DOCSLIB.ORG

Thesis Resubmission Daphne Chen

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Thesis Resubmission Daphne Chen Integrative Modelling of Glucocorticoid Induced Apoptosis with a Systems Biology Approach A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Life Sciences 2012 Daphne Wei-Chen Chen 1 Table of Contents List of Abbreviations ..................................................................................................................... 7 List of Tables ................................................................................................................................ 11 List of Figures .............................................................................................................................. 12 Abstract ........................................................................................................................................ 14 Short Abstract ............................................................................................................................. 15 Declaration ................................................................................................................................... 15 Copyright Statement ................................................................................................................... 15 Acknowledgements ...................................................................................................................... 16 1 CHAPTER 1: Introduction .......................................................................................... 17 1.1 Glucocorticoids (GCs) .................................................................................................. 17 1.1.1 Structure............................................................................................................... 17 1.1.2 Physiological role of glucocorticoids .................................................................. 18 1.1.3 Risks of treatment with glucocorticoids side effects ........................................... 19 1.1.4 Acute Lymphoblastic Leukaemia (ALL) ............................................................ 20 1.2 The Glucocorticoid Receptor (GR) .............................................................................. 21 1.2.1 Expression of human glucocorticoid receptor gene ............................................ 21 1.2.2 GR Protein Structure ........................................................................................... 22 1.2.3 Mode of action of GR .......................................................................................... 25 1.3 GR: the transcription factor .......................................................................................... 27 1.3.1 General transcription ........................................................................................... 27 1.3.2 Transactivation .................................................................................................... 28 1.3.3 Transrepression .................................................................................................... 29 1.4 Post translational modifications .................................................................................... 31 1.5 GR cofactors ................................................................................................................. 33 1.5.1 Coactivators ......................................................................................................... 35 1.5.2 Corepressors ........................................................................................................ 37 1.6 GC induced apoptosis and resistance ........................................................................... 38 1.6.1 GC resistance ....................................................................................................... 38 1.6.2 GC induced apoptosis: extrinsic and intrinsic pathways ..................................... 39 1.7 Mechanism of GR induced apoptosis ........................................................................... 41 1.7.1 The Bcl-2 family: the pro- and anti-survival members ....................................... 41 1.7.2 Post translational regulation of the Bcl-2 family in apoptosis............................. 43 1.7.3 GR: Transcriptional regulator of the Bcl-2 family .............................................. 45 1.7.4 Bcl-XL .................................................................................................................. 47 2 1.7.5 Bim ...................................................................................................................... 48 1.7.6 Bmf ...................................................................................................................... 49 1.8 The AP-1 complex: Jun and Fos ................................................................................... 50 1.8.1 Jun ........................................................................................................................ 50 1.8.2 Fos ....................................................................................................................... 51 1.8.3 Crosstalk between AP-1 and GR ......................................................................... 52 1.9 The Ets proteins: Erg and its relevance to GR in ALL ................................................. 53 1.10 Systems Biology: The integrated approach to study gene network .............................. 55 1.10.1 Microarray, clustering and the identification of biomarkers ............................... 56 1.10.2 Overview: Gene network modelling.................................................................... 58 1.10.3 Systems biology approach and the kinetic modelling of GR .............................. 61 1.10.4 Modelling and Parameter Estimation tools ......................................................... 62 1.11 Hypothesis and Aims .................................................................................................... 63 1.12 References ..................................................................................................................... 65 2 CHAPTER 2: Quantitative analysis of glucocorticoid controlled genes ................. 80 2.1 Abstract ......................................................................................................................... 80 2.2 Introduction ................................................................................................................... 80 2.3 Material and Methods ................................................................................................... 83 2.3.1 Cell culture & treatments ..................................................................................... 83 2.3.2 Immunoblotting ................................................................................................... 83 2.3.3 Quantitative real-time PCR ................................................................................. 84 2.3.4 Statistical analysis................................................................................................ 84 2.3.5 Model development ............................................................................................. 85 2.3.6 Simulations .......................................................................................................... 86 2.4 Results........................................................................................................................... 86 2.4.1 Analysis of GR-mediated gene expression in GC-sensitive cell line CEM-C7-14 . ............................................................................................................................. 86 2.4.2 Analysis of GR-mediated gene expression in the GC-resistant cell line CEM-C1- 15 ............................................................................................................................. 90 2.4.3 Model simulations in CEM-C7-14 ...................................................................... 92 2.4.4 Model simulations in CEM-C1-15 ...................................................................... 99 2.5 Discussion ................................................................................................................... 101 2.6 Conclusion .................................................................................................................. 104 2.7 Supplementary data .................................................................................................... 106 2.7.1 Supplementary Tables ....................................................................................... 106 3 2.7.2 Supplementary figures ....................................................................................... 107 2.8 References ................................................................................................................... 110 CHAPTER 3: Erg and AP-1 as determinants of glucocorticoid response in acute lymphoblastic leukaemia ....................................................................................................... 115 3.1 Abstract ....................................................................................................................... 115 3.2 Introduction ................................................................................................................. 116 3.3 Material and Methods ................................................................................................. 117 3.3.1 Cell culture & treatments ..................................................................................
Load more

Recommended publications
  • Sprouty2 Deficiency in Mice Leads to the Development of Achalasia Benjamin Lee Staal Grand Valley State University
    Grand Valley State University ScholarWorks@GVSU Masters Theses Graduate Research and Creative Practice 12-2011 Sprouty2 Deficiency in Mice Leads to the Development of Achalasia Benjamin Lee Staal Grand Valley State University Follow this and additional works at: http://scholarworks.gvsu.edu/theses Recommended Citation Staal, Benjamin Lee, "Sprouty2 Deficiency in Mice Leads to the Development of Achalasia" (2011). Masters Theses. 11. http://scholarworks.gvsu.edu/theses/11 This Thesis is brought to you for free and open access by the Graduate Research and Creative Practice at ScholarWorks@GVSU. It has been accepted for inclusion in Masters Theses by an authorized administrator of ScholarWorks@GVSU. For more information, please contact scholarworks@gvsu.edu. SPROUTY2 DEFICIENCY IN MICE LEADS TO THE DEVELOPMENT OF ACHALASIA Benjamin Lee Staal A Thesis Submitted to the Graduate Faculty of GRAND VALLEY STATE UNIVERSITY In Partial Fulfillment of the Requirements For the Degree of Master of Science Cell and Molecular Biology December 2011 ACKNOWLEDGEMENTS First, I thank God for the privilege of studying His handiwork. I also wish to thank the members of my Graduate Committee for their support and guidance throughout this project. Finally, I thank my family, friends, and colleagues for their continual motivation. iii ABSTRACT SPROUTY2 DEFICIENCY IN MICE LEADS TO THE DEVELOPMENT OF ACHALASIA Sprouty 2 (Spry2), one of the four mammalian Spry family members, is a negative feedback regulator of many receptor tyrosine kinases (RTKs) signaling including Met. It fine-tunes RTKs signaling through multiple levels of regulations starting from RTK itself to several downstream molecules that are crucial for signal transduction.
    [Show full text]
  • Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma Alice M
    Published OnlineFirst May 1, 2015; DOI: 10.1158/1541-7786.MCR-14-0183-T Oncogenes and Tumor Suppressors Molecular Cancer Research Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma Alice M. Walsh1, Gurpreet S. Kapoor2, Janine M. Buonato3, Lijoy K. Mathew4,5,Yingtao Bi6, Ramana V. Davuluri6, Maria Martinez-Lage7, M. Celeste Simon4,5, Donald M. O'Rourke2,7, and Matthew J. Lazzara3,1 Abstract Glioblastoma multiforme (GBM) is notoriously resistant to demonstrated that SPRY2 protein is definitively expressed in therapy, and the development of a durable cure will require the GBM tissue, that SPRY2 expression is elevated in GBM tumors identification of broadly relevant regulators of GBM cell tumor- expressing EGFR variant III (EGFRvIII), and that elevated igenicity and survival. Here, we identify Sprouty2 (SPRY2), a SPRY2 mRNA expression portends reduced GBM patient sur- known regulator of receptor tyrosine kinases (RTK), as one such vival. Overall, these results identify SPRY2 and the pathways regulator. SPRY2 knockdown reduced proliferation and anchor- it regulates as novel candidate biomarkers and therapeutic age-independent growth in GBM cells and slowed xenograft targets in GBM. tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor Implications: SPRY2, counter to its roles in other cancer settings, receptor (EGFR) and the c-MET receptor in GBM cells, an effect promotes glioma cell and tumor growth and cellular resistance to that involved regulation of the ability of the p38 mitogen-acti- targeted inhibitors of oncogenic RTKs, thus making SPRY2 and vated protein kinase (MAPK) to drive cell death in response to the cell signaling processes it regulates potential novel therapeutic inhibitors.
    [Show full text]
  • Spry2 Regulates Signalling Dynamics and Terminal Bud Branching Behaviour During Lung Development
    Genet. Res., Camb. (2015), vol. 97, e5. © Cambridge University Press 2015 1 doi:10.1017/S0016672315000026 Spry2 regulates signalling dynamics and terminal bud branching behaviour during lung development 1,2 2 YINGYING ZHAO AND TIMOTHY P. O’BRIEN * 1Shenzhen University Diabetes Center, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen 518060, China 2Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA (Received 7 November 2014; revised 12 January 2015; accepted 3 February 2015) Summary Development of mammalian lung involves reiterative outgrowth and branching of an epithelial tube into the surrounding mesenchymal bed. Each coordinated growth and branching cycle is driven by reciprocal signal- ling between epithelial and adjacent mesenchymal cells. This signalling network includes FGF, SHH, BMP4 and other pathways. We have characterized lung defects in 36Pub mice carrying a deletion that removes an antagonist of FGF signalling, Spry2. Spry2 deficient mice show an enlarged cystic structure located in the ter- minus of each lobes. Our study shows that Spry2 deficient lungs have reduced lung branching and the cystic structure forms in the early lung development stage. Furthermore, mice carrying a targeted disruption of Spry2 fail to complement the lung phenotype characterized in 36Pub mice. A Spry2-BAC transgene rescues the defect. Interestingly, cystic structure growth is accompanied by the reduced and spatially disorganized ex- pression of Fgf10 and elevated expression of Shh and Bmp4. Altered signalling balance due to the loss of Spry2 causes a delayed branch cycle and cystic growth. Our data underscores the importance of restricting cellular responsiveness to signalling and highlights the interplay between morphogenesis events and spatial localization of gene expression.
    [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]
  • Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6 Dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-Cell Lymphoma
    BCL6 suppresses an IL10RA/JAK2/STAT3 pathway Synthetic lethal screen demonstrates that a JAK2 inhibitor suppresses a BCL6 dependent IL10RA/JAK2/STAT3 pathway in high grade B-cell lymphoma. Daniel Beck1,6, Jenny Zobel3,6, Ruth Barber1,2,6, Sian Evans1, Larissa Lezina1, Rebecca L. Allchin1, Matthew Blades4, Richard Elliott5, Christopher J. Lord5, Alan Ashworth5, Andrew C.G. Porter3, Simon D. Wagner1 1Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute and, 2 Leicester Diagnostic and Drug Development (LD3) Centre, University of Leicester, Lancaster Road, Leicester LE1 7HB, UK, 3Department of Haematology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. 4Bioinformatics and Biostatistics Analysis Support Hub (B/BASH), University of Leicester, Lancaster Road, Leicester LE1 9HN and 5The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK. 6The first three authors contributed equally to this work Running title: BCL6 suppresses an IL10RA/JAK2/STAT3 pathway. To whom correspondence should be addressed: Simon D. Wagner, Department of Cancer Studies, Room 104, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 7HB, UK. Tel: 0441162525584, Fax: 0441162525616, Email: sw227@le.ac.uk Keywords: cancer therapy, Janus kinase (JAK), lymphocyte, lymphoma, transcription factor, B-cell lymphoma 6 (BCL-6), synthetic lethal screen. ABSTRACT which shows higher levels of IL10RA, JAK2 and We demonstrate the usefulness of synthetic lethal STAT3 but lower levels of BCL6 than GC- screening of a conditionally BCL6 deficient DLBCL and might be usefully combined with Burkitt lymphoma cell line, DG75-AB7, with a novel approaches such as inhibition of IL10RA.
    [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]
  • Supplementary Material
    BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Neurol Neurosurg Psychiatry Page 1 / 45 SUPPLEMENTARY MATERIAL Appendix A1: Neuropsychological protocol. Appendix A2: Description of the four cases at the transitional stage. Table A1: Clinical status and center proportion in each batch. Table A2: Complete output from EdgeR. Table A3: List of the putative target genes. Table A4: Complete output from DIANA-miRPath v.3. Table A5: Comparison of studies investigating miRNAs from brain samples. Figure A1: Stratified nested cross-validation. Figure A2: Expression heatmap of miRNA signature. Figure A3: Bootstrapped ROC AUC scores. Figure A4: ROC AUC scores with 100 different fold splits. Figure A5: Presymptomatic subjects probability scores. Figure A6: Heatmap of the level of enrichment in KEGG pathways. Kmetzsch V, et al. J Neurol Neurosurg Psychiatry 2021; 92:485–493. doi: 10.1136/jnnp-2020-324647 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Neurol Neurosurg Psychiatry Appendix A1. Neuropsychological protocol The PREV-DEMALS cognitive evaluation included standardized neuropsychological tests to investigate all cognitive domains, and in particular frontal lobe functions. The scores were provided previously (Bertrand et al., 2018). Briefly, global cognitive efficiency was evaluated by means of Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS). Frontal executive functions were assessed with Frontal Assessment Battery (FAB), forward and backward digit spans, Trail Making Test part A and B (TMT-A and TMT-B), Wisconsin Card Sorting Test (WCST), and Symbol-Digit Modalities test.
    [Show full text]
  • Investigation Into the Effect of LRRK2-Rab10 Protein Interactions on the Proboscis Extension Response of the Fruit Fly Drosophila Melanogaster
    Investigation into the effect of LRRK2-Rab10 protein interactions on the Proboscis Extension Response of the fruit fly Drosophila melanogaster Laura Covill Masters by Research University of York Biology December 2018 Abstract Parkinson’s Disease (PD) is a debilitating disease which affects 1% of the population worldwide and is characterised by stiffness, tremor and bradykinesia. PD is a complex disease with many suspected genetic and environmental causes, and it is critical to understand all the pathways involved in disease progression to develop effective therapies for PD, which currently has no cure. A kinase- coding gene, LRRK2 has emerged as a focal point for much PD research, particularly PD-associated SNP LRRK2-G2019S, which leads to LRRK2 overactivity. Rab proteins, a series of small GTPases, have been identified among the proteins phosphorylated by LRRK2. These interactions may be modelled in the fruit fly Drosophila melanogaster. Using optogenetics in the fly, this project investigates the relationship between the LRRK2-G2019S and Rab10 interaction, and the speed and degree of tremor of Proboscis Extension Response (PER) by triggering a PER in fly lines of different genotypes. Significant bradykinesia in Rab10 null flies which was not recreated in flies with dopaminergic neuron Rab10RNAi suggests that the bradykinesia PER phenotype is caused by off-target effect of Rab10-KO in another tissue of the fly than the dopaminergic neurons. Over-expression of Rab10 in dopaminergic neurons of flies also expressing LRRK2-G2019S produced
    [Show full text]
  • CHML Promotes Liver Cancer Metastasis by Facilitating Rab14 Recycle
    ARTICLE https://doi.org/10.1038/s41467-019-10364-0 OPEN CHML promotes liver cancer metastasis by facilitating Rab14 recycle Tian-Wei Chen1,2,3, Fen-Fen Yin1,2, Yan-Mei Yuan1,2, Dong-Xian Guan1, Erbin Zhang1,2, Feng-Kun Zhang1,2, Hao Jiang1,2, Ning Ma1,2, Jing-Jing Wang1, Qian-Zhi Ni1,2, Lin Qiu1, Jing Feng3, Xue-Li Zhang3, Ying Bao4, Kang Wang5, Shu-Qun Cheng5, Xiao-Fan Wang6, Xiang Wang7, Jing-Jing Li1,2 & Dong Xie1,2,8,9 Metastasis-associated recurrence is the major cause of poor prognosis in hepatocellular 1234567890():,; carcinoma (HCC), however, the underlying mechanisms remain largely elusive. In this study, we report that expression of choroideremia-like (CHML) is increased in HCC, associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promotes migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. Mechanism study reveals that CHML facilitates constant recycling of Rab14 by escorting Rab14 to the membrane. Furthermore, we identify several metastasis regulators as cargoes carried by Rab14-positive vesicles, including Mucin13 and CD44, which may contribute to metastasis- promoting effects of CHML. Altogether, our data establish CHML as a potential promoter of HCC metastasis, and the CHML-Rab14 axis may be a promising therapeutic target for HCC. 1 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Xuhui district 200031, China. 2 University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui district 200031, China. 3 Department of General Surgery, Fengxian Hospital Affiliated to Southern Medical University, 6600 Nanfeng Road, Shanghai 201499, China.
    [Show full text]
  • Sprouty Proteins, Masterminds of Receptor Tyrosine Kinase Signaling
    CORE Metadata, citation and similar papers at core.ac.uk Provided by RERO DOC Digital Library Angiogenesis (2008) 11:53–62 DOI 10.1007/s10456-008-9089-1 ORIGINAL PAPER Sprouty proteins, masterminds of receptor tyrosine kinase signaling Miguel A. Cabrita Æ Gerhard Christofori Received: 14 December 2007 / Accepted: 7 January 2008 / Published online: 25 January 2008 Ó Springer Science+Business Media B.V. 2008 Abstract Angiogenesis relies on endothelial cells prop- Abbreviations erly processing signals from growth factors provided in Ang Angiopoietin both an autocrine and a paracrine manner. These mitogens c-Cbl Cellular homologue of Casitas B-lineage bind to their cognate receptor tyrosine kinases (RTKs) on lymphoma proto-oncogene product the cell surface, thereby activating a myriad of complex EGF Epidermal growth factor intracellular signaling pathways whose outputs include cell EGFR EGF receptor growth, migration, and morphogenesis. Understanding how eNOS Endothelial nitric oxide synthase these cascades are precisely controlled will provide insight ERK Extracellular signal-regulated kinase into physiological and pathological angiogenesis. The FGF Fibroblast growth factor Sprouty (Spry) family of proteins is a highly conserved FGFR FGF receptor group of negative feedback loop modulators of growth GDNF Glial-derived neurotrophic factor factor-mediated mitogen-activated protein kinase (MAPK) Grb2 Growth factor receptor-bound protein 2 activation originally described in Drosophila. There are HMVEC Human microvascular endothelial cell four mammalian orthologs (Spry1-4) whose modulation of Hrs Hepatocyte growth factor-regulated tyrosine RTK-induced signaling pathways is growth factor – and kinase substrate cell context – dependant. Endothelial cells are a group of HUVEC Human umbilical vein endothelial cell highly differentiated cell types necessary for defining the MAPK Mitogen-activated protein kinase mammalian vasculature.
    [Show full text]
  • T Cell Depending on the Differentiation State of the Dual
    Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell This information is current as Heonsik Choi, Sung-Yup Cho, Ronald H. Schwartz and of September 29, 2021. Kyungho Choi J Immunol 2006; 176:6034-6045; ; doi: 10.4049/jimmunol.176.10.6034 http://www.jimmunol.org/content/176/10/6034 Downloaded from References This article cites 63 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/176/10/6034.full#ref-list-1 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 by guest on September 29, 2021 *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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell1 Heonsik Choi,* Sung-Yup Cho,† Ronald H. Schwartz,* and Kyungho Choi2* Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/ MAPK pathway.
    [Show full text]
  • Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
    ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight.
    [Show full text]