrometer (Thermo Fisher Scientific, Waltham, MA). Tryptic peptides were dissolved in 20 µL of 0.1% formic acid, and 10 µL were injected for each analysis. Peptides were delivered to a trap column (2 cm length with 100 µm inner diameter, packed with 5 µm C18 resin) at a flow rate of 5 µL/min in 100% buffer A (0.1% FA in HPLC grade water). After 10 min of loading and washing, the peptides were transferred to an analytical column (17 cm× 79 μm, 3-μm particle size, Dikma, China) coupled to Easy nLC 1000 (Thermo Fisher Scientific, Waltham, MA). The separated peptides were ionized using NSI source, then analyzed in an Orbitrap Fusion mass spectrometer (Thermo Fisher Scientific, Waltham, MA) with a top speed 3s data-dependent mode. For MS/MS scan, ions with 7 Diabetes Page 8 of 48 8 intensity above 5,000 and charge state 2-6 in each full MS spectrum were sequentially fragmented by Higher Collision Dissociation with normalized collision energy of 32%. The dynamic exclusion duration was set to be 60 s, and the precursor ions were isolated by quadrupole with isolation window 1 Da. The fragment ions were analyzed in ion trap with AGC 7,000 at rapid scan mode. The raw spectra data was processed by protein discover and MS/MS spectra data was searched against the Uniprot human database (88,817 sequences) by Mascot (v.2.4, Matrix Science, London, UK) Bioinformatics analysis The molecular function, cellular component analysis of the glycoproteins was performed using Database for Annotation, Visualization and Integrated Discovery Bioinformatics Database (DAVID 6.7) (10; 11). Glucose and insulin tolerance tests Glucose tolerance tests were performed by intraperitoneal injection of D-glucose (Sigma-Aldrich, USA) at a dose of 2.0 mg/g body weight after a 16-hour fast. For insulin tolerance tests, mice were injected with regular human insulin (Eli Lily, Indianapolis, Indiana, USA) at a dose of 0.75 U/kg 8 Page 9 of 48 Diabetes 9 body weight after a 6-hour fast. Blood glucose was measured by a portable blood glucose meter (Lifescan, Johnson & Johnson, New Brunswick, New Jersey, USA). Western blots Hepatic tissues or cells were lysed in radioimmunoprecipitation buffer containing 50 mM Tris-HCl, 150 mM NaCl, 5 mM MgCl2, 2 mM EDTA, 1 mM NaF, 1% NP-40, and 0.1% sodium dodecyl sulfate. Western blots were performed using antibodies against FBXO2 (ab133717; Abcam), IRβ (ab131238; Abcam), AKT (13038, 4821; Cell Signaling) and GAPDH (5174; Cell Signaling). Analysis of tyrosine phosphorylation of IRS1 was performed by immunoprecipitation of IRS1 with anti-IRS1 from total lysate, followed by western blot with anti-pTyr antibody (PY100). Luciferase reporter and Chromatin immunoprecipitation assays All the transient transfections were conducted using Lipofectamine 2000 (Invitrogen, Shanghai, China).
Load more

Recommended publications
  • FBXO2 Antibody Cat
    FBXO2 Antibody Cat. No.: 55-088 FBXO2 Antibody Western blot analysis in mouse brain tissue and HepG2,293 cell line lysates (35ug/lane). Specifications HOST SPECIES: Rabbit SPECIES REACTIVITY: Human, Mouse This FBXO2 antibody is generated from rabbits immunized with a KLH conjugated IMMUNOGEN: synthetic peptide between 244-271 amino acids from the C-terminal region of human FBXO2. TESTED APPLICATIONS: Flow, WB For FACS starting dilution is: 1:10~50 APPLICATIONS: For WB starting dilution is: 1:1000 PREDICTED MOLECULAR 33 kDa WEIGHT: September 24, 2021 1 https://www.prosci-inc.com/fbxo2-antibody-55-088.html Properties This antibody is purified through a protein A column, followed by peptide affinity PURIFICATION: purification. CLONALITY: Polyclonal ISOTYPE: Rabbit Ig CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: Supplied in PBS with 0.09% (W/V) sodium azide. CONCENTRATION: batch dependent Store at 4˚C for three months and -20˚C, stable for up to one year. As with all antibodies STORAGE CONDITIONS: care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to prolonged high temperatures. Additional Info OFFICIAL SYMBOL: FBXO2 ALTERNATE NAMES: F-box only protein 2, FBXO2, FBX2 ACCESSION NO.: Q9UK22 PROTEIN GI NO.: 51338836 GENE ID: 26232 USER NOTE: Optimal dilutions for each application to be determined by the researcher. Background and References This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination.
    [Show full text]
  • ACE2 Interaction Networks in COVID-19: a Physiological Framework for Prediction of Outcome in Patients with Cardiovascular Risk Factors
    Journal of Clinical Medicine Article ACE2 Interaction Networks in COVID-19: A Physiological Framework for Prediction of Outcome in Patients with Cardiovascular Risk Factors Zofia Wicik 1,2 , Ceren Eyileten 2, Daniel Jakubik 2,Sérgio N. Simões 3, David C. Martins Jr. 1, Rodrigo Pavão 1, Jolanta M. Siller-Matula 2,4,* and Marek Postula 2 1 Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Santo Andre 09606-045, Brazil; zofi[email protected] (Z.W.); [email protected] (D.C.M.J.); [email protected] (R.P.) 2 Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, 02-091 Warsaw, Poland; [email protected] (C.E.); [email protected] (D.J.); [email protected] (M.P.) 3 Federal Institute of Education, Science and Technology of Espírito Santo, Serra, Espírito Santo 29056-264, Brazil; [email protected] 4 Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090 Vienna, Austria * Correspondence: [email protected]; Tel.: +43-1-40400-46140; Fax: +43-1-40400-42160 Received: 9 October 2020; Accepted: 17 November 2020; Published: 21 November 2020 Abstract: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcomes in patients with cardiovascular disease (CVD). The aim of the study was to characterize the interaction between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) functional networks with a focus on CVD. Methods: Using the network medicine approach and publicly available datasets, we investigated ACE2 tissue expression and described ACE2 interaction networks that could be affected by SARS-CoV-2 infection in the heart, lungs and nervous system.
    [Show full text]
  • Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
    [Show full text]
  • Greg's Awesome Thesis
    Analysis of alignment error and sitewise constraint in mammalian comparative genomics Gregory Jordan European Bioinformatics Institute University of Cambridge A dissertation submitted for the degree of Doctor of Philosophy November 30, 2011 To my parents, who kept us thinking and playing This dissertation is the result of my own work and includes nothing which is the out- come of work done in collaboration except where specifically indicated in the text and acknowledgements. This dissertation is not substantially the same as any I have submitted for a degree, diploma or other qualification at any other university, and no part has already been, or is currently being submitted for any degree, diploma or other qualification. This dissertation does not exceed the specified length limit of 60,000 words as defined by the Biology Degree Committee. November 30, 2011 Gregory Jordan ii Analysis of alignment error and sitewise constraint in mammalian comparative genomics Summary Gregory Jordan November 30, 2011 Darwin College Insight into the evolution of protein-coding genes can be gained from the use of phylogenetic codon models. Recently sequenced mammalian genomes and powerful analysis methods developed over the past decade provide the potential to globally measure the impact of natural selection on pro- tein sequences at a fine scale. The detection of positive selection in particular is of great interest, with relevance to the study of host-parasite conflicts, immune system evolution and adaptive dif- ferences between species. This thesis examines the performance of methods for detecting positive selection first with a series of simulation experiments, and then with two empirical studies in mammals and primates.
    [Show full text]
  • Human Lectins, Their Carbohydrate Affinities and Where to Find Them
    biomolecules Review Human Lectins, Their Carbohydrate Affinities and Where to Review HumanFind Them Lectins, Their Carbohydrate Affinities and Where to FindCláudia ThemD. Raposo 1,*, André B. Canelas 2 and M. Teresa Barros 1 1, 2 1 Cláudia D. Raposo * , Andr1 é LAQVB. Canelas‐Requimte,and Department M. Teresa of Chemistry, Barros NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829‐516 Caparica, Portugal; [email protected] 12 GlanbiaLAQV-Requimte,‐AgriChemWhey, Department Lisheen of Chemistry, Mine, Killoran, NOVA Moyne, School E41 of ScienceR622 Co. and Tipperary, Technology, Ireland; canelas‐ [email protected] NOVA de Lisboa, 2829-516 Caparica, Portugal; [email protected] 2* Correspondence:Glanbia-AgriChemWhey, [email protected]; Lisheen Mine, Tel.: Killoran, +351‐212948550 Moyne, E41 R622 Tipperary, Ireland; [email protected] * Correspondence: [email protected]; Tel.: +351-212948550 Abstract: Lectins are a class of proteins responsible for several biological roles such as cell‐cell in‐ Abstract:teractions,Lectins signaling are pathways, a class of and proteins several responsible innate immune for several responses biological against roles pathogens. such as Since cell-cell lec‐ interactions,tins are able signalingto bind to pathways, carbohydrates, and several they can innate be a immuneviable target responses for targeted against drug pathogens. delivery Since sys‐ lectinstems. In are fact, able several to bind lectins to carbohydrates, were approved they by canFood be and a viable Drug targetAdministration for targeted for drugthat purpose. delivery systems.Information In fact, about several specific lectins carbohydrate were approved recognition by Food by andlectin Drug receptors Administration was gathered for that herein, purpose. plus Informationthe specific organs about specific where those carbohydrate lectins can recognition be found by within lectin the receptors human was body.
    [Show full text]
  • Human Transcription Factor and Protein Kinase Gene Fusions in Human Cancer
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.09.033613; this version posted April 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Human Transcription Factor and Protein Kinase Gene Fusions in Human Cancer Kari Salokas1, Rigbe G. Weldatsadik1 and Varjosalo Markku1* 1Systems Pathology/Biology Research Group, Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland. * Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.04.09.033613; this version posted April 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ABSTRACT Oncogenic gene fusions are estimated to account for up-to 20 % of cancer morbidity. Originally, oncofusions were identified in blood cancer, but recently multiple sequence-level studies of cancer genomes have established oncofusions throughout all tissue types. However, the functional implications of the identified oncofusions have often not been investigated. In this study, the identified oncofusions from a fusion detection approach (DEEPEST) were analyzed in more detail. In total, DEEPEST contains 28863 unique fusions. From sequence analysis, we found that almost 30% of them (8225) are expected to produce functional fusion proteins with features from both parent genes. Kinases and transcription factors were found to be the main gene families of the protein producing fusions. Considering their role as initiators, actors, and termination points of cellular signaling pathways, we focused our in-depth analyses on them.
    [Show full text]
  • Plasma Cells in Vitro Generation of Long-Lived Human
    Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021 is online at: average * The Journal of Immunology , 32 of which you can access for free at: 2012; 189:5773-5785; Prepublished online 16 from submission to initial decision 4 weeks from acceptance to publication November 2012; doi: 10.4049/jimmunol.1103720 http://www.jimmunol.org/content/189/12/5773 In Vitro Generation of Long-lived Human Plasma Cells Mario Cocco, Sophie Stephenson, Matthew A. Care, Darren Newton, Nicholas A. Barnes, Adam Davison, Andy Rawstron, David R. Westhead, Gina M. Doody and Reuben M. Tooze J Immunol cites 65 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/11/16/jimmunol.110372 0.DC1 This article http://www.jimmunol.org/content/189/12/5773.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 24, 2021. The Journal of Immunology In Vitro Generation of Long-lived Human Plasma Cells Mario Cocco,*,1 Sophie Stephenson,*,1 Matthew A.
    [Show full text]
  • In This Table Protein Name, Uniprot Code, Gene Name P-Value
    Supplementary Table S1: In this table protein name, uniprot code, gene name p-value and Fold change (FC) for each comparison are shown, for 299 of the 301 significantly regulated proteins found in both comparisons (p-value<0.01, fold change (FC) >+/-0.37) ALS versus control and FTLD-U versus control. Two uncharacterized proteins have been excluded from this list Protein name Uniprot Gene name p value FC FTLD-U p value FC ALS FTLD-U ALS Cytochrome b-c1 complex P14927 UQCRB 1.534E-03 -1.591E+00 6.005E-04 -1.639E+00 subunit 7 NADH dehydrogenase O95182 NDUFA7 4.127E-04 -9.471E-01 3.467E-05 -1.643E+00 [ubiquinone] 1 alpha subcomplex subunit 7 NADH dehydrogenase O43678 NDUFA2 3.230E-04 -9.145E-01 2.113E-04 -1.450E+00 [ubiquinone] 1 alpha subcomplex subunit 2 NADH dehydrogenase O43920 NDUFS5 1.769E-04 -8.829E-01 3.235E-05 -1.007E+00 [ubiquinone] iron-sulfur protein 5 ARF GTPase-activating A0A0C4DGN6 GIT1 1.306E-03 -8.810E-01 1.115E-03 -7.228E-01 protein GIT1 Methylglutaconyl-CoA Q13825 AUH 6.097E-04 -7.666E-01 5.619E-06 -1.178E+00 hydratase, mitochondrial ADP/ATP translocase 1 P12235 SLC25A4 6.068E-03 -6.095E-01 3.595E-04 -1.011E+00 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 Protein kinase C and casein Q9BY11 PACSIN1 3.837E-03 -5.863E-01 3.680E-06 -1.824E+00 kinase substrate in neurons protein 1 Tubulin polymerization- O94811 TPPP 6.466E-03 -5.755E-01 6.943E-06 -1.169E+00 promoting protein MIC C9JRZ6 CHCHD3 2.912E-02 -6.187E-01 2.195E-03 -9.781E-01 Mitochondrial 2-
    [Show full text]
  • FBXO2 (1-296, His-Tag) Human Protein – AR51572PU-S | Origene
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for AR51572PU-S FBXO2 (1-296, His-tag) Human Protein Product data: Product Type: Recombinant Proteins Description: FBXO2 (1-296, His-tag) human protein, 50 µg Species: Human Expression Host: E. coli Tag: His-tag Predicted MW: 35.7 kDa Concentration: lot specific Purity: >80% by SDS - PAGE Buffer: Presentation State: Purified State: Liquid purified protein Buffer System: 20 mM Tris-HCl buffer (pH 8.0) containing 0.15M NaCl, 30% glycerol, 1mM DTT Preparation: Liquid purified protein Storage: Store undiluted at 2-8°C for one week or (in aliquots) at -20°C to -80°C for longer. Avoid repeated freezing and thawing. Stability: Shelf life: one year from despatch. RefSeq: NP_036300 Locus ID: 26232 UniProt ID: Q9UK22 Cytogenetics: 1p36.22 Synonyms: FBG1; Fbs1; FBX2; NFB42; OCP1 This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 FBXO2 (1-296, His-tag) Human Protein – AR51572PU-S Summary: This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs.
    [Show full text]
  • Fbxo2 Mediates Clearance of Damaged Lysosomes and Modifies Neurodegeneration in the Niemann-Pick C Brain
    Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain Elaine A. Liu, … , Henry L. Paulson, Andrew P. Lieberman JCI Insight. 2020. https://doi.org/10.1172/jci.insight.136676. Research In-Press Preview Neuroscience Graphical abstract Find the latest version: https://jci.me/136676/pdf Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain Elaine A. Liu1, 2, 3, Mark L. Schultz1, Chisaki Mochida4, Chan Chung1, Henry L. Paulson5, Andrew P. Lieberman1 1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104 USA 2Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109 USA 3Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109 USA 4Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505 Japan 5Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109 USA *To whom correspondence should be addressed: Department of Pathology University of Michigan Medical School 3510 MSRB1, 1150 W. Medical Center Dr. Ann Arbor, MI 48109 Telephone: (734) 647-4624 Email: [email protected] The authors have declared that no conflict of interest exists. Abstract A critical response to lysosomal membrane permeabilization (LMP) is the clearance of damaged lysosomes through a selective form of macroautophagy known as lysophagy. Although regulators of this process are emerging, whether organ and cell specific components contribute to the control of lysophagy remains incompletely understood. Here, we examine LMP and lysophagy in Niemann-Pick type C disease (NPC), an autosomal recessive disorder characterized by the accumulation of unesterified cholesterol within late endosomes and lysosomes, leading to neurodegeneration and early death.
    [Show full text]
  • Deciphering the Molecular Profile of Plaques, Memory Decline And
    ORIGINAL RESEARCH ARTICLE published: 16 April 2014 AGING NEUROSCIENCE doi: 10.3389/fnagi.2014.00075 Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer’s disease by deep sequencing Yvonne Bouter 1†,Tim Kacprowski 2,3†, Robert Weissmann4, Katharina Dietrich1, Henning Borgers 1, Andreas Brauß1, Christian Sperling 4, Oliver Wirths 1, Mario Albrecht 2,5, Lars R. Jensen4, Andreas W. Kuss 4* andThomas A. Bayer 1* 1 Division of Molecular Psychiatry, Georg-August-University Goettingen, University Medicine Goettingen, Goettingen, Germany 2 Department of Bioinformatics, Institute of Biometrics and Medical Informatics, University Medicine Greifswald, Greifswald, Germany 3 Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany 4 Human Molecular Genetics, Department for Human Genetics of the Institute for Genetics and Functional Genomics, Institute for Human Genetics, University Medicine Greifswald, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany 5 Institute for Knowledge Discovery, Graz University of Technology, Graz, Austria Edited by: One of the central research questions on the etiology of Alzheimer’s disease (AD) is the Isidro Ferrer, University of Barcelona, elucidation of the molecular signatures triggered by the amyloid cascade of pathological Spain events. Next-generation sequencing allows the identification of genes involved in disease Reviewed by: Isidro Ferrer, University of Barcelona, processes in an unbiased manner. We have combined this technique with the analysis of Spain two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneu- Dietmar R. Thal, University of Ulm, ronal Ab aggregation, neuron loss, and behavioral deficits. (2)TheTg4–42 model expresses Germany N-truncated Ab4–42 and develops neuron loss and behavioral deficits albeit without plaque *Correspondence: formation.
    [Show full text]
  • Team Publications Diversity and Plasticity of Childhood Tumors (Depict)
    Team Publications Diversity and Plasticity of Childhood Tumors (DePiCT) Year of publication 2005 Franck Bourdeaut, Delphine Trochet, Isabelle Janoueix-Lerosey, Agnès Ribeiro, Anne Deville, Carole Coz, Jean-François Michiels, Stanislas Lyonnet, Jeanne Amiel, Olivier Delattre (2005 Jun 14) Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Cancer letters : 51-8 Summary Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung’s disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung’s disease in another branch. A constitutional R100L PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline PHOX2B mutation in one patient treated for Hirschsprung’s disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the PHOX2B protein. No loss of heterozygosity at the PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify PHOX2B as the first predisposing gene to hereditary neuroblastic tumours.
    [Show full text]