DOCSLIB.ORG

The Role of Dubs in the Post-Translational Control of Cell Migration

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Dubs in the Post-Translational Control of Cell Migration Essays in Biochemistry (2019) 63 579–594 https://doi.org/10.1042/EBC20190022 Review Article The role of DUBs in the post-translational control of cell migration Guillem Lambies1,2, Antonio Garc´ıade Herreros1,2 and V´ıctor M. D´ıaz1,2,3 1Programa de Recerca en Cancer,` Institut Hospital del Mar d’Investigacions Mediques` (IMIM), Unidad Asociada CSIC, Barcelona, Spain; 2Departament de Ciencies` Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), Barcelona, Spain; 3Faculty of Medicine and Health Sciences, International University of Catalonia, Sant Cugat del Valles,` Barcelona, Spain Downloaded from https://portlandpress.com/essaysbiochem/article-pdf/63/5/579/859061/ebc-2019-0022c.pdf by guest on 05 November 2019 Correspondence: V.M. Dıaz´ ([email protected])orA.Garcıa´ de Herreros ([email protected]) Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulat- ing Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full mi- gratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degra- dation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT. Introduction Epithelial-to-mesenchymal transition (EMT) is a cell process allowing epithelial cells to adopt mesenchy- mal properties and enhance their migratory capability [1]. Although some other types of migration have been described [3,4], in this review, we will focus on that related with EMT and describe how it is modu- lated by a myriad of labile proteins that need to be stabilized. In particular, we will analyze the role of an emergent class of enzymes called deubiquitinases (DUBs) in several aspects of cell migration. Typesofcellmigration Physiological cell migration during embryonic development and wound healing EMT is particularly relevant during embryonic development since it allows cells to migrate over extremely long distances in the embryo, giving rise to the formation of the three-dimensional structures and orig- ination of the different organs in the final organism. EMT happens early in embryonic development, in the generation of parietal endoderm and in the mesoderm and neural crest formation [2–4]. For instance, neural crest arises from a population of precursor cells that escape from the neural tube and migrate a long distance in the embryo, promoting the formation of different subtypes of cells [5]. Upon migra- tion of neural crest cells to the different locations, cells become again epithelial undergoing the opposite Received: 21 June 2019 process, the mesenchymal-to-epithelial transition, performing transient epithelial structures such as the Revised: 30 September 2019 somites, the precursors of the urogenital system and the splachnopleure. These structures again undergo Accepted: 01 October 2019 EMT to promote mesenchymal cells with a more restricted differentiation potential [5]. Besides morpho- Version of Record published: genesis, the acquisition of migratory properties through an EMT in physiological conditions plays a key 11 October 2019 role in other physiological processes such as wound healing, the response of the organism to an injury in © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 579 Essays in Biochemistry (2019) 63 579–594 https://doi.org/10.1042/EBC20190022 the skin. Keratinocytes from the epidermis located at the wound border undergo a partial EMT, acquiring the capa- bilities to migrate [2]. Pathological cell migration: fibrosis and cancer metastasis Cell migration is also involved in pathological processes such as fibrosis and cancer invasion. Fibrosis involves organ degeneration and takes place following tissue injuries such as cardiac failure [6]. This results in a massive deposition of collagen fibers mediated by fibroblastic cells derived from a set of epithelial cells via an EMT process. These cells migrate to the injured tissue and secrete a huge amount of fibroblastic proteins such as Collagen I and alpha-smooth muscle actin (α-SMA) [6]. The fibrotic EMT has been observed in many organs, such as liver, lung and intestine [7]. EMT also plays a crucial role in cancer. Even though EMT features had been largely observed in in vitro and in vivo cancer models, the relevance of EMT for cancer metastasis has been a matter of debate for many years [8]. This is due to the similarity between the mesenchymal cells derived from an EMT program and the stromal cells, two cell Downloaded from https://portlandpress.com/essaysbiochem/article-pdf/63/5/579/859061/ebc-2019-0022c.pdf by guest on 05 November 2019 types sharing similar markers [2]. The first relationship between EMT and cancer metastasis was observed in HER2 transgenic mice showing cancer cells with migratory features [9]. On the other hand, detection of cell aggregates detaching from the tumor into the adjacent stroma further confirmed the involvement of EMT in cancer metastasis [10]. Genetic lineage-tracing experiments have formally demonstrated the role of EMT during invasion [11], although other studies have questioned a critical role of EMT in metastasis [12,13]. In any case, besides metastasis formation, the role of EMT in chemo-resistance is beyond any doubt [14,15]. Molecular mechanisms controlling cell migration Epithelial cells maintain cell contacts between them through the arrangement of tight junctions, desmosomes and adherent junctions which are lost during EMT promotion. Occludins, claudins and Zona-Occludens 1 (components of tight junctions) or desmoplakins (of desmosomes) are down-regulated during EMT. However, the most relevant feature of EMT is the loss of the essential homotypic adherent junction E-cadherin [16], encoded by the CDH1 gene, which mediates homophilic intercellular interactions through its extracellular domain. These junctions are main- tained by anchoring its intracellular domain to actin filaments via β-catenin association [17]. This loss of the epithe- lial markers is accompanied by an up-regulation of mesenchymal proteins such as Fibronectin. Fibronectin mediates extracellular matrix (ECM) assembly through the binding to α5β1 integrins; this stimulates its self-association and organizes the actin cytoskeleton to promote cell contractility. It also allows the assembly of other fibrous proteins such as Collagen I [18]. Another relevant trait in the modulation of cell migration is the positive modulation of the Rho-GTPases, involved in lamelipodium extension at the front of the cell, formation of new adhesions of the cell to surrounding matrix proteins, cell body contraction and tail retraction [19]. Moreover, Rho is essential to mediate actin contractility to promote fibronectin-dependent ECM assembly [20]. Cell migration also requires the up-regulation of proteases that degrade basement membranes, enhancing the capability of cells to invade and migrate [21,22]. Transcription factors modulating EMT and cell migration The expression of epithelial and mesenchymal markers is tightly regulated by different transcription factors collec- tively known as transcription factors modulating EMT (EMT-TFs). Snail1 is considered the main EMT-TF [16]. It binds sequences with a 5-CACCTG-3 core located in the promoters of CDH1 and other epithelial markers, such as occludins and claudins. Besides its role as a repressor, Snail1 also works as an activator, up-regulating the expression of mesenchymal markers such as fibronectin and the EMT-TFs Zeb1 and 2 [23–25]. Similar to Snail1, Zeb1 and 2 repress E-cadherin and are required for EMT [26]. Besides Snail1 and Zeb1/2, other EMT-TFs also promoting migra- tion are the basic helix–loop–helix proteins Twist1 and 2 [27]. Snail1 and EMT-TFs induce all the molecular events required for cell migration such as a high protease secretion and a stimulation of Rho-GTPase and Akt activity, a proteinkinasealsorequiredforcellinvasion[4]. Signaling pathways controlling EMT Different signaling pathways induce EMT being the most studied that are triggered by TGF-β [28]. TGF-β signals through serine/threonine kinase receptors; it binds to the TGF-β receptor type II (TβRII) that associates with the typeI(TβRI), phosphorylating its Ser/Thr kinase domain; this propagates the signal through the recruitment and phosphorylation of the Smad proteins [29]. TGF-β activates Snai1 transcription through Smad–HMGA2 complex that binds to the Snai1 promoter [30]. TGF-β pathway also cross-talks with other signaling pathways, such as Wnt and Notch. Canonical Wnt ligands interact with the transmembrane proteins LRP5/6 and Frizzled promoting the recruitment of the adenomatous polyposis coli (APC)/Axin/Glycogen-synthase kinase 3 complex to the membrane 580 © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society Essays in Biochemistry (2019) 63 579–594 https://doi.org/10.1042/EBC20190022 and preventing β-catenin degradation; consequently, β-catenintranslocatestothenucleusandinducestheexpression
Load more

Recommended publications
  • View of HER2: Human Epidermal Growth Factor Receptor 2; TNBC: Triple-Negative Breast Resistance to Systemic Therapy in Patients with Breast Cancer
    Wen et al. Cancer Cell Int (2018) 18:128 https://doi.org/10.1186/s12935-018-0625-9 Cancer Cell International PRIMARY RESEARCH Open Access Sulbactam‑enhanced cytotoxicity of doxorubicin in breast cancer cells Shao‑hsuan Wen1†, Shey‑chiang Su2†, Bo‑huang Liou3, Cheng‑hao Lin1 and Kuan‑rong Lee1* Abstract Background: Multidrug resistance (MDR) is a major obstacle in breast cancer treatment. The predominant mecha‑ nism underlying MDR is an increase in the activity of adenosine triphosphate (ATP)-dependent drug efux trans‑ porters. Sulbactam, a β-lactamase inhibitor, is generally combined with β-lactam antibiotics for treating bacterial infections. However, sulbactam alone can be used to treat Acinetobacter baumannii infections because it inhibits the expression of ATP-binding cassette (ABC) transporter proteins. This is the frst study to report the efects of sulbactam on mammalian cells. Methods: We used the breast cancer cell lines as a model system to determine whether sulbactam afects cancer cells. The cell viabilities in the present of doxorubicin with or without sulbactam were measured by MTT assay. Protein identities and the changes in protein expression levels in the cells after sulbactam and doxorubicin treatment were determined using LC–MS/MS. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was used to analyze the change in mRNA expression levels of ABC transporters after treatment of doxorubicin with or without sulbactam. The efux of doxorubicin was measures by the doxorubicin efux assay. Results: MTT assay revealed that sulbactam enhanced the cytotoxicity of doxorubicin in breast cancer cells. The results of proteomics showed that ABC transporter proteins and proteins associated with the process of transcription and initiation of translation were reduced.
    [Show full text]
  • Tgfβ-Activated USP27X Deubiquitinase Regulates Cell Migration And
    Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 TGFβ-activated USP27X deubiquitinase regulates cell migration and 2 chemoresistance via stabilization of Snail1 3 4 Guillem Lambies1,2, Martina Miceli1, Catalina Martínez-Guillamon1, Rubén 5 Olivera-Salguero1, Raúl Peña1, Carolina-Paola Frías1, Irene Calderón1, Boyko S. 6 Atanassov3, Sharon Y. R. Dent4, Joaquín Arribas5,6,7, Antonio García de 7 Herreros1,2*, and Víctor M. Díaz1,2*. 8 1 9 Programa de Recerca en Càncer, Institut Hospital del Mar d’Investigacions Mèdiques 10 (IMIM), Unidad Asociada CSIC, Barcelona, Spain. 2 11 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra 12 (UPF), Barcelona, Spain. 3 13 Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer 14 Center, Buffalo, NY 15 4 Department of Epigenetics and Molecular Carcinogenesis, Center for Cancer 16 Epigenetics, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 17 5 Preclinical Research Program, Vall d’Hebron Institute of Oncology (VHIO) 18 CIBERONC, Barcelona, Spain 19 6 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain 20 7 Department of Biochemistry and Molecular Biology, Universitat Autònoma de 21 Barcelona, Campus de la UAB, Bellaterra, Spain 22 23 Running title: USP27X deubiquitinates Snail1 in tumor cells. 24 1 Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2018; DOI: 10.1158/0008-5472.CAN-18-0753 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • SUPPLEMENTARY TABLES and FIGURE LEGENDS Supplementary
    SUPPLEMENTARY TABLES AND FIGURE LEGENDS Supplementary Figure 1. Quantitation of MYC levels in vivo and in vitro. a) MYC levels in cell lines 6814, 6816, 5720, 966, and 6780 (corresponding to first half of Figure 1a in main text). MYC is normalized to tubulin. b) MYC quantitations (normalized to tubulin) for cell lines Daudi, Raji, Jujoye, KRA, KRB, GM, and 6780 corresponding to second half of Figure 1a. c) In vivo MYC quantitations, for mice treated with 0-0.5 ug/ml doxycycline in their drinking water. MYC is normalized to tubulin. d) Quantitation of changing MYC levels during in vitro titration, normalized to tubulin. e) Levels of Odc (normalized to tubulin) follow MYC levels in titration series. Supplementary Figure 2. Evaluation of doxycycline concentration in the plasma of mice treated with doxycycline in their drinking water. Luciferase expressing CHO cells (Tet- off) (Clonethech Inc) that is responsive to doxycycline by turning off luciferase expression was treated with different concentrations of doxycycline in culture. A standard curve (blue line) correlating luciferase activity (y-axis) with treatment of doxycycline (x- axis) was generated for the CHO cell in culture. Plasma from mice treated with different concentrations of doxycycline in their drinking water was separated and added to the media of the CHO cells. Luciferase activity was measured and plotted on the standard curve (see legend box). The actual concentration of doxycycline in the plasma was extrapolated for the luciferase activity measured. The doxycycline concentration 0.2 ng/ml measured in the plasma of mice correlates with 0.05 μg/ml doxycycline treatment in the drinking water of mice, the in vivo threshold for tumor regression.
    [Show full text]
  • (DHFR) As a Modulator of B- Catenin/GSK3 Signaling
    A Lentivirus-Mediated Genetic Screen Identifies Dihydrofolate Reductase (DHFR) as a Modulator of b- Catenin/GSK3 Signaling Richard A. Klinghoffer1*, Jason Frazier1, James Annis1, Jason D. Berndt2, Brian S. Roberts1, William T. Arthur1, Raul Lacson3, Xiaohua Douglas Zhang4, Marc Ferrer3, Randall T. Moon2, Michele A. Cleary1 1 Rosetta Inpharmatics, LLC, Seattle, Washington, United States of America, 2 Howard Hughes Medical Institute, Institute for Stem Cell and Regenerative Medicine, and Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington, United States of America, 3 Department of Automated Biotechnology, Merck Research Laboratories, Merck & Co., Inc., North Wales, Pennsylvania, United States of America, 4 Department of Biometrics Research, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania, United States of America Abstract The multi-protein b-catenin destruction complex tightly regulates b-catenin protein levels by shuttling b-catenin to the proteasome. Glycogen synthase kinase 3b (GSK3b), a key serine/threonine kinase in the destruction complex, is responsible for several phosphorylation events that mark b-catenin for ubiquitination and subsequent degradation. Because modulation of both b-catenin and GSK3b activity may have important implications for treating disease, a complete understanding of the mechanisms that regulate the b-catenin/GSK3b interaction is warranted. We screened an arrayed lentivirus library expressing small hairpin RNAs (shRNAs) targeting 5,201 human druggable genes for silencing events that activate a b- catenin pathway reporter (BAR) in synergy with 6-bromoindirubin-39oxime (BIO), a specific inhibitor of GSK3b. Top screen hits included shRNAs targeting dihydrofolate reductase (DHFR), the target of the anti-inflammatory compound methotrexate. Exposure of cells to BIO plus methotrexate resulted in potent synergistic activation of BAR activity, reduction of b-catenin phosphorylation at GSK3-specific sites, and accumulation of nuclear b-catenin.
    [Show full text]
  • NATURAL KILLER CELLS, HYPOXIA, and EPIGENETIC REGULATION of HEMOCHORIAL PLACENTATION by Damayanti Chakraborty Submitted to the G
    NATURAL KILLER CELLS, HYPOXIA, AND EPIGENETIC REGULATION OF HEMOCHORIAL PLACENTATION BY Damayanti Chakraborty Submitted to the graduate degree program in Pathology and Laboratory Medicine and the Graduate Faculty of the University of Kansas in partial fulfillment ofthe requirements for the degree of Doctor of Philosophy. ________________________________ Chair: Michael J. Soares, Ph.D. ________________________________ Jay Vivian, Ph.D. ________________________________ Patrick Fields, Ph.D. ________________________________ Soumen Paul, Ph.D. ________________________________ Michael Wolfe, Ph.D. ________________________________ Adam J. Krieg, Ph.D. Date Defended: 04/01/2013 The Dissertation Committee for Damayanti Chakraborty certifies that this is the approved version of the following dissertation: NATURAL KILLER CELLS, HYPOXIA, AND EPIGENETIC REGULATION OF HEMOCHORIAL PLACENTATION ________________________________ Chair: Michael J. Soares, Ph.D. Date approved: 04/01/2013 ii ABSTRACT During the establishment of pregnancy, uterine stromal cells differentiate into decidual cells and recruit natural killer (NK) cells. These NK cells are characterized by low cytotoxicity and distinct cytokine production. In rodent as well as in human pregnancy, the uterine NK cells peak in number around mid-gestation after which they decline. NK cells associate with uterine spiral arteries and are implicated in pregnancy associated vascular remodeling processes and potentially in modulating trophoblast invasion. Failure of trophoblast invasion and vascular remodeling has been shown to be associated with pathological conditions like preeclampsia syndrome, hypertension in mother and/or fetal growth restriction. We hypothesize that NK cells fundamentally contribute to the organization of the placentation site. In order to study the in vivo role of NK cells during pregnancy, gestation stage- specific NK cell depletion was performed in rats using anti asialo GM1 antibodies.
    [Show full text]
  • Intratumoral Injection of SYNB1891, a Synthetic Biotic Medicine Designed
    Intratumoral injection of SYNB1891 A Synthetic Biotic medicine designed to activate the innate immune system. Therapy demonstrates target engagement in humans including intratumoral STING activation. Janku F, MD Anderson Cancer Center; Luke JJ, UPMC Hillman Cancer Center; Brennan AM, Synlogic; Riese RJ, Synlogic; Varterasian M, Pharmaceutical Consultant; Kuhn K, Synlogic; Sokolovska A, Synlogic; Strauss J, Mary Crowley Cancer Research Presented by Filip Janku, MD, PhD Study supported by Synlogic, Inc American Association for Cancer Research (AACR) April 2021 Introduction and Methods SYNB1891 Strain Phase 1 First-in-Human Clinical Trial • Live, modified strain of the probiotic E. coli • Enrolling patients with refractory advanced solid Nissle engineered to produce cyclic tumors or lymphoma dinucleotides (CDN) under hypoxia leading to stimulator of interferon genes (STING)- • Intratumoral (IT) injection of SYNB1891 on Days activation 1, 8 and 15 of the first 21-day cycle and then on Day 1 of each subsequent cycle. • Preferentially taken up by phagocytic antigen- presenting cells in tumors, activating • Dose escalation planned across 7 cohorts (1x106 complementary innate immune pathways – 1x109 live cells) with Arm 1 consisting of (direct CDN STING activation; cGAS-mediated SYNB1891 as monotherapy, and Arm 2 in STING activation and TLR4/MyD88 activation by combination with atezolizumab the bacterial chassis) SYNB1891 was safe and well-tolerated in heterogenous population Nov 2020: Interim Analysis IA Updated through 15 Mar 2021 15 Mar 2021:
    [Show full text]
  • Functional Gene Clusters in Global Pathogenesis of Clear Cell Carcinoma of the Ovary Discovered by Integrated Analysis of Transcriptomes
    International Journal of Environmental Research and Public Health Article Functional Gene Clusters in Global Pathogenesis of Clear Cell Carcinoma of the Ovary Discovered by Integrated Analysis of Transcriptomes Yueh-Han Hsu 1,2, Peng-Hui Wang 1,2,3,4,5 and Chia-Ming Chang 1,2,* 1 Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan; [email protected] (Y.-H.H.); [email protected] (P.-H.W.) 2 School of Medicine, National Yang-Ming University, Taipei 112, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan 4 Department of Medical Research, China Medical University Hospital, Taichung 440, Taiwan 5 Female Cancer Foundation, Taipei 104, Taiwan * Correspondence: [email protected]; Tel.: +886-2-2875-7826; Fax: +886-2-5570-2788 Received: 27 April 2020; Accepted: 31 May 2020; Published: 2 June 2020 Abstract: Clear cell carcinoma of the ovary (ovarian clear cell carcinoma (OCCC)) is one epithelial ovarian carcinoma that is known to have a poor prognosis and a tendency for being refractory to treatment due to unclear pathogenesis. Published investigations of OCCC have mainly focused only on individual genes and lack of systematic integrated research to analyze the pathogenesis of OCCC in a genome-wide perspective. Thus, we conducted an integrated analysis using transcriptome datasets from a public domain database to determine genes that may be implicated in the pathogenesis involved in OCCC carcinogenesis. We used the data obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) DataSets. We found six interactive functional gene clusters in the pathogenesis network of OCCC, including ribosomal protein, eukaryotic translation initiation factors, lactate, prostaglandin, proteasome, and insulin-like growth factor.
    [Show full text]
  • Correction1 4784..4785
    Correction Correction: PCI-24781 Induces Caspase and Reactive Oxygen Species-Dependent Apoptosis In the article on PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis published in the May 15, 2009 issue of Clinical Cancer Research, there was an error in Table 1. Down-regulated genes were incorrectly labeled as up-regulated genes. The correct table appears here. Bhalla S, Balasubramanian S, David K, et al. PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-nB mechanisms and is synergistic with bortezomib in lymphoma cells. Clin Cancer Res 2009;15:3354–65. Table 1. Selected genes from expression analysis following 24-h treatment with PCI-24781, bortezomib, or the combination (in Ramos cells) Accn # Down-regulated genes 0.25 Mmol/L PCI/3 nmol/L Bor Name PCI-24781 Bortezomib Combination* Cell cycle-related NM_000075 Cyclin-dependent kinase 4 (CDK4) 0.49 0.83 0.37 NM_001237 Cyclin A2 (CCNA2) 0.43 0.87 0.37 NM_001950 E2F transcription factor 4, p107/p130-binding (E2F4) 0.48 0.79 0.40 NM_001951 E2F transcription factor 5, p130-binding (E2F5) 0.46 0.98 0.43 NM_003903 CDC16 cell division cycle 16 homolog (S cerevisiae) (CDC16) 0.61 0.78 0.43 NM_031966 Cyclin B1 (CCNB1) 0.55 0.90 0.43 NM_001760 Cyclin D3 (CCND3) 0.48 1.02 0.46 NM_001255 CDC20 cell division cycle 20 homolog (S cerevisiae; CDC20) 0.61 0.82 0.46 NM_001262 Cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4; CDKN2C) 0.61 1.15 0.56 NM_001238 Cyclin E1 (CCNE1) 0.56 1.05 0.60 NM_001239 Cyclin H (CCNH) 0.74 0.90 0.64 NM_004701
    [Show full text]
  • Genome-Wide Transcript and Protein Analysis Reveals Distinct Features of Aging in the Mouse Heart
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.28.272260; this version posted April 21, 2021. 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-ND 4.0 International license. Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart Isabela Gerdes Gyuricza1, Joel M. Chick2, Gregory R. Keele1, Andrew G. Deighan1, Steven C. Munger1, Ron Korstanje1, Steven P. Gygi3, Gary A. Churchill1 1The Jackson Laboratory, Bar Harbor, Maine 04609 USA; 2Vividion Therapeutics, San Diego, California 92121, USA; 3Harvard Medical School, Boston, Massachusetts 02115, USA Corresponding author: [email protected] Key words for online indexing: Heart Aging Transcriptomics Proteomics eQTL pQTL Stoichiometry ABSTRACT Investigation of the molecular mechanisms of aging in the human heart is challenging due to confounding factors, such as diet and medications, as well limited access to tissues. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyzed transcriptome and proteome data from hearts of genetically diverse mice at ages 6, 12 and 18 months to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal distinct biological processes that are altered through the course of natural aging. Transcriptome analysis reveals a scenario of cardiac hypertrophy, fibrosis, and reemergence of fetal gene expression patterns.
    [Show full text]
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
    [Show full text]
  • I FOUR JOINTED BOX ONE, a NOVEL PRO-ANGIOGENIC PROTEIN IN
    FOUR JOINTED BOX ONE, A NOVEL PRO-ANGIOGENIC PROTEIN IN COLORECTAL CARCINOMA. BY Nicole Theresa Al-Greene 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 Cell and Developmental Biology. December, 2013 Nashville Tennessee Approved: R. Daniel Beauchamp Susan Wente James Goldenring Albert Reynolds i DEDICATION To my parents, Karen and John, who have helped me in every way possible, every single day. ii ACKNOWLEDGMENTS. Funding for this work was supported by grants DK052334, CA069457, The GI Cancer SPORE, GM088822, the VICC, the Clinical and Translational Science Award (NCRR/NIH UL1RR024975), the DDRC (P30DK058404), and the Cooperative Human Tissue Network (UO1CA094664) and U01CA094664. I was lucky enough to be allowed to perform research as an undergraduate in the lab of Ken Belanger. I will be forever grateful for that opportunity that sparked my love of research. Equally important was my time as a technician in Len Zon’s lab where I confirmed the fact that I needed to go graduate school and earn my degree. During my time at Vanderbilt I have been helped by so many individuals, and the collaborative nature of everyone I have met with is truly an amazing aspect of the research community here. I am especially thankful for all the technical help and insightful conversations I have had with Natasha Deane, Anna Means, Claudia Andl, Tanner Freeman, Connie Weaver, Keeli Lewis, Jalal Hamaamen, Jenny Zi, John Neff, Christian Kis, Andries Zjistra, Trennis Palmer, Joseph Roland, and Lynn LaPierre.
    [Show full text]
  • Theranostics the PSMD14 Inhibitor Thiolutin As a Novel Therapeutic
    Theranostics 2021, Vol. 11, Issue 12 5847 Ivyspring International Publisher Theranostics 2021; 11(12): 5847-5862. doi: 10.7150/thno.46109 Research Paper The PSMD14 inhibitor Thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation Chao Jing1*, Xingchen Li1*, Mengqian Zhou1*, Shengchi Zhang1,2*, Qingchuan Lai1, Dandan Liu1, Beibei Ye1, Linqi Li1, Yue Wu1, Hong Li1, Kai Yue1, Peng Chen1, Xiaofeng Yao1, Yansheng Wu1, Yuansheng Duan1, Xudong Wang1 1. Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin 300060, China. 2. Department of Ear, Nose and Throat, Tianjin 1st Centre Hospital, Tianjin 300192, China. * These authors contributed equally to this work. Corresponding authors: Dr. Xudong Wang ([email protected]), Ms Yuansheng Duan ([email protected]) and Dr. Yansheng Wu ([email protected]). Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, 18 Huanhuxi Road, Tianjin 300060, China. Tel: +86-22-23340123. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.03.17; Accepted: 2021.03.11; Published: 2021.04.03 Abstract Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB).
    [Show full text]