DOCSLIB.ORG

TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2 Dmitri I

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2 Dmitri I TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2 Dmitri I. Kotov, Jason S. Mitchell, Thomas Pengo, Christiane Ruedl, Sing Sing Way, Ryan A. Langlois, Brian This information is current as T. Fife and Marc K. Jenkins of October 1, 2021. J Immunol published online 11 March 2019 http://www.jimmunol.org/content/early/2019/03/08/jimmun ol.1801609 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/03/08/jimmunol.180160 Material 9.DCSupplemental http://www.jimmunol.org/ 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 by guest on October 1, 2021 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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 11, 2019, doi:10.4049/jimmunol.1801609 The Journal of Immunology TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2 Dmitri I. Kotov,*,† Jason S. Mitchell,†,‡,x Thomas Pengo,{ Christiane Ruedl,‖ Sing Sing Way,#,** Ryan A. Langlois,*,† Brian T. Fife,†,x and Marc K. Jenkins*,† Naive CD4+ T lymphocytes differentiate into various Th cell subsets following TCR binding to microbial peptide:MHC class II (p:MHCII) complexes on dendritic cells (DCs). The affinity of the TCR interaction with p:MHCII plays a role in Th differen- tiation by mechanisms that are not completely understood. We found that low-affinity TCRs biased mouse naive T cells to become T follicular helper (Tfh) cells, whereas higher-affinity TCRs promoted the formation of Th1 or Th17 cells. We explored the basis for this phenomenon by focusing on IL-2R signaling, which is known to promote Th1 and suppress Tfh cell differentiation. SIRP⍺+ DCs produce abundant p:MHCII complexes and consume IL-2, whereas XCR1+ DCs weakly produce p:MHCII but do not consume IL-2. We found no evidence, however, of preferential interactions between Th1 cell–prone, high-affinity T cells and Downloaded from XCR1+ DCs or Tfh cell–prone, low-affinity T cells and SIRP⍺+ DCs postinfection with bacteria expressing the peptide of interest. Rather, high-affinity T cells sustained IL-2R expression longer and expressed two novel Th cell differentiation regulators, Eef1e1 and Gbp2, to a higher level than low-affinity T cells. These results suggest that TCR affinity does not influence Th cell differen- tiation by biasing T cell interactions with IL-2–consuming DCs, but instead, directly regulates genes in naive T cells that control the differentiation process. The Journal of Immunology, 2019, 202: 000–000. D4+ T lymphocytes are critical for controlling infections B cell–helping T follicular helper (Tfh) cells (4, 5, 7). Al- http://www.jimmunol.org/ through their ability to provide help to B cells, cytotoxic though Th1 cell differentiation fostered by high-affinity TCR C T cells, or myeloid cells (1). CD4+ T cells provide these interactions is related to strong induction of the IRF4 tran- diverse functions by differentiating into specialized subsets fol- scription factor (8), additional aspects of the mechanism by lowing TCR recognition of peptide:MHC class II (p:MHCII) which TCR affinity affects T cell differentiation have yet to be complexes on the surface of dendritic cells (DCs) and in the determined. context of cytokines from the innate immune system (1–3). IL-2R signaling promotes Th1 cells and suppresses Tfh cell Work by our group and others has shown that TCR dwell time differentiation by driving STAT5 activation and induction of on p:MHCII, which strongly correlates with TCR affinity, also Blimp1, a repressor for the Tfh cell–promoting transcription factor by guest on October 1, 2021 influences Th cell differentiation (4–6). In our experiments, Bcl-6 (9–15). Potentially, TCR affinity regulates Th cell differ- increases in TCR affinity corresponding to p:MHCII dwell entiation, in part, by influencing IL-2 signaling. We therefore times of 0.9–2.3 s correlated with increased differentiation of tested two TCR affinity–regulated, IL-2 signaling–based mecha- macrophage-helping Th1 cells and decreased formation of nisms, one rooted in DC Ag presentation and another focused on IL-2R a-chain (CD25) expression. The two major classical DCs in the spleen differ in p:MHCII presentation and IL-2 consumption *Department of Microbiology and Immunology, University of Minnesota, Minneapolis, potential (16–18). XCR1+ DCs are potent producers of the Th1 MN 55455; †Center for Immunology, University of Minnesota, Minneapolis, MN 55455; ‡University Imaging Centers, University of Minnesota, Minneapolis, MN 55455; cell–inducing cytokine IL-12 (18) but are relatively poor pro- x { + Department of Medicine, University of Minnesota, Minneapolis, MN 55455; University ducers of p:MHCII complexes, whereas SIRP⍺ DCs consume of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN 55455; ‖ IL-2 and are weak IL-12 producers but are strong producers of School of Biological Sciences, Nanyang Technological University, Singapore 637551; #Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Univer- p:MHCII complexes (17). Thus, it is possible that high TCR af- sity of Cincinnati College of Medicine, Cincinnati, OH 45229; and **Perinatal Institute, finity could bias toward Th1 cell differentiation because only Th Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Med- cells with high-affinity TCRs cells could access the small number icine, Cincinnati, OH 45229 of p:MHCII complexes displayed on XCR1+ DCs, whereas low- ORCIDs: 0000-0001-7843-1503 (D.I.K.); 0000-0002-9632-918X (T.P.); 0000-0002- 5599-6541 (C.R.); 0000-0001-9826-5637 (B.T.F.); 0000-0001-8009-7655 (M.K.J.). affinity cells could access the abundant p:MHCII complexes on ⍺+ Received for publication December 10, 2018. Accepted for publication February 20, SIRP DCs favoring Tfh cell differentiation (19). Alternatively, 2019. because IL-2R expression is proportional to the strength of TCR This work was supported by National Institutes of Health Grants R01 AI039614 and signaling and drives Th1 cell–promoting STAT5 activation (9–15), P01 AI35296 (to M.K.J.), T32 AI083196 and T32 AI007313 (to D.I.K.), and R01 Th cells with high-affinity TCRs may be intrinsically more likely AI106791 and P01 AI35296 (to B.T.F.). to become Th1 cells than Th cells with low-affinity TCRs. Address correspondence and reprint requests to Prof. Marc K. Jenkins, University of We tested these models by examining the influence of TCR Minnesota Medical School, Campus Code 2641, 2101 6th Street SE, Minneapolis, MN 55455. E-mail address: [email protected] affinity on differentiation and T cell/DC interactions using two The online version of this article contains supplemental material. TCR transgenic (Tg) strains that contain T cells with differing TCR Abbreviations used in this article: B6, C57BL/6; DC, dendritic cell; Eef1e1, eukaryotic affinities for the same p:MHCII ligand (20). We found that Th cells translation elongation factor 1 ε 1; Gbp2, guanylate binding protein 2; gRNA, guide with low-, medium-, or high-affinity TCR T cells tended to adopt RNA; p:MHCII, peptide:MHC class II; qPCR, quantitative PCR; Tfh, T follicular uncommitted, Tfh, or non-Tfh cell fates, respectively, after ex- helper; Tg, transgenic; tRNA, transfer RNA; WT, wild-type. posure to bacteria or viruses expressing the relevant peptide. In all + Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 cases, Th cells interacted more frequently with SIRP⍺ DCs than www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801609 2 TCR AFFINITY–BASED CONTROL OF Th CELL FATE with XCR1+ DCs, indicating that differential interactions with CD90.1 (HIS51; Thermo Fisher Scientific). All samples were also stained DCs did not account for TCR affinity–based differences in Th1/Tfh with a fixable viability dye (Ghost Dye Red 780; Tonbo Biosciences). For cell formation. Rather, TCR affinity influenced Th differentia- transcription factor staining, samples were fixed with the eBioscience Foxp3/Transcription Factor Staining Kit (Thermo Fisher Scientific) and tion by controlling the expression of the IL-2R and eukaryotic then stained with BV421-labeled RORɣt (Q31-378; BD Biosciences), translation elongation factor 1 ε 1 (Eef1e1), which promoted Th1 BV605-labeled or BV421-labeled T-bet (4B10; BioLegend), and AF488- cells, and guanylate binding protein 2 (Gbp2), which promoted labeled Bcl-6 (K112-91; BD Biosciences) Abs. To calculate cell numbers, Tfh cells. Our results suggest that TCR affinity–based effects on fluorescent AccuCheck Counting Beads (Invitrogen) were added to each sample after the final wash step. Cells were then analyzed on an LSR II Th differentiation are related to the capacity of the TCR to induce or Fortessa (BD Biosciences) flow cytometer. Data were analyzed with different genetic programs at different affinity levels. FlowJo (Tree Star). Cell sorting and coculture Materials and Methods Mice Spleens were harvested from mice 48 h after i.v. infection with L. mono- cytogenes/P5R bacteria. The spleens were chopped into small pieces and Six- to eight-week-old C57BL/6 (B6) mice were purchased from The digested with Collagenase P (MilliporeSigma) for 20 min at 37˚C prior to Jackson Laboratory or the National Cancer Institute Mouse Repository hand-mashing in a petri dish to generate a single-cell suspension.
Load more

Recommended publications
  • Disease-Related Cellular Protein Networks Differentially Affected
    www.nature.com/scientificreports OPEN Disease‑related cellular protein networks diferentially afected under diferent EGFR mutations in lung adenocarcinoma Toshihide Nishimura1,8*, Haruhiko Nakamura1,2,8, Ayako Yachie3,8, Takeshi Hase3,8, Kiyonaga Fujii1,8, Hirotaka Koizumi4, Saeko Naruki4, Masayuki Takagi4, Yukiko Matsuoka3, Naoki Furuya5, Harubumi Kato6,7 & Hisashi Saji2 It is unclear how epidermal growth factor receptor EGFR major driver mutations (L858R or Ex19del) afect downstream molecular networks and pathways. This study aimed to provide information on the infuences of these mutations. The study assessed 36 protein expression profles of lung adenocarcinoma (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Weighted gene co-expression network analysis together with analysis of variance-based screening identifed 13 co-expressed modules and their eigen proteins. Pathway enrichment analysis for the Ex19del mutation demonstrated involvement of SUMOylation, epithelial and mesenchymal transition, ERK/mitogen- activated protein kinase signalling via phosphorylation and Hippo signalling. Additionally, analysis for the L858R mutation identifed various pathways related to cancer cell survival and death. With regard to the Ex19del mutation, ROCK, RPS6KA1, ARF1, IL2RA and several ErbB pathways were upregulated, whereas AURK and GSKIP were downregulated. With regard to the L858R mutation, RB1, TSC22D3 and DOCK1 were downregulated, whereas various networks, including VEGFA, were moderately upregulated. In all mutation types, CD80/CD86 (B7), MHC, CIITA and IFGN were activated, whereas CD37 and SAFB were inhibited. Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our fndings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.
    [Show full text]
  • Supplementary Data Vigneswaran Et Al Supplementary Data
    Vigneswaran et al Supplementary Data Vigneswaran et al Supplementary Data Figure S1: Yki is required for EGFR-PI3K-driven glial neoplasia in Drosophila (A) Optical projections of whole brain-nerve cord complexes from 3rd instar larvae approximately 130 hrs old. Dorsal view; anterior up. CD8-GFP (green) labels glial cell bodies. Compared to repo>dEGFRλ;dp110CAAX, warts knockdown (repo>wartsdsRNA; dEGFRλ;dp110CAAX) increased neoplastic brain overgrowth and yki knockdown (repo>ykidsRNA;dEGFRλ;dp110CAAX) decreased neoplastic brain overgrowth. (B) 3 µm optical projections of brain hemispheres, age-matched 3rd instar larvae. Frontal sections; anterior up; midline to left. Repo (red) labels glial cell nuclei; CD8-GFP (green) labels glial cell bodies; anti-HRP (blue) counter-stains for neurons and neuropil. (middle) repo>dEGFRλ;dp110CAAX showed increased glial cell numbers (red nuclei) compared to (upper left) wild-type. Compared to repo>dEGFRλ;dp110CAAX, (right) warts knockdown increased neoplastic glial cell numbers (red nuclei), whereas (lower left) yki knockdown reduced neoplastic glial cell numbers (red nuclei). (C, D) Low levels of Yki protein (red) was observed in wild-type central brain glia (white arrows, left panel in C) compared to high levels of cytoplasmic and nuclear Yki protein in dEGFRλ;dp110CAAX neoplastic glia (white arrows, left panel in D); Repo (blue) labels glial cell nuclei; CD8-GFP (green) labels glial cell bodies. Vigneswaran et al Supplementary Data Figure S2: YAP/TAZ expression confined to RTK-amplified tuMor cells and Maintained in patient-derived xenografts (A) On the left, immunohistochemical (IHC) staining in representative normal brain parenchyma in the cortex where YAP expression and TAZ expression was limited to vascular cells and was not detectable in normal neuronal and glial cells.
    [Show full text]
  • Comparative Transcriptome Analysis Reveals Different Host Cell Responses to Acute and Persistent Foot-And-Mouth Disease Virus Infection
    Virologica Sinica www.virosin.org https://doi.org/10.1007/s12250-019-00155-8 www.springer.com/12250 (0123456789().,-volV)(0123456789().,-volV) RESEARCH ARTICLE Comparative Transcriptome Analysis Reveals Different Host Cell Responses to Acute and Persistent Foot-and-Mouth Disease Virus Infection 1 1 1 1 1 1 1 Jiadai Li • Lingling Han • Yao Hao • Yuncong Yuan • Mingzhen Wang • Xiu Xin • Hailong Wang • 2 1,3 1,3 Fang Yu • Congyi Zheng • Chao Shen Received: 15 March 2019 / Accepted: 3 July 2019 Ó Wuhan Institute of Virology, CAS 2019 Abstract Foot-and-mouth disease virus (FMDV) rapidly causes cytopathic effects in susceptible cells. Incomplete viral clearance during the acute infection leads to persistent infection. The relationship between host gene expression and the persistent infection remains unclear. In this study, we analyzed the transcriptome profiles of BHK-21 cells acutely and persistently infected with FMDV to identify differences in gene expression. GO and KEGG enrichment analyses showed that the 8,378 differentially expressed genes were significantly enriched in categories including metabolism, biosynthesis, ribosome function, and endocytosis. In persistently infected BHK-21 cells, ribosome- and translation-related genes were significantly down-regulated. There were more differentially expressed immune-related genes during persistent infection than during acute infection. Two hundred and seventy-four genes were differentially expressed in both acutely and persistently infected BHK-21 cells. Among these genes, heat shock protein family B member 1 (Hspb1) knockdown significantly inhibited FMDV replication. Our research provides a basis for further research to understand the mechanisms of persistent FMDV infection including the genes involved in FMDV replication.
    [Show full text]
  • Data-Driven Analysis of Age, Sex, and Tissue Effects on Gene Expression Variability in Alzheimer’S Disease Lavida R.K
    bioRxiv preprint doi: https://doi.org/10.1101/498527; this version posted December 17, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Data-Driven Analysis of Age, Sex, and Tissue Effects on Gene Expression Variability in Alzheimer’s Disease Lavida R.K. Brooks 1, George I. Mias,2;∗ 1 Institute for Quantitative Health Science and Engineering, Michigan State University, Microbiology and Molecular Genetics, East Lansing, 48824, USA 2 Institute for Quantitative Health Science and Engineering, Michigan State University, Biochemistry and Molecular Biology, East Lansing, 48824, USA Correspondence*: George I. Mias [email protected] 2 ABSTRACT 3 Alzheimer’s disease (AD) has been categorized by the Centers for Disease Control and 4 Prevention (CDC) as the 6th leading cause of death in the United States. AD is a significant 5 health-care burden because of its increased occurrence (specifically in the elderly population) 6 and the lack of effective treatments and preventive methods. With an increase in life expectancy, 7 the CDC expects AD cases to rise to 15 million by 2060. Aging has been previously associated 8 with susceptibility to AD, and there are ongoing efforts to effectively differentiate between normal 9 and AD age-related brain degeneration and memory loss. AD targets neuronal function and can 10 cause neuronal loss due to the buildup of amyloid-beta plaques and intracellular neurofibrillary 11 tangles. 12 Our study aims to identify temporal changes within gene expression profiles of healthy controls 13 and AD subjects.
    [Show full text]
  • Global Analysis of Trna and Translation Factor Expression Reveals a Dynamic Landscape of Translational Regulation in Human Cancers
    ARTICLE https://doi.org/10.1038/s42003-018-0239-8 OPEN Global analysis of tRNA and translation factor expression reveals a dynamic landscape of translational regulation in human cancers Zhao Zhang1, Youqiong Ye1, Jing Gong1, Hang Ruan1, Chun-Jie Liu2, Yu Xiang1, Chunyan Cai3, An-Yuan Guo2, 1234567890():,; Jiqiang Ling4, Lixia Diao5, John N. Weinstein5 & Leng Han 1,6 The protein translational system, including transfer RNAs (tRNAs) and several categories of enzymes, plays a key role in regulating cell proliferation. Translation dysregulation also contributes to cancer development, though relatively little is known about the changes that occur to the translational system in cancer. Here, we present global analyses of tRNAs and three categories of enzymes involved in translational regulation in ~10,000 cancer patients across 31 cancer types from The Cancer Genome Atlas. By analyzing the expression levels of tRNAs at the gene, codon, and amino acid levels, we identified unequal alterations in tRNA expression, likely due to the uneven distribution of tRNAs decoding different codons. We find that overexpression of tRNAs recognizing codons with a low observed-over-expected ratio may overcome the translational bottleneck in tumorigenesis. We further observed overall overexpression and amplification of tRNA modification enzymes, aminoacyl-tRNA synthe- tases, and translation factors, which may play synergistic roles with overexpression of tRNAs to activate the translational systems across multiple cancer types. 1 Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. 2 Department of Bioinformatics and Systems Biology, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology Wuhan, 430074 Hubei, People’s Republic of China.
    [Show full text]
  • Rare Disruptive Variants in the DISC1 Interactome and Regulome: Association with Cognitive Ability and Schizophrenia
    OPEN Molecular Psychiatry (2018) 23, 1270–1277 www.nature.com/mp ORIGINAL ARTICLE Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia S Teng1,2,10, PA Thomson3,4,10, S McCarthy1,10, M Kramer1, S Muller1, J Lihm1, S Morris3, DC Soares3, W Hennah5, S Harris3,4, LM Camargo6, V Malkov7, AM McIntosh8, JK Millar3, DH Blackwood8, KL Evans4, IJ Deary4,9, DJ Porteous3,4 and WR McCombie1 Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339).
    [Show full text]
  • Lkb1 Loss Induces Characteristic Pathway Activation in Human
    LKB1 LOSS INDUCES CHARACTERISTIC PATHWAY ACTIVATION IN HUMAN TUMORS AND CONFERS SENSITIVITY TO MEK INHIBITION ASSOCIATED WITH ATTENUATED PI3K-AKT-FOXO3 SIGNALING By JACOB KAUFMAN Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Cancer Biology December, 2013 Nashville, Tennessee Approved: Professor William Pao Professor Alissa M. Weaver Professor Ethan Lee Professor Pierre P. Massion Professor David P. Carbone This work is dedicated, with love, to my amazing wife, Elizabeth and To our three wonderful daughters, Claire, Caroline, and Mary ii!! ACKNOWLEDGMENTS This work would not have been possible without the financial support from Vanderbilt’s Medical Scientist Training Program and the Strategic Partnering to Evaluate Cancer Signatures grant NCI U01CA114771. It is a privilege to have had such resources available to fund my training and education. I am deeply grateful for the incredible support of my mentor, David Carbone. Dr. Carbone has shared not only his inexhaustible knowledge of biology and cancer, but also his dedication to improving the lives of others, and his sincere compassion both for patients and colleagues. Working with him has given me a model of what being a physician scientist should be, and I hope to emulate his character and compassion throughout my career. This work could not have been completed without the help of my co-authors, especially Joe Amann and Paul Park, as well as Horton Li, Rajesh Arasada and Yu Shyr. I have also benefited immeasurably from many faculty members with whom I’ve had the honor of working and interacting, especially Yu Shyr, Pierre Massion and David Johnson, and my committee members William Pao, Alissa Weaver, and Ethan Lee.
    [Show full text]
  • Cell Division & Proliferation
    ptglab.com 1 ANTIBODIES FOR CELL BIOLOGY CELL DIVISION & PROLIFERATION www.ptglab.com 2 Antibodies For Cell Biology: Cell Division & Proliferation Front & Back Cover: Immunohistochemistry of paraffin-embedded human skin tissue slide using Involucrin Antibody (55328-1-AP) at a dilution of 1:50 (10x objective). ptglab.com 3 WELCOME Foreword Cell division and proliferation are processes essential to life; they are processes that underpin growth and development and tissue maintenance. Cell division is the process by which cells must partition their DNA and cell contents appropriately into new daughter cells. This intricate mechanism enables cell proliferation, which must be tightly regulated in balance with cell loss through apoptosis or necrosis. These two processes can go wrong, leading to pathological proliferation, and in so doing form the basis of neoplastic disease. Throughout this catalog you will find hundreds The processes of cell division and proliferation of Proteintech®* antibodies relevant to cell require a wealth of proteins, as demonstrated division and proliferation. They cover mitosis by the long list of components above; if you and meiosis, DNA replication, transcription cannot identify an antibody for your target and translation, as well as protein expression, protein in these pages, please visit our website folding and trafficking and nutrient sensing at ptglab.com to search our full catalog of over and metabolism. There are also antibodies 10,000 pre-made antibodies. We’re confident against cell cycle control proteins featured; you will find the antibody you’re looking for. for instance you will find a poster dedicated to BRCA signaling, a pathway deregulated in many cancers.
    [Show full text]
  • Inflammatory and Adipogenic Stromal Subpopulations in Visceral Adipose Tissue Of
    RESEARCH COMMUNICATION Identification of functionally distinct fibro- inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice Chelsea Hepler1†, Bo Shan1, Qianbin Zhang1, Gervaise H Henry2, Mengle Shao1, Lavanya Vishvanath1, Alexandra L Ghaben1, Angela B Mobley3, Douglas Strand2, Gary C Hon4, Rana K Gupta1* 1Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States; 2Department of Urology, University of Texas Southwestern Medical Center, Dallas, United States; 3Department of Immunology, University of Texas Southwestern Medical Center, Dallas, United States; 4Cecil H. and Ida Green Center for Reproductive Biology Sciences, Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, United States Abstract White adipose tissue (WAT) remodeling is dictated by coordinated interactions between adipocytes and resident stromal-vascular cells; however, the functional heterogeneity of adipose stromal cells has remained unresolved. We combined single-cell RNA-sequencing and FACS to identify and isolate functionally distinct subpopulations of PDGFRb+ stromal cells within visceral WAT of adult mice. LY6C- CD9- PDGFRb+ cells represent highly adipogenic visceral adipocyte precursor cells (‘APCs’), whereas LY6C+ PDGFRb+ cells represent fibro-inflammatory progenitors (‘FIPs’). FIPs lack adipogenic capacity, display pro-fibrogenic/pro-inflammatory *For correspondence:
    [Show full text]
  • Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis
    Page 1 of 73 Diabetes Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis Jacqueline A. Koehler1, Laurie L. Baggio1, Xiemin Cao1, Tahmid Abdulla1, Jonathan E. Campbell, Thomas Secher2, Jacob Jelsing2, Brett Larsen1, Daniel J. Drucker1 From the1 Department of Medicine, Tanenbaum-Lunenfeld Research Institute, Mt. Sinai Hospital and 2Gubra, Hørsholm, Denmark Running title: GLP-1 increases pancreatic protein synthesis Key Words: glucagon-like peptide 1, glucagon-like peptide-1 receptor, incretin, exocrine pancreas Word Count 4,000 Figures 4 Tables 1 Address correspondence to: Daniel J. Drucker M.D. Lunenfeld-Tanenbaum Research Institute Mt. Sinai Hospital 600 University Ave TCP5-1004 Toronto Ontario Canada M5G 1X5 416-361-2661 V 416-361-2669 F [email protected] 1 Diabetes Publish Ahead of Print, published online October 2, 2014 Diabetes Page 2 of 73 Abstract Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67+ cells in the exocrine compartment, however pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 kinase phosphorylation, and mediated through the GLP-1 receptor.
    [Show full text]
  • Supplementary Table S1. Relative Change in Proteins Associated with Heme Biosynthesis and Degradation
    Supplementary Table S1. Relative change in proteins associated with heme biosynthesis and degradation. hPXR mPxr–/– Protein Gene RIF/INH INH RIF RIF/INH p Value 5-aminolevulinate synthase Alas1 1.90 2.61 1.05 1.41 0.28 5-aminolevulinate synthase Alas2 0.86 1.38 0.73 1.18 0.018 Delta-aminolevulinic acid Alad 0.96 1.00 1.02 0.95 0.75 dehydratase Porphobilinogen deaminase Hmbs 1.04 0.99 1.10 1.05 0.67 Uroporphyrinogen-III synthase Uros 1.19 1.09 1.31 1.38 0.012 Uroporphyrinogen decarboxylase Urod 0.92 1.03 0.94 0.92 0.33 Oxygen-dependent Cpox 1.13 1.04 1.18 1.15 0.20 coproporphyrinogen-III oxidase, Protoporphyrinogen oxidase Ppox 0.69 0.81 0.85 0.83 0.013 Ferrochelatase, Fech 0.39 0.50 0.88 0.43 0.000002 Heme oxygenase 1 Hmox1 1.15 0.86 0.91 1.11 0.34 Heme oxygenase 2 Hmox2 0.96 0.98 0.89 0.88 0.22 Biliverdin reductase A Blvra 0.84 0.92 0.82 0.92 0.032 UDP-glucuronosyltransferase 1-6 Ugt1a6 1.22 0.96 1.10 1.13 0.30 NADPH--cytochrome P450 Por 1.28 0.92 1.18 1.12 0.019 reductase INH, isoniazid; RIF, rifampicin; RIF/INH, rifampicin and isoniazid. Supplementary Table S2. Relative change in protein nuclear receptors. hPXR mPxr–/– Protein Gene RIF/INH INH RIF RIF/INH p Value Aryl hydrocarbon receptor Ahr 1.09 0.91 1.00 1.26 0.092 Hepatocyte nuclear factor Hnf1a 0.87 0.97 0.82 0.79 0.027 1-alpha Hepatocyte nuclear factor Hnf4a 0.95 1.05 0.97 1.08 0.20 4-alpha Oxysterols receptor LXR- Nr1h3 0.94 1.16 1.03 1.02 0.42 alpha Bile acid receptor Nr1h4 1.05 1.17 0.98 1.19 0.12 Retinoic acid receptor Rxra 0.88 1.03 0.83 0.95 0.12 RXR-alpha Peroxisome proliferator-
    [Show full text]
  • The Expression Profile and Prognostic Significance of Eukaryotic Translation Elongation Factors in Different Cancers
    RESEARCH ARTICLE The expression profile and prognostic significance of eukaryotic translation elongation factors in different cancers Md. Khurshidul Hassan, Dinesh Kumar, Monali Naik, Manjusha Dixit* School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhimpur- Padanpur, Jatni, Khurda, Odisha, India * [email protected] a1111111111 Abstract a1111111111 Eukaryotic translation factors, especially initiation factors have garnered much attention a1111111111 a1111111111 with regards to their role in the onset and progression of different cancers. However, the a1111111111 expression levels and prognostic significance of translation elongation factors remain poorly explored in different cancers. In this study, we have investigated the mRNA transcript levels of seven translation elongation factors in different cancer types using Oncomine and TCGA databases. Furthermore, we have identified the prognostic significance of these factors OPEN ACCESS using Kaplan-Meier Plotter and SurvExpress databases. We observed altered expression levels of all the elongation factors in different cancers. Higher expression of EEF1A2, Citation: Hassan MK, Kumar D, Naik M, Dixit M (2018) The expression profile and prognostic EEF1B2, EEF1G, EEF1D, EEF1E1 and EEF2 was observed in most of the cancer types, significance of eukaryotic translation elongation whereas reverse trend was observed for EEF1A1. Overexpression of many factors pre- factors in different cancers. PLoS ONE 13(1): dicted poor prognosis in breast (EEF1D, EEF1E1, EEF2) and lung cancer (EEF1A2, e0191377. https://doi.org/10.1371/journal. EEF1B2, EEF1G, EEF1E1). However, we didn't see any common correlation of expression pone.0191377 levels of elongation factors with survival outcomes across cancer types. Cancer subtype Editor: Aamir Ahmad, University of South Alabama stratification showed association of survival outcomes and expression levels of elongation Mitchell Cancer Institute, UNITED STATES factors in specific sub-types of breast, lung and gastric cancer.
    [Show full text]