DOCSLIB.ORG

PKA Signaling Drives Mammary Tumorigenesis Through Src

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PKA Signaling Drives Mammary Tumorigenesis Through Src Oncogene (2015) 34, 1160–1173 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE PKA signaling drives mammary tumorigenesis through Src AG Beristain1, SD Molyneux1,2, PA Joshi1,2, NC Pomroy1, MA Di Grappa1, MC Chang3, LS Kirschner4, GG Privé2, MA Pujana5 and R Khokha1,2,3 Protein kinase A (PKA) hyperactivation causes hereditary endocrine neoplasias; however, its role in sporadic epithelial cancers is unknown. Here, we show that heightened PKA activity in the mammary epithelium generates tumors. Mammary-restricted biallelic ablation of Prkar1a, which encodes for the critical type-I PKA regulatory subunit, induced spontaneous breast tumors characterized by enhanced type-II PKA activity. Downstream of this, Src phosphorylation occurs at residues serine-17 and tyrosine-416 and mammary cell transformation is driven through a mechanism involving Src signaling. The phenotypic consequences of these alterations consisted of increased cell proliferation and, accordingly, expansion of both luminal and basal epithelial cell populations. In human breast cancer, low PRKAR1A/high SRC expression defines basal-like and HER2 breast tumors associated with poor clinical outcome. Together, the results of this study define a novel molecular mechanism altered in breast carcinogenesis and highlight the potential strategy of inhibiting SRC signaling in treating this cancer subtype in humans. Oncogene (2015) 34, 1160–1173; doi:10.1038/onc.2014.41; published online 24 March 2014 INTRODUCTION of Prkar1a in mesenchymal lineage cells is sufficient for 18 Cyclic-AMP dependent protein kinase A (PKA) ubiquitously spontaneous osteosarcoma development. However, the role of functions as a signaling hub downstream of G-protein coupled PKA signaling in other cancer types and, particularly, in mammary receptors and cAMP to regulate a spectrum of biological processes carcinogenesis remains unknown. across tissues.1–6 PKA impacts multiple signaling networks in both In this study, we show that altered PKA regulation leading to physiological and pathological conditions by phosphorylating increased PKA activity in mammary tissue promotes carcino- target proteins on serine/threonine residues. The complexity genesis. Prkar1a loss results in heightened PKA activity defined by associated with PKA function stems from its presence as two an increase in type-II PKA isozyme in mammary epithelial cells and distinct heterotetramers, termed type-I and type-II PKA,4,7 with this hyperactivation drives mammary cell transformation through each PKA isozyme varying with respect to protein subunit a mechanism involving Src. We further find that low PRKAR1A/high composition, cellular localization and turnover. Four regulatory SRC marks a tumor subset of poor-prognosis basal-like and HER2 (R) subunits (R1α,R1β,R2α and R2β) and four catalytic (C) subunits breast cancer. (Cα,Cβ,Cγ and Prkx) have been identified, where the presence of R1 or R2 subunits defines the type of PKA isozyme as type-I or RESULTS type-II, respectively.8 The balance between type-I/-II PKA can influence cell cycle entry and terminal differentiation in multiple Prkar1a loss in the mammary gland is sufficient to cause systems.4,7 Dysregulated PKA activity leads to the development of mammary tumors tumors in cAMP-responsive endocrine tissues9,10 and this is To explore the effects of PKA hyperactivation in epithelial cells, thought to stem from imbalances in activities of either type-I or we selected the mammary gland, a tissue outside of classical type-II PKA;7,11 however, its role as a cancer driver in a wider endocrine epithelium harboring an extensive ductal network with spectrum of tissues is less well known. marker-defined lineages. It can develop a diverse family of The discovery of autosomal dominant inactivating mutations of molecular cancer subtypes in humans.19,20 Several mouse models the PRKAR1A gene as the cause of Carney complex syndrome first are available, including those that allow homozygous gene linked PKA dysregulation to carcinogenesis.12,13 PRKAR1A encodes deletion in the majority of mammary ductal epithelium. We the PKA regulatory subunit R1α, and of the four PKA regulatory adopted a genetic strategy (Figure 1a) in which mammary-specific subunits, only PRKAR1A is essential for tissue development and deletion of Prkar1a was created by crossing Prkar1alox/lox mice cAMP-dependent regulation.14 Mutations to this gene in humans (Prkar1a exon 2 flanked by LoxP sites) with transgenic mice and mice induce multiple endocrine tumors as well as myxomas, expressing Cre recombinase under the mammary epithelial- osteoblastic neoplasias and schwannomas.9,15 When combined specific MMTV promoter. Unexpectedly, MMTV-Cre deletion of À À À with Tp53+/ or Rb1+/ backgrounds, Prkar1a+/ mice exhibit a Prkar1a was sufficient to generate mammary tumors (Figure 1b); generally increased incidence of sarcomas, pituitary tumors, Cre-mediated excision of the Prkar1a gene in this cohort of mice is thyroid tumors and chemically induced skin papillomas.10,16,17 In shown in Figure 1c. Prkar1aΔMam mice developed multiple tumors addition, we have found that tissue-specific heterozygous deletion with 100% penetrance and a latency of 9–15 months of age (18/18 1Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada; 2Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 4Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA and 5Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain. Correspondence: Dr R Khokha, Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada M5G 2M9. E-mail: [email protected] Received 1 August 2013; revised 20 December 2013; accepted 24 December 2013; published online 24 March 2014 PKA-induced Src drives mammary tumorigenesis AG Beristain et al 1161 Figure 1. Conditional loss of Prkar1a is sufficient to generate mammary tumors. (a) Schematic describes mouse-breeding strategy for the generation of Prkar1aΔMam mice. Prkar1aΔMam (MMTV-Cre/Prkar1afl/fl) denotes homozygous deletion by Cre recombinase expressed under the control of the MMTV promoter. (b) Survival plot of Prkar1aΔMam (n = 18; solid black line) and control MMTV-Cre mice (n = 6; dashed line). (c) Cre-mediated genomic excision of Prkar1a in primary mammary epithelial cells derived from Prkar1aΔMam mice assessed by PCR; MMTV-Cre mammary epithelial cells do not exhibit Cre-directed Prkar1a excision shown by lack of 175-bp PCR product. Prkar1afl/+ mouse osteoblast cultures transduced with retroviral Cre-recombinase (p-Cre) or GFP (p-GFP) serve as positive or negative controls.19 ‘L’ indicates DNA ladder. (d) Mammary gland whole-mounts of Prkar1aΔMam from 1.4 to 13 months of age highlights tissue progression to tumors. LN denotes lymph node; red arrows highlight progression to tumors, ‘mo’ indicates age in months. Representative (e) H&E staining of tumors from Prkar1aΔMam mice showing papillary, mixed (mix) and invasive ductal carcinoma (IDC) mammary tumors. Scale bars, 100 μm. (f) Representative immunofluorescent images of Prkar1aΔMam mammary tumors dual-labeled with epithelial lineage markers keratin 14 (basal) and keratin 18 (luminal). Merged images show the combination of keratin 14 (red), keratin 18 (green) and DAPI (blue) positivity. Scale bars, 50 μm. See also Supplementary Figure 1 mice aged o16 months; Figure 1b; Supplementary Figure 1A) mammary tumors showed immunohistochemical positivity for and progression from ductal hyperplasia (4.2 months) to palpable estrogen receptor α (Erα) and progesterone receptor (Pgr), tumors (13 months) was observed by whole-mount analysis whereas less-differentiated tumors harboring an invasive pheno- (Figure 1d). type were immuno-negative for Erα (Supplementary Figure 1B). Histologically, mammary glands of >10 month-old Prkar1aΔMam Next, to examine whether Prkar1a loss cooperates with mice had an abundance of lobular hyperplasia, back-to-back molecular pathways known to be activated in human breast growth and areas of atypia (Figure 1e). The tumors had cancer, Prkar1aΔMam mice were bred into the widely used MMTV- characteristics of papillomas with gradual progression to ductal PyMT (polyoma virus middle T-antigen) model that induces carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) activation of ErbB2, Src, c-Myc and Ras/PI3 kinase signaling (Figure 1e). In the majority of mammary tumors, a profound networks (Figure 2a).21,22 Confirmation of Cre-mediated Prkar1a expansion of keratin 18-positive luminal cells was observed, which gene excision in this cohort was confirmed by PCR (Figure 2b). was accompanied with scattered expression of the myoepithelial Tumor development was faster, with increased tumor burden, in marker keratin 14 (Figure 1f). Additionally, select Prkar1aΔMam Prkar1aΔMam/PyMT mice compared with PyMT controls (Figures 2). © 2015 Macmillan Publishers Limited Oncogene (2015) 1160 – 1173 PKA-induced Src drives mammary tumorigenesis AG Beristain et al 1162 Figure 2. Prkar1a ablation in the PyMT mammary tumor model accelerates tumorigenesis. (a) Schematic describes mouse-breeding strategy for the generation of Prkar1aΔMam/PyMT mice. (b) Cre-mediated
Load more

Recommended publications
  • Gpr161 Anchoring of PKA Consolidates GPCR and Camp Signaling
    Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling Verena A. Bachmanna,1, Johanna E. Mayrhofera,1, Ronit Ilouzb, Philipp Tschaiknerc, Philipp Raffeinera, Ruth Röcka, Mathieu Courcellesd,e, Federico Apeltf, Tsan-Wen Lub,g, George S. Baillieh, Pierre Thibaultd,i, Pia Aanstadc, Ulrich Stelzlf,j, Susan S. Taylorb,g,2, and Eduard Stefana,2 aInstitute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, 6020 Innsbruck, Austria; bDepartment of Chemistry and Biochemistry, University of California, San Diego, CA 92093; cInstitute of Molecular Biology, University of Innsbruck, 6020 Innsbruck, Austria; dInstitute for Research in Immunology and Cancer, Université de Montréal, Montreal, QC, Canada H3C 3J7; eDépartement de Biochimie, Université de Montréal, Montreal, QC, Canada H3C 3J7; fOtto-Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; gDepartment of Pharmacology, University of California, San Diego, CA 92093; hInstitute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom; iDepartment of Chemistry, Université de Montréal, Montreal, QC, Canada H3C 3J7; and jInstitute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, 8010 Graz, Austria Contributed by Susan S. Taylor, May 24, 2016 (sent for review February 18, 2016; reviewed by John J. G. Tesmer and Mark von Zastrow) Scaffolding proteins organize the information flow from activated G accounts for nanomolar binding affinities to PKA R subunit dimers protein-coupled receptors (GPCRs) to intracellular effector cascades (12, 13). Moreover, additional components of the cAMP signaling both spatially and temporally. By this means, signaling scaffolds, such machinery, such as GPCRs, adenylyl cyclases, and phosphodiester- as A-kinase anchoring proteins (AKAPs), compartmentalize kinase ases, physically interact with AKAPs (1, 5, 11, 14).
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • PI3K Catalytic Isoform Alteration Promotes the LIMK1-Related
    ANTICANCER RESEARCH 37 : 1805-1818 (2017) doi:10.21873/anticanres.11515 PI3K Catalytic Isoform Alteration Promotes the LIMK1-related Metastasis Through the PAK1 or ROCK1/2 Activation in Cigarette Smoke-exposed Ovarian Cancer Cells GA BIN PARK 1 and DAEJIN KIM 2 1Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea; 2Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea Abstract. Aim: To investigate the molecular mechanisms Several studies have shown a strong correlation between by which long-term exposure to cigarette smoke extract cigarette smoke (CS) and cancer metastasis through the (CSE) contributes to ovarian cancer metastasis. Materials induction of numerous factors involved in migration activity and Methods: Western blot analysis for diverse p110 (1-3). The exposure to CS induces the epithelial- isoforms of phosphoinositide 3-kinase (PI3K)-related mesenchymal transition (EMT) process and up-regulates the signaling pathway and epithelial-mesenchymal transition expression of EMT markers, including N-cadherin and (EMT) markers was performed to analyze the underlying vimentin (4, 5). Cigarette smoke extract (CSE) treatment mechanisms. Migratory activity of CSE-exposed ovarian significantly induces interleukin-8 (IL-8) and transforming cancer cells was determined by transendothelial migration growth factor-beta 1 (TGF- β1 ) production and profoundly and invasion assay. Results: After exposure to CSE for four suppresses the proliferation and growth of erythroid and weeks, CaOV3 (primary) and SKOV3 (metastatic) ovarian granulocyte-macrophage progenitors (6). Stimulation with cancer cells showed enhanced mesenchymal characteristics CSE in human lung fibroblast cells induces the expression and produced EMT-related cytokines [intwerleukin-8 (IL-8), of phosphorylated Smad3, a main downstream target of the vascular endothelial growth factor (VEGF) and TGF- β1 receptor, which results in the secretion of vascular transforming growth factor-beta 1 (TGF- β1 )].
    [Show full text]
  • Identification and Characterization of RHOA-Interacting Proteins in Bovine Spermatozoa1
    BIOLOGY OF REPRODUCTION 78, 184–192 (2008) Published online before print 10 October 2007. DOI 10.1095/biolreprod.107.062943 Identification and Characterization of RHOA-Interacting Proteins in Bovine Spermatozoa1 Sarah E. Fiedler, Malini Bajpai, and Daniel W. Carr2 Department of Medicine, Oregon Health & Sciences University and Veterans Affairs Medical Center, Portland, Oregon 97239 ABSTRACT Guanine nucleotide exchange factors (GEFs) catalyze the GDP for GTP exchange [2]. Activation is negatively regulated by In somatic cells, RHOA mediates actin dynamics through a both guanine nucleotide dissociation inhibitors (RHO GDIs) GNA13-mediated signaling cascade involving RHO kinase and GTPase-activating proteins (GAPs) [1, 2]. Endogenous (ROCK), LIM kinase (LIMK), and cofilin. RHOA can be RHO can be inactivated via C3 exoenzyme ADP-ribosylation, negatively regulated by protein kinase A (PRKA), and it and studies have demonstrated RHO involvement in actin-based interacts with members of the A-kinase anchoring (AKAP) cytoskeletal response to extracellular signals, including lyso- family via intermediary proteins. In spermatozoa, actin poly- merization precedes the acrosome reaction, which is necessary phosphatidic acid (LPA) [2–4]. LPA is known to signal through for normal fertility. The present study was undertaken to G-protein-coupled receptors (GPCRs) [4, 5]; specifically, LPA- determine whether the GNA13-mediated RHOA signaling activated GNA13 (formerly Ga13) promotes RHO activation pathway may be involved in acrosome reaction in bovine through GEFs [4, 6]. Activated RHO-GTP then signals RHO caudal sperm, and whether AKAPs may be involved in its kinase (ROCK), resulting in the phosphorylation and activation targeting and regulation. GNA13, RHOA, ROCK2, LIMK2, and of LIM-kinase (LIMK), which in turn phosphorylates and cofilin were all detected by Western blot in bovine caudal inactivates cofilin, an actin depolymerizer, the end result being sperm.
    [Show full text]
  • Circular RNA Hsa Circ 0005114‑Mir‑142‑3P/Mir‑590‑5P‑ Adenomatous
    ONCOLOGY LETTERS 21: 58, 2021 Circular RNA hsa_circ_0005114‑miR‑142‑3p/miR‑590‑5p‑ adenomatous polyposis coli protein axis as a potential target for treatment of glioma BO WEI1*, LE WANG2* and JINGWEI ZHAO1 1Department of Neurosurgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033; 2Department of Ophthalmology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, P.R. China Received September 12, 2019; Accepted October 22, 2020 DOI: 10.3892/ol.2020.12320 Abstract. Glioma is the most common type of brain tumor APC expression with a good overall survival rate. UALCAN and is associated with a high mortality rate. Despite recent analysis using TCGA data of glioblastoma multiforme and the advances in treatment options, the overall prognosis in patients GSE25632 and GSE103229 microarray datasets showed that with glioma remains poor. Studies have suggested that circular hsa‑miR‑142‑3p/hsa‑miR‑590‑5p was upregulated and APC (circ)RNAs serve important roles in the development and was downregulated. Thus, hsa‑miR‑142‑3p/hsa‑miR‑590‑5p‑ progression of glioma and may have potential as therapeutic APC‑related circ/ceRNA axes may be important in glioma, targets. However, the expression profiles of circRNAs and their and hsa_circ_0005114 interacted with both of these miRNAs. functions in glioma have rarely been studied. The present study Functional analysis showed that hsa_circ_0005114 was aimed to screen differentially expressed circRNAs (DECs) involved in insulin secretion, while APC was associated with between glioma and normal brain tissues using sequencing the Wnt signaling pathway. In conclusion, hsa_circ_0005114‑ data collected from the Gene Expression Omnibus database miR‑142‑3p/miR‑590‑5p‑APC ceRNA axes may be potential (GSE86202 and GSE92322 datasets) and explain their mecha‑ targets for the treatment of glioma.
    [Show full text]
  • Oncogenic Activation of Pak1-Dependent Pathway of Macropinocytosis Determines BCG Entry Into Bladder Cancer Cells
    Cancer Molecular and Cellular Pathobiology Research Oncogenic Activation of Pak1-Dependent Pathway of Macropinocytosis Determines BCG Entry into Bladder Cancer Cells Gil Redelman-Sidi1,2, Gopa Iyer3,4, David B. Solit3,4, and Michael S. Glickman1,2 Abstract Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here, we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42, and their effector kinase Pak1. The difference in susceptibility between BCG- permissive and -resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with phosphoinositide 3-kinase inhibitor activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell. Cancer Res; 73(3); 1156–67. Ó2013 AACR. Introduction Despite more than 30 years of clinical experience with Bladder cancer is among the most common tumors diag- intravesical BCG for bladder cancer, its mechanism of antitu- nosed in the United States, with an estimated annual incidence mor effect remains unknown and no markers exist to predict of 70,530 new cases and 14,680 deaths in 2010 (1).
    [Show full text]
  • Role of Rac1-Pak Pathway in Aggressive B-Cell Lymphoma
    University of Nebraska Medical Center DigitalCommons@UNMC Theses & Dissertations Graduate Studies Spring 5-4-2019 Role of Rac1-Pak pathway in aggressive b-cell lymphoma Tian Tian University of Nebraska Medical Center Follow this and additional works at: https://digitalcommons.unmc.edu/etd Part of the Hemic and Lymphatic Diseases Commons, and the Neoplasms Commons Recommended Citation Tian, Tian, "Role of Rac1-Pak pathway in aggressive b-cell lymphoma" (2019). Theses & Dissertations. 344. https://digitalcommons.unmc.edu/etd/344 This Dissertation is brought to you for free and open access by the Graduate Studies at DigitalCommons@UNMC. It has been accepted for inclusion in Theses & Dissertations by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. i Role of Rac1-PAK Pathway in Aggressive B-cell Lymphomas By Tian Tian A DISSERTATION Presented to the Faculty of The University of Nebraska Graduate College in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Pathology & Microbiology Graduate program Under the Supervision of Professor Kai Fu University of Nebraska Medical Center, Omaha, Nebraska Dec, 2018 Supervisory Committee: Ying Yan, Ph.D. John S Davis, Ph.D. Timothy C Greiner, M.D. Javeed Iqbal, Ph.D. ii Role of Rac1-PAK pathway in Aggressive B-cell Lymphomas Tian Tian University of Nebraska Medical Center, 2018 Advisor: Kai Fu, M.D. Ph.D. Aggressive B-cell lymphomas are diverse group of neoplasms that arise at different stages of B-cell development and by various mechanisms of neoplastic transformation. Aggressive B-cell lymphomas include many types, subtypes and variants of diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL) and B lymphoblastic lymphoma.
    [Show full text]
  • A SARS-Cov-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
    A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing Supplementary Information Supplementary Discussion All SARS-CoV-2 protein and gene functions described in the subnetwork appendices, including the text below and the text found in the individual bait subnetworks, are based on the functions of homologous genes from other coronavirus species. These are mainly from SARS-CoV and MERS-CoV, but when available and applicable other related viruses were used to provide insight into function. The SARS-CoV-2 proteins and genes listed here were designed and researched based on the gene alignments provided by Chan et. al. 1 2020 .​ Though we are reasonably sure the genes here are well annotated, we want to note that not every ​ protein has been verified to be expressed or functional during SARS-CoV-2 infections, either in vitro or in vivo. ​ ​ In an effort to be as comprehensive and transparent as possible, we are reporting the sub-networks of these functionally unverified proteins along with the other SARS-CoV-2 proteins. In such cases, we have made notes within the text below, and on the corresponding subnetwork figures, and would advise that more caution be taken when examining these proteins and their molecular interactions. Due to practical limits in our sample preparation and data collection process, we were unable to generate data for proteins corresponding to Nsp3, Orf7b, and Nsp16. Therefore these three genes have been left out of the following literature review of the SARS-CoV-2 proteins and the protein-protein interactions (PPIs) identified in this study.
    [Show full text]
  • Whole Exome Sequencing of Thymic Neuroendocrine Tumor with Ectopic
    176:2 Y Li, Y Peng and others Sequencing thymic 176:2 187–194 Clinical Study neuroendocrine tumor Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome Yanli Li1,*, Ying Peng1,*, Xiuli Jiang1, Yulong Cheng3, Weiwei Zhou1, Tingwei Su1, Jing Xie2, Xu Zhong1, Dalong Song1, Luming Wu1, Liwen Fan1, Min Li1, Jie Hong1, Weiqing Wang1, Guang Ning1,3 and Yanan Cao1 1Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors and 2Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China, and 3Laboratory of Endocrinology and Metabolism, Institute of Health Correspondence Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & should be addressed Shanghai Jiao-Tong University School of Medicine (SJTUSM), Shanghai, China to Y Cao *(Y Li and Y Peng contributed equally to this work) Email [email protected] Abstract Objective: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing. Design and methods: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform.
    [Show full text]
  • Mir-17-92 Fine-Tunes MYC Expression and Function to Ensure
    ARTICLE Received 31 Mar 2015 | Accepted 22 Sep 2015 | Published 10 Nov 2015 DOI: 10.1038/ncomms9725 OPEN miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth Marija Mihailovich1, Michael Bremang1, Valeria Spadotto1, Daniele Musiani1, Elena Vitale1, Gabriele Varano2,w, Federico Zambelli3, Francesco M. Mancuso1,w, David A. Cairns1,w, Giulio Pavesi3, Stefano Casola2 & Tiziana Bonaldi1 The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well-documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 30 untranslated region (UTR) analysis upon miR-17-19b overexpression. We identify over one hundred miR-17-19b targets, of which 40% are co-regulated by c-MYC. Downregulation of a new miR-17/20 target, checkpoint kinase 2 (Chek2), increases the recruitment of HuR to c- MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 30 UTR shortening at different stages of tumorigenesis. 1 Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan 20139, Italy. 2 Units of Genetics of B cells and lymphomas, IFOM, FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
    [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]
  • Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened.
    [Show full text]