DOCSLIB.ORG

Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival to Dampen the Autoantibody Response In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival to Dampen the Autoantibody Response In Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus This information is current as of September 26, 2021. Tonika Lam, Dennis V. Kulp, Rui Wang, Zheng Lou, Julia Taylor, Carlos E. Rivera, Hui Yan, Qi Zhang, Zhonghua Wang, Hong Zan, Dmitri N. Ivanov, Guangming Zhong, Paolo Casali and Zhenming Xu J Immunol 2016; 197:3792-3805; Prepublished online 14 Downloaded from October 2016; doi: 10.4049/jimmunol.1601427 http://www.jimmunol.org/content/197/10/3792 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/10/13/jimmunol.160142 Material 7.DCSupplemental References This article cites 70 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/197/10/3792.full#ref-list-1 by guest on September 26, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Small Molecule Inhibition of Rab7 Impairs B Cell Class Switching and Plasma Cell Survival To Dampen the Autoantibody Response in Murine Lupus Tonika Lam,*,1 Dennis V. Kulp,*,1 Rui Wang,*,1,2 Zheng Lou,* Julia Taylor,* Carlos E. Rivera,* Hui Yan,* Qi Zhang,* Zhonghua Wang,† Hong Zan,* Dmitri N. Ivanov,† Guangming Zhong,* Paolo Casali,*,3 and Zhenming Xu*,3 IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the class- switched IgG autoantibody response in MRL/Faslpr/lpr and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated Downloaded from with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell–dependent and T cell–independent Ab responses, but it did not affect T cell–mediated clearance of Chlamydia infection, consistent with a B cell–specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class switching and survival, respectively, whereas proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-kB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-kB activation, indicated that Rab7 mediates these http://www.jimmunol.org/ processes by promoting NF-kB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus. The Journal of Immunology, 2016, 197: 3792–3805. lass switch DNA recombination (CSR) in the IgH locus underlying B cell class switching and plasma cell generation/ substitutes the IgH constant (CH) region, such as Cm of maintenance targets of new lupus therapeutics. C IgM expressed in naive B cells, with Cg,Ca,orCε, thereby Similar to SHM, CSR requires activation-induced cytidine de- giving rise to IgG, IgA, or IgE Abs. Together with somatic hyper- aminase (AID, encoded by AICDA in humans and Aicda in mice). by guest on September 26, 2021 mutation (SHM), CSR is central to the maturation of the Ab response AID expression is mainly restricted in peripheral B cells activated to pathogens, as class-switched Abs display wide tissue distributions by CD154 engagement of CD40 on the B cell surface or by com- and possess diverse biological effector functions (1). These traits also plex Ags that engage both a TLR and the BCR (7). AID is elevated make IgG and IgA autoantibodies highly pathogenic and capable of in B cells of lupus patients and lupus mice, consistent with the mediating multiple organ damage in systemic lupus erythematosus heightened CSR/SHM in these B cells (8), and AID deficiency (SLE) (2, 3). Unswitched IgM autoantibodies are mostly nonpatho- abrogates IgG autoantibodies in lupus-prone MRL/Faslpr/lpr mice genic and, rather, may mediate frontline immune protection as natural (8, 9). Inhibitors of AID deaminase activity are yet to be developed, polyreactive Abs (4). Class-switched B cells further differentiate into thereby emphasizing the need for molecules that target the mech- memory B cells or plasma cells, which secrete Abs at a high rate. A anisms underlying AID induction to dampen the class-switched hallmark of active lupus is the high number of IgG+ Ab-secreting cells pathogenic autoantibody response. (ASCs) that produce autoantibodies. These are diverse but generally Ras-related in brain 7 (Rab7; encoded by RAB7A in humans and target nuclear Ags, such as DNA (5, 6), making the mechanisms Rab7 in mice) is a small GTPase that, when bound to its GTP *Department of Microbiology, Immunology and Molecular Genetics, University of Identification in Lupus Grant ALR 295955 and the Zachry Foundation Distinguished Texas School of Medicine, University of Texas Health Science Center at San Anto- Chair, D.N.I. by a Voelcker Fund Young Investigator Award, H.Z. by an Arthritis nio, San Antonio, TX 78229; and †Department of Biochemistry, University of Texas National Research Foundation research grant, and R.W. by the Xiangya School of School of Medicine, University of Texas Health Science Center at San Antonio, San Medicine, Central South University of China. Antonio, TX 78229 Address correspondence and reprint requests to Dr. Paolo Casali and Dr. Zhenming 1T.L., D.V.K., and R.W. contributed equally to this work. Xu, Department of Microbiology, Immunology and Molecular Genetics, University of Texas School of Medicine, University of Texas Health Science Center at San 2Current address: Xiangya School of Medicine, Central South University of China, Antonio, 7703 Floyd Curl Drive, Mail Code 7758, San Antonio, TX 78229. E-mail Changsha, Hunan, China. addresses: [email protected] (P.C.) and [email protected] (Z.X.) 3P.C. and Z.X. jointly directed the study. The online version of this article contains supplemental material. ORCIDs: 0000-0002-6270-7234 (T.L.); 0000-0002-9048-7048 (D.V.K.); 0000-0002- Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; AID, activation- 7549-0812 (J.T.); 0000-0001-6906-107X (Z.W.); 0000-0001-7053-5009 (G.Z.); induced cytidine deaminase; ANA, anti-nuclear Ab; ASC, Ab-secreting cell; C57, 0000-0002-8982-5177 (P.C.). C57BL/6; CGG, chicken g-globulin; CSR, class switch DNA recombination; DC, Received for publication August 16, 2016. Accepted for publication September 9, dendritic cell; NMR, nuclear magnetic resonance; NP, (4-hydroxy-3-nitrophenyl)acetyl; 2016. PAS, periodic acid–Schiff; PNA, peanut agglutinin; qRT-PCR, quantitative RT-PCR; RA, retinoic acid; Rab7, Ras-related in brain 7; SLE, systemic lupus erythematosus. This work was supported by National Institutes of Health Grants AI 079705 and AI 105813 (to P.C.), AI 124172 (to Z.X.), AI 104476 (to D.N.I.), and AI 047997 (to Ó G.Z.). P.C. was also partially supported by Alliance for Lupus Research Target Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601427 The Journal of Immunology 3793 substrate, promotes endosome maturation and autophagy. As we 1067700 for 10 wk and maintained until moribund (e.g., showing signs of have shown (10), Rab7 is induced in activated B cells in vivo (i.e., in severe loss of mobility, hunched back, piloerection, ruffled fur, dyspnea, peanut agglutinin [PNA]hi germinal center B cells) and in vitro, for gasping, and weight loss), at which point they were euthanized. For other clinical, serological, cellular, and molecular analyses (see below), mice example, by CD154 and TLR ligands, the same stimuli that induce were treated for 7 wk in a double-blind manner, as their identities were AID expression and CSR. It plays a B cell–intrinsic role in Ab re- made unknown to investigators who performed these assays. sponses, as mice that conditionally knockout Rab7 in activated For immunization, C57 mice were treated with nil or CID 1067700 7 d B cells cannot mount mature Ab responses to T cell–dependent or – before i.p. injection with 100 mg of (4-hydroxy-3-nitrophenyl)acetyl (NP)– chicken g-globulin (CGG) (in average 16 molecules of NP conjugated to 1 independent Ags (10). Rab7 promotes CSR (to IgG, IgE, and IgA) molecule of CGG; Biosearch Technologies) in 100 ml of aluminum hydroxide and does so by mediating AID induction, as enforced expression of (Imject Alum; Pierce) or 25 mg of NP-LPS (0.2 NP molecule conjugated to 1 AID rescues CSR in Rab7 knockout B cells. Furthermore, Rab7 plays LPS molecule; Biosearch Technologies) in 100 ml of PBS. Mice were treated an important role in CD40- or TLR-triggered activation of NF-kB, with nil or CID 1067700 once every 3 d until being sacrificed.
Load more

Recommended publications
  • An Overview of the Role of Hdacs in Cancer Immunotherapy
    International Journal of Molecular Sciences Review Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy Debarati Banik, Sara Moufarrij and Alejandro Villagra * Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, 800 22nd St NW, Suite 8880, Washington, DC 20052, USA; [email protected] (D.B.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: +(202)-994-9547 Received: 22 March 2019; Accepted: 28 April 2019; Published: 7 May 2019 Abstract: Long-standing efforts to identify the multifaceted roles of histone deacetylase inhibitors (HDACis) have positioned these agents as promising drug candidates in combatting cancer, autoimmune, neurodegenerative, and infectious diseases. The same has also encouraged the evaluation of multiple HDACi candidates in preclinical studies in cancer and other diseases as well as the FDA-approval towards clinical use for specific agents. In this review, we have discussed how the efficacy of immunotherapy can be leveraged by combining it with HDACis. We have also included a brief overview of the classification of HDACis as well as their various roles in physiological and pathophysiological scenarios to target key cellular processes promoting the initiation, establishment, and progression of cancer. Given the critical role of the tumor microenvironment (TME) towards the outcome of anticancer therapies, we have also discussed the effect of HDACis on different components of the TME. We then have gradually progressed into examples of specific pan-HDACis, class I HDACi, and selective HDACis that either have been incorporated into clinical trials or show promising preclinical effects for future consideration.
    [Show full text]
  • Table 2. Significant
    Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S.
    [Show full text]
  • Evidence for Differential Alternative Splicing in Blood of Young Boys With
    Stamova et al. Molecular Autism 2013, 4:30 http://www.molecularautism.com/content/4/1/30 RESEARCH Open Access Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders Boryana S Stamova1,2,5*, Yingfang Tian1,2,4, Christine W Nordahl1,3, Mark D Shen1,3, Sally Rogers1,3, David G Amaral1,3 and Frank R Sharp1,2 Abstract Background: Since RNA expression differences have been reported in autism spectrum disorder (ASD) for blood and brain, and differential alternative splicing (DAS) has been reported in ASD brains, we determined if there was DAS in blood mRNA of ASD subjects compared to typically developing (TD) controls, as well as in ASD subgroups related to cerebral volume. Methods: RNA from blood was processed on whole genome exon arrays for 2-4–year-old ASD and TD boys. An ANCOVA with age and batch as covariates was used to predict DAS for ALL ASD (n=30), ASD with normal total cerebral volumes (NTCV), and ASD with large total cerebral volumes (LTCV) compared to TD controls (n=20). Results: A total of 53 genes were predicted to have DAS for ALL ASD versus TD, 169 genes for ASD_NTCV versus TD, 1 gene for ASD_LTCV versus TD, and 27 genes for ASD_LTCV versus ASD_NTCV. These differences were significant at P <0.05 after false discovery rate corrections for multiple comparisons (FDR <5% false positives). A number of the genes predicted to have DAS in ASD are known to regulate DAS (SFPQ, SRPK1, SRSF11, SRSF2IP, FUS, LSM14A). In addition, a number of genes with predicted DAS are involved in pathways implicated in previous ASD studies, such as ROS monocyte/macrophage, Natural Killer Cell, mTOR, and NGF signaling.
    [Show full text]
  • Parental Balanced Chromosomal Rearrangement Leading to Major Genomic Imbalance and an Autosomal Trisomy Resulting in Consecutive Pregnancy Loss: a Case Report
    Journal of Genetics (2021)100:54 Ó Indian Academy of Sciences https://doi.org/10.1007/s12041-021-01304-3 (0123456789().,-volV)(0123456789().,-volV) RESEARCH NOTE Parental balanced chromosomal rearrangement leading to major genomic imbalance and an autosomal trisomy resulting in consecutive pregnancy loss: a case report ANUSHKA SHRIVASTAVA1,2, SEEMA THAKUR3, TARA NATH2, ABHIPSA V. F. DEBNATH1 and SONAL R. BAKSHI1* 1Institute of Science, Nirma University, Ahmedabad 382 481, India 2Advanced Genomic Institute and Laboratory Medicine (Labassure), New Delhi 110 003, India 3Department of Clinical Genetics and Fetal Medicine, Fortis Hospital, New Delhi 110 088, India *For correspondence. E-mail: [email protected]. Received 8 November 2020; revised 9 February 2021; accepted 23 March 2021 Abstract. Chromosomal aberrations such as parental balanced translocation contribute to a significant proportion of recurrent pregnancy losses. These have extreme genetic implications on the foetus which can either cause physical and/or mental retardation or early death. In this study, we report a unique clinical case of a couple with three consecutive pregnancy losses and we aim to determine the genetic abnormalities causing the miscarriages. Conventional cytogenetic and molecular genetic analysis were performed on the products of conception as well as for the parents. Chromosomal analysis was performed based on the ISCN 2016 guidelines. This was followed by Chromosomal microarray analysis carried out using ISCA consortium probe set (8X60K). Genetic testing for the 1st product of conception was not performed. However, the 2nd and 3rd products of conception indicated an autosomal trisomy 22 and a 3.7 Mb deletion of 2p (cytoband p25.3) along with 13.6 Mb duplication of 16p (cytoband p13.3p13.12), respectively.
    [Show full text]
  • Determining HDAC8 Substrate Specificity by Noah Ariel Wolfson A
    Determining HDAC8 substrate specificity by Noah Ariel Wolfson A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biological Chemistry) in the University of Michigan 2014 Doctoral Committee: Professor Carol A. Fierke, Chair Professor Robert S. Fuller Professor Anna K. Mapp Associate Professor Patrick J. O’Brien Associate Professor Raymond C. Trievel Dedication My thesis is dedicated to all my family, mentors, and friends who made getting to this point possible. ii Table of Contents Dedication ....................................................................................................................................... ii List of Figures .............................................................................................................................. viii List of Tables .................................................................................................................................. x List of Appendices ......................................................................................................................... xi Abstract ......................................................................................................................................... xii Chapter 1 HDAC8 substrates: Histones and beyond ...................................................................... 1 Overview ..................................................................................................................................... 1 HDAC introduction
    [Show full text]
  • Common Variants in SOX-2 and Congenital Cataract Genes Contribute to Age-Related Nuclear Cataract
    ARTICLE https://doi.org/10.1038/s42003-020-01421-2 OPEN Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract Ekaterina Yonova-Doing et al.# 1234567890():,; Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this dis- ease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cat- aract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye. #A list of authors and their affiliations appears at the end of the paper. COMMUNICATIONS BIOLOGY | (2020) 3:755 | https://doi.org/10.1038/s42003-020-01421-2 | www.nature.com/commsbio 1 ARTICLE COMMUNICATIONS BIOLOGY | https://doi.org/10.1038/s42003-020-01421-2 ge-related cataract is the leading cause of blindness, structure (meta-analysis genomic inflation factor λ = 1.009, accounting for more than one-third of blindness Supplementary Table 4 and Supplementary Fig.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Molecular Interactions Underpinning the Phenotype of Hibernation in Mammals Matthew T
    © 2019. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2019) 222, jeb160606. doi:10.1242/jeb.160606 REVIEW Molecular interactions underpinning the phenotype of hibernation in mammals Matthew T. Andrews* ABSTRACT most mammals. This Review covers recent advances in the Mammals maintain a constant warm body temperature, facilitating a molecular biology of hibernation, with a focus on molecular wide variety of metabolic reactions. Mammals that hibernate have the interactions underpinning the hibernation phenotype. Specific – ability to slow their metabolism, which in turn reduces their body topics include the torpor arousal cycle, the role of small temperature and leads to a state of hypothermic torpor. For this molecules, changes in gene expression, cold-inducible RNA- metabolic rate reduction to occur on a whole-body scale, molecular binding proteins, the somatosensory system and emerging interactions that change the physiology of cells, tissues and organs information on hibernating primates. This new information not are required, resulting in a major departure from normal mammalian only is beginning to explain how natural hibernators survive homeostasis. The aim of this Review is to cover recent advances in the physiological extremes that would be lethal to most mammals, but molecular biology of mammalian hibernation, including the role of also identifies molecular mechanisms that may prove useful to small molecules, seasonal changes in gene expression, cold- human medicine. inducible RNA-binding proteins,
    [Show full text]
  • Augmenter of Liver Regeneration Essential for Growth and Beyond
    Cytokine and Growth Factor Reviews 45 (2019) 65–80 Contents lists available at ScienceDirect Cytokine and Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr Augmenter of liver regeneration: Essential for growth and beyond T ⁎ Sara Ibrahima,b, Thomas S. Weissa,b, a Children’s University Hospital (KUNO), University of Regensburg, Regensburg, Germany b Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany ARTICLE INFO ABSTRACT Keywords: Liver regeneration is a well-orchestrated process that is triggered by tissue loss due to trauma or surgical re- Augmenter of liver regeneration section and by hepatocellular death induced by toxins or viral infections. Due to the central role of the liver for GFER body homeostasis, intensive research was conducted to identify factors that might contribute to hepatic growth Isoforms and regeneration. Using a model of partial hepatectomy several factors including cytokines and growth factors Function that regulate this process were discovered. Among them, a protein was identified to specifically support liver Regulation regeneration and therefore was named ALR (Augmenter of Liver Regeneration). ALR protein is encoded by GFER Location (growth factor erv1-like) gene and can be regulated by various stimuli. ALR is expressed in different tissues in three isoforms which are associated with multiple functions: The long forms of ALR were found in the inner- mitochondrial space (IMS) and the cytosol. Mitochondrial ALR (23 kDa) was shown to cooperate with Mia40 to insure adequate protein folding during import into IMS. On the other hand short form ALR, located mainly in the cytosol, was attributed with anti-apoptotic and anti-oxidative properties as well as its inflammation and me- tabolism modulating effects.
    [Show full text]
  • 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
    [Show full text]
  • Supp Table 6.Pdf
    Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin
    [Show full text]
  • Structure and Function of Metallohydrolases in the Arginase- Deacetylase Family
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2016 Structure and Function of Metallohydrolases in the Arginase- Deacetylase Family Yang Hai University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biochemistry Commons Recommended Citation Hai, Yang, "Structure and Function of Metallohydrolases in the Arginase-Deacetylase Family" (2016). Publicly Accessible Penn Dissertations. 1753. https://repository.upenn.edu/edissertations/1753 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1753 For more information, please contact [email protected]. Structure and Function of Metallohydrolases in the Arginase-Deacetylase Family Abstract Arginases and deacetylases are metallohydrolases that catalyze two distinct chemical transformations. The arginases catalyze the hydrolysis of the guanidinium group of arginine by using a hydroxide ion 2+ 2+ bridging the binuclear manganese cluster (Mn A-Mn B) for nucleophilic attack. The deacetylases catalyze the hydrolysis of amide bonds by using a mononuclear Zn2+-ion activated water molecule as the nucleophile. Despite the diverse functions, metallohydrolases of the arginase-deacetylase superfamily 2+ share the same characteristic α/β hydrolase core fold and a conserved metal binding site (the Mn B site in arginase corresponds to the catalytic Zn2+ site in deacetylase) which is essential for catalysis in both enzymes. We report crystal structure of formiminoglutamase from the parasitic protozoan Trypanosoma cruzi and confirm that formiminoglutamase is a Mn2+-requiring hydrolase that belongs to the arginase- deacetylase superfamily. We also report the crystal structure of an arginase-like protein from Trypanosoma brucei (TbARG) with unknown function. Although its biological role remains enigmatic, the 2+ evolutionarily more conserved Mn B site can be readily restored in TbARG through side-directed mutagenesis.
    [Show full text]