DOCSLIB.ORG

Common Genetic Variants in the PSCA Gene in Fluence Gene Expression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Common Genetic Variants in the PSCA Gene in Fluence Gene Expression Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk Yi-Ping Fua, Indu Kohaara, Nathaniel Rothmanb, Julie Earlc, Jonine D. Figueroab, Yuanqing Yed, Núria Malatse, Wei Tanga, Luyang Liua, Montserrat Garcia-Closasb,f, Brian Muchmorea, Nilanjan Chatterjeeb, McAnthony Tarwaya, Manolis Kogevinasg,h,i,j, Patricia Porter-Gilla, Dalsu Barisb, Adam Mumya, Demetrius Albanesb, Mark P. Purdueb, Amy Hutchinsonk, Alfredo Carratol, Adonina Tardónh,m, Consol Serran, Reina García-Closaso, Josep Lloretap, Alison Johnsonq, Molly Schwennr, Margaret R. Karagass, Alan Schneds, W. Ryan Divert, Susan M. Gapsturt, Michael J. Thunt, Jarmo Virtamou, Stephen J. Chanocka, Joseph F. Fraumeni, Jr.b,1, Debra T. Silvermanb, Xifeng Wud, Francisco X. Realc,n, and Ludmila Prokunina-Olssona,1 aLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, and bDivision of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; cEpithelial Carcinogenesis Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain; dDepartment of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; eGenetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid 28029, Spain; fDivision of Genetics and Epidemiology, Institute of Cancer Research, London SW7 3RP, United Kingdom; gCentre for Research in Environmental Epidemiology, Barcelona 08003, Spain; hMunicipal Institute of Medical Research, Barcelona 08003, Spain; iCentro de Investiación de Biomédica en Red Epidemiología y Salud Pública, Barcelona 08003, Spain; jNational School of Public Health, Athens 11521, Greece; kCore Genotyping Facility, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702; lRamón y Cajal University Hospital, Madrid 28034, Spain; mInstituto Universitario de Oncología, Universidad de Oviedo, Oviedo 33003, Spain; nDepartament de Ciències Experimentals i de la Salut, and pHospital del Mar-Institut Municipal d’Investigació Mèdica, Universitat Pompeu Fabra, Barcelona 08003, Spain; oUnidad de Investigación, Hospital Universitario de Canarias, La Laguna 38320, Spain; qVermont Cancer Registry, Burlington, VT 05401; rMaine Cancer Registry, Augusta, ME 04333; sDartmouth Medical School, Hanover, NH 03755; tEpidemiology Research Program, American Cancer Society, Atlanta, GA 30303; and uDepartment of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki 00271, Finland Contributed by Joseph F. Fraumeni, Jr., February 15, 2012 (sent for review January 11, 2012) Genome-wide association studies have identified a SNP, rs2294008, genetic architecture of bladder cancer by discovering a number of on 8q24.3 within the prostate stem cell antigen (PSCA)gene,asa new bladder cancer-associated loci (13–17). risk factor for bladder cancer. To fine-map this region, we imputed One of these variants to achieve genome-wide significance with 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers bladder cancer was SNP rs2294008 (C/T) within the prostate stem PSCA genotyped in one of the reported genome-wide association study cell antigen ( ) gene on 8q24.3 (14, 15). PSCA is a glyco- sylphosphatidylinositol-anchored cell membrane glycoprotein ini- in 8,652 subjects. A multivariable logistic regression model adjusted fi fi for rs2294008 revealed a unique signal, rs2978974 (r2 =0.02,D′ = 0.19 tially identi ed as a prostate-speci c cell-surface antigen (18), but with rs2294008). In the combined analysis of 5,393 cases and 7,324 later found to be expressed in many human tissues. Humanized controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confi- monoclonal anti-PSCA antibodies are currently under evaluation − in clinical trials for the treatment of pancreatic and prostate cancers dence interval (CI) = 1.06–1.17, P =5.8× 10 5] for rs2294008 and OR = – P × −3 (19, 20). Although many studies have supported the important role 1.07 (95% CI = 1.02 1.13, =9.7 10 ) for rs2978974. The effect was of PSCA in carcinogenesis, little is known about the function of stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08– PSCA P × −3 fi in normal and tumor tissues. 1.41, =1.8 10 )andtherewasasigni cant multiplicative in- In this study, we aimed to comprehensively explore the genetic P teraction ( = 0.035) between these two SNPs, which requires repli- landscape of the PSCA region to map genetic variants contributing cation in future studies. The T risk allele of rs2294008 was associated to bladder cancer susceptibility, as well as to investigate the mo- with increased PSCA mRNA expression in two sets of bladder tumor lecular phenotype of these variants and their role in cancer biology. samples (n =36,P = 0.0007 and n =34,P = 0.0054) and in normal bladder samples (n =35,P = 0.0155), but rs2978974 was not associ- Results ated with PSCA expression. SNP rs2978974 is located 10 Kb upstream Fine-Mapping and Genetic Association of the PSCA Region. PSCA is of rs2294008, within an alternative untranslated first exon of PSCA. located in 8q24.3 locus, 12.5 Mb telomeric from the region asso- The non-risk allele G of rs2978974 showed strong interaction with ciated with multiple cancers (21). Based on the combined reference nuclear proteins from five cell lines tested, implying a regulatory panel of the 1000 Genomes Project and HapMap 3 CEU (Utah function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 residents with Northern and Western European ancestry) data, we and rs2978974, suggests that both variants may be important for expanded the SNP coverage of the 200 Kb PSCA region (chr8: bladder cancer susceptibility, possibly through different mechanisms 143,658,933–143,858,933, University of California at Santa Cruz that influence the control of mRNA expression and interaction with (UCSC) genome build hg18), which covers eight genes: ARC, JRK, regulatory factors. PSCA, LY6K, C8orf55, SLURP1, LYPD2,andLYNX1. In addition rinary bladder cancer ranks as the ninth most common ma- Ulignancy worldwide (1) and the sixth in the United States, with Author contributions: Y.-P.F., I.K., N.R., J.E., J.D.F., S.J.C., J.F.F., D.T.S., X.W., F.X.R., and L.P.-O. designed research; Y.-P.F., I.K., J.E., Y.Y., N.M., W.T., L.L., B.M., M.T., M.K., P.P.-G., D.B., 73,510 new cases and 14,880 deaths expected in the United States A.M., D.A., M.P.P., A.H., A.C., A.T., C.S., R.G.-C., J.L., A.J., M.S., M.R.K., A.S., W.R.D., S.M.G., in 2012 (2). Because of a 70% 10-y survival rate and 50–70% re- M.J.T., J.V., X.W., F.X.R., and L.P.-O. performed research; J.D.F., M.G.-C., and N.C. contrib- currence rate (3), patients require life-long surveillance and treat- uted new reagents/analytic tools; Y.-P.F., I.K., J.E., J.D.F., Y.Y., W.T., M.G.-C., N.C., X.W., ment, making bladder cancer one of the most expensive cancers F.X.R., and L.P.-O. analyzed data; N.R., Y.Y., N.M., M.G.-C., M.K., D.B., D.A., M.P.P., A.H., A.C., A.T., C.S., R.G.-C., J.L., A.J., M.S., M.R.K., A.S., W.R.D., S.M.G., M.J.T., J.V., S.J.C., J.F.F., to live with and a major economic burden on the health care system D.T.S., X.W., and F.X.R. subject enrollment and data collection; and Y.-P.F., I.K., N.R., S.J.C., (4, 5). Cigarette smoking and occupational exposures to aromatic J.F.F., D.T.S., X.W., F.X.R., and L.P.-O. wrote the paper. amines are established risk factors for bladder cancer (6). The authors declare no conflict of interest. – Genetic factors are estimated to explain 7 31% of bladder cancer Freely available online through the PNAS open access option. susceptibility (7, 8). Traditional candidate gene association studies 1To whom correspondence may be addressed. E-mail: [email protected] or prokuninal@ focused on genes involved in detoxification of environmental car- mail.nih.gov. – cinogens and DNA repair pathways (9 12). Recently, genome-wide This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. association studies (GWAS) have advanced our knowledge of the 1073/pnas.1202189109/-/DCSupplemental. 4974–4979 | PNAS | March 27, 2012 | vol. 109 | no. 13 www.pnas.org/cgi/doi/10.1073/pnas.1202189109 Downloaded by guest on September 29, 2021 region, we adjusted for the effect of rs2294008 along with age, sex, study regions, and smoking habit, and found the strongest signal for an additional variant, already genotyped in the GWAS, rs2978974 − (OR = 1.11, 95% CI = 1.04–1.19, P = 1.80 × 10 3)(Fig.1B and Dataset S1). Among 446 markers examined in this study, 46 SNPs areinstrongLD(r2 > 0.8) with rs2294008, but rs2978974 is a unique variant that is in low LD with rs2294008 (D′ = 0.19, r2 = 0.02) and 2 not well tagged by other SNPs (r max = 0.19) (Fig. S1 and Dataset S1). Additionally, rs2294008 and rs2978974 were genotyped in three independent studies, New England Bladder Cancer Study from New Hampshire (NEBCS-NH, a component of NEBCS not used in stage 1 GWAS), and Texas Bladder Cancer Study discovery set and validation set (TXBCS1 and TXBCS2, respectively). In the combined analysis of all eight studies that included 5,393 cases and 7,324 controls, rs2294008 and rs2978974 were associated with bladder cancer with a per-allele OR = 1.11 (95% CI = 1.06–1.17, − P = 5.79 × 10 5) and OR = 1.07 (95% CI = 1.02–1.13, P = 9.66 × − 10 3), respectively (Table 1).
Load more

Recommended publications
  • Association of MUC1 5640G>A and PSCA 5057C>T Polymorphisms
    Alikhani et al. BMC Medical Genetics (2020) 21:148 https://doi.org/10.1186/s12881-020-01085-z RESEARCH ARTICLE Open Access Association of MUC1 5640G>A and PSCA 5057C>T polymorphisms with the risk of gastric cancer in Northern Iran Reza Alikhani1, Ali Taravati1 and Mohammad Bagher Hashemi-Soteh2* Abstract Background: Gastric cancer is one of the four most common cancer that causing death worldwide. Genome-Wide Association Studies (GWAS) have shown that genetic diversities MUC1 (Mucin 1) and PSCA (Prostate Stem Cell Antigen) genes are involved in gastric cancer. The aim of this study was avaluating the association of rs4072037G > A polymorphism in MUC1 and rs2294008 C > T in PSCA gene with risk of gastric cancer in northern Iran. Methods: DNA was extracted from 99 formalin fixed paraffin-embedded (FFPE) tissue samples of gastric cancer and 96 peripheral blood samples from healthy individuals (sex matched) as controls. Two desired polymorphisms, 5640G > A and 5057C > T for MUC1 and PSCA genes were genotyped using PCR-RFLP method. Results: The G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR = 0.507, 95% CI: 0.322–0.799, p = 0.003). A significant decreased risk of gastric cancer was observed in people with either AG vs. AA, AG + AA vs. GG and AA+GG vs. AG genotypes of MUC1 polymorphism (OR = 4.296, 95% CI: 1.190–15.517, p =0.026), (OR = 3.726, 95% CI: 2.033–6.830, p = 0.0001) and (OR = 0.223, 95% CI: 0.120–0.413, p = 0.0001) respectively.
    [Show full text]
  • Anti-PSCA (Extracellular Domain) Polyclonal Antibody (DPAB1998RH) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-PSCA (extracellular domain) polyclonal antibody (DPAB1998RH) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview Rabbit anti-human prostate stem cell antigen polyclonal antibody is intended for qualitative immunohistochemistry with normal and neoplastic formalin-fixed, paraffin-embedded tissue sections, to be viewed by light microscopy. Clinical interpretation of st Antigen Description Prostate stem cell antigen is a protein that in humans is encoded by the PSCA gene. This gene encodes a glycosylphosphatidylinositol-anchored cell membrane glycoprotein. In addition to being highly expressed in the prostate it is also expressed in the bladder, placenta, colon, kidney, and stomach. This gene is up-regulated in a large proportion of prostate cancers and is also detected in cancers of the bladder and pancreas. This gene has a nonsynonymous nucleotide polymorphism at its start codon. Specificity This antibody reacts with a ~14 kD protein. Prostate Stem Cell Antigen (PSCA) is a cell surface antigen which is overexpressed in ~ 40% of primary prostate cancers and in nearly 100% of metastatic cancers. PSCA is also overexpressed in the majority of tra Immunogen A synthetic peptide derived from extracellular region of human PSCA protein. Isotype IgG Source/Host Rabbit Species Reactivity Human Conjugate Unconjugated Applications IHC Cellular Localization Cell membrane, cytoplasmic Positive Control Bladder carcinoma, prostate carcinoma Format Purified immunoglobulin fraction of rabbit
    [Show full text]
  • Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population
    pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2019;51(2):748-757 https://doi.org/10.4143/crt.2018.162 Original Article Open Access Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population Boyoung Park, MD, PhD1,2 Purpose Sarah Yang, PhD3,4 Half of the world’s gastric cancer cases and the highest gastric cancer mortality rates are observed in Eastern Asia. Although several genome-wide association studies (GWASs) have Jeonghee Lee, MS3 revealed susceptibility genes associated with gastric cancer, no GWASs have been con- PhD3 Hae Dong Woo, ducted in the Korean population, which has the highest incidence of gastric cancer. Il Ju Choi, MD, PhD5 Young Woo Kim, MD, PhD5 Materials and Methods Keun Won Ryu, MD, PhD5 We performed genome scanning of 450 gastric cancer cases and 1,134 controls via Affymetrix Axiom Exome 319 arrays, followed by replication of 803 gastric cancer cases and Young-Il Kim, MD, PhD5 3,693 healthy controls. Jeongseon Kim, PhD2,3 Results We showed that the rs2976394 in the prostate stem cell antigen (PSCA) gene is a gastric- 1Department of Medicine, Hanyang cancer-susceptibility gene in a Korean population, with genome-wide significance and an University College of Medicine, Seoul, odds ratio (OR) of 0.70 (95% confidence interval [CI], 0.64 to 0.77). A strong linkage dise- 2 Graduate School of Cancer Science and quilibrium with rs2294008 was also found, indicating an association with susceptibility. Policy, National Cancer Center, Goyang, 3Molecular Epidemiology Branch, Division of Individuals with the CC genotype of the PSCA gene showed an approximately 2-fold lower Cancer Epidemiology and Prevention, risk of gastric cancer compared to those with the TT genotype (OR, 0.47; 95% CI, 0.39 to Research Institute, National Cancer Center, 0.57).
    [Show full text]
  • Prostate Stem Cell Antigen Is Expressed in Normal and Malignant Human Brain Tissues
    ONCOLOGY LETTERS 15: 3081-3084, 2018 Prostate stem cell antigen is expressed in normal and malignant human brain tissues HIROE ONO, HIROMI SAKAMOTO, TERUHIKO YOSHIDA and NORIHISA SAEKI Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan Received June 25, 2015; Accepted October 24, 2016 DOI: 10.3892/ol.2017.7632 Abstract. Prostate stem cell antigen (PSCA) is a glyco- functions in subcellular signal transduction (2). Originally, sylphosphatidylinositol (GPI)-anchored cell surface protein PSCA was identified as a gene upregulated in prostate cancer (3), and exhibits an organ-dependent expression pattern in cancer. and later its upregulation was demonstrated in other types of PSCA is upregulated in prostate cancer and downregulated in tumor, including urinary bladder cancer, renal cell carcinoma, gastric cancer. PSCA is expressed in a variety of human organs. hydatidiform mole and ovarian mucinous tumor, where PSCA is Although certain studies previously demonstrated its expres- thought to be involved in tumor progression (1). However, down- sion in the mammalian and avian brain, its expression in the regulation of the gene was reported in gastric and gallbladder human brain has not been thoroughly elucidated. Additionally, cancer, where it may act as a tumor suppressor (4,5). As another it was previously reported that PSCA is weakly expressed in the pattern of its expression in cancer, PSCA is not expressed in the astrocytes of the normal human brain but aberrantly expressed ductal cells of the normal pancreas or the epithelial cells in the in glioma, suggesting that PSCA is a promising target of normal lung, however, it is expressed in their malignant coun- glioma therapy and prostate cancer therapy.
    [Show full text]
  • Organization, Evolution and Functions of the Human and Mouse Ly6/Upar Family Genes Chelsea L
    Loughner et al. Human Genomics (2016) 10:10 DOI 10.1186/s40246-016-0074-2 GENE FAMILY UPDATE Open Access Organization, evolution and functions of the human and mouse Ly6/uPAR family genes Chelsea L. Loughner1, Elspeth A. Bruford2, Monica S. McAndrews3, Emili E. Delp1, Sudha Swamynathan1 and Shivalingappa K. Swamynathan1,4,5,6,7* Abstract Members of the lymphocyte antigen-6 (Ly6)/urokinase-type plasminogen activator receptor (uPAR) superfamily of proteins are cysteine-rich proteins characterized by a distinct disulfide bridge pattern that creates the three-finger Ly6/uPAR (LU) domain. Although the Ly6/uPAR family proteins share a common structure, their expression patterns and functions vary. To date, 35 human and 61 mouse Ly6/uPAR family members have been identified. Based on their subcellular localization, these proteins are further classified as GPI-anchored on the cell membrane, or secreted. The genes encoding Ly6/uPAR family proteins are conserved across different species and are clustered in syntenic regions on human chromosomes 8, 19, 6 and 11, and mouse Chromosomes 15, 7, 17, and 9, respectively. Here, we review the human and mouse Ly6/uPAR family gene and protein structure and genomic organization, expression, functions, and evolution, and introduce new names for novel family members. Keywords: Ly6/uPAR family, LU domain, Three-finger domain, uPAR, Lymphocytes, Neutrophils Introduction an overview of the Ly6/uPAR gene family and their gen- The lymphocyte antigen-6 (Ly6)/urokinase-type plas- omic organization, evolution, as well as functions, and minogen activator receptor (uPAR) superfamily of struc- provide a nomenclature system for the newly identified turally related proteins is characterized by the LU members of this family.
    [Show full text]
  • Prostate Stem Cell Antigen (PSCA) Variants and Subsequences Thereof
    (19) TZZ ¥_ _T (11) EP 2 319 524 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: A61K 38/00 (2006.01) C07K 14/00 (2006.01) of the grant of the patent: C07K 16/00 (2006.01) G01N 33/532 (2006.01) 21.08.2013 Bulletin 2013/34 G01N 33/574 (2006.01) (21) Application number: 11152953.3 (22) Date of filing: 28.05.2004 (54) Prostate stem cell antigen (PSCA) variants and subsequences thereof Prostatstammzellenantigen-Varianten und Untersequenzen davon Variantes de l’antigène de cellules souches de la prostate (PSCA) et sous-séquences de celles-ci (84) Designated Contracting States: • Raitano, Arthur B. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Los Angeles, CA 90066 (US) HU IE IT LI LU MC NL PL PT RO SE SI SK TR Designated Extension States: (74) Representative: Lord, Hilton David AL HR LT LV MK Marks & Clerk LLP 90 Long Acre (30) Priority: 30.05.2003 US 475064 P London WC2E 9RA (GB) (43) Date of publication of application: 11.05.2011 Bulletin 2011/19 (56) References cited: WO-A-01/40309 WO-A-98/40403 (62) Document number(s) of the earlier application(s) in WO-A1-01/04311 US-A1- 2002 102 666 accordance with Art. 76 EPC: 04785910.3 / 1 629 088 • GU Z ET AL: "MONOCLONAL ANTIBODIES AGAINST PROSTATE STEM CELL ANTIGEN (73) Proprietor: Agensys, Inc. (PSCA) DETECT HIGH LEVELS OF PSCA Santa Monica CA 90404 (US) EXPRESSION IN PROSTATE CANCER BONE METASTATES", JOURNAL OF UROLOGY, (72) Inventors: LIPPINCOTT WILLIAMS & WILKINS, • Jakobovits, Aya BALTIMORE, MD, US, vol.
    [Show full text]
  • Enhancement in Motor Learning Through Genetic Manipulation of the Lynx1 Gene
    Enhancement in Motor Learning through Genetic Manipulation of the Lynx1 Gene Julie M. Miwa1*, Andreas Walz2 1 California Institute of Technology, Pasadena, California, United States of America, 2 Ophidion, Inc., Pasadena, California, United States of America Abstract The cholinergic system is a neuromodulatory neurotransmitter system involved in a variety of brain processes, including learning and memory, attention, and motor processes, among others. The influence of nicotinic acetylcholine receptors of the cholinergic system are moderated by lynx proteins, which are GPI-anchored membrane proteins forming tight associations with nicotinic receptors. Previous studies indicate lynx1 inhibits nicotinic receptor function and limits neuronal plasticity. We sought to investigate the mechanism of action of lynx1 on nicotinic receptor function, through the generation of lynx mouse models, expressing a soluble version of lynx and comparing results to the full length overexpression. Using rotarod as a test for motor learning, we found that expressing a secreted variant of lynx leads to motor learning enhancements whereas overexpression of full-length lynx had no effect. Further, adult lynx1KO mice demonstrated comparable motor learning enhancements as the soluble transgenic lines, whereas previously, aged lynx1KO mice showed performance augmentation only with nicotine treatment. From this we conclude the motor learning is more sensitive to loss of lynx function, and that the GPI anchor plays a role in the normal function of the lynx protein. In addition, our data suggests that the lynx gene plays a modulatory role in the brain during aging, and that a soluble version of lynx has potential as a tool for adjusting cholinergic-dependent plasticity and learning mechanisms in the brain.
    [Show full text]
  • Activation of Somatostatin Inhibitory Neurons by Lypd6-Nachrα2 System Restores Juvenile
    bioRxiv preprint doi: https://doi.org/10.1101/155465; this version posted August 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Activation of Somatostatin Inhibitory Neurons by Lypd6-nAChRα2 System Restores Juvenile- like Plasticity in Adult Visual Cortex Masato Sadahiro1-5†, Michael P. Demars1-5†, Poromendro Burman1-5, Priscilla Yevoo1-5, Milo R. Smith1-5, Andreas Zimmer6, Hirofumi Morishita1-5* 1 Department of Psychiatry, 2 Department of Neuroscience, 3 Department of Ophthalmology, 4 Mindich Child Health and Development Institute,5 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA 6 Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Bonn 53127, Germany *Contact to: [email protected] † M.S. and M.P.D. share co-first authorship bioRxiv preprint doi: https://doi.org/10.1101/155465; this version posted August 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Heightened juvenile cortical plasticity declines into adulthood, posing a challenge for functional recovery following brain injury or disease. A network of inhibition is critical for regulating plasticity in adulthood, yet contributions of interneuron types other than parvalbumin (PV) interneurons have been underexplored. Here we show Lypd6, an endogenous positive modulator of nicotinic acetylcholine receptors (nAChRs), as a specific molecular target in somatostatin (SST) interneurons for reactivating cortical plasticity in adulthood. Selective overexpression of Lypd6 in adult SST interneurons reactivates plasticity through the α2 subtype of nAChR by rapidly activating SST interneurons and in turn inhibiting sub-population of PV interneurons, a key early trigger of the juvenile form of plasticity.
    [Show full text]
  • Biochemical Pharmacology 97 (2015) 418–424
    Biochemical Pharmacology 97 (2015) 418–424 Contents lists available at ScienceDirect Biochemical Pharmacology journa l homepage: www.elsevier.com/locate/biochempharm Review Long-lasting changes in neural networks to compensate for altered nicotinic input a,b a,b, Danielle John , Darwin K. Berg * a Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093-0357, United States b Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA 92093-0357, United States A R T I C L E I N F O A B S T R A C T Article history: The nervous system must balance excitatory and inhibitory input to constrain network activity levels Received 30 May 2015 within a proper dynamic range. This is a demanding requirement during development, when networks Accepted 7 July 2015 form and throughout adulthood as networks respond to constantly changing environments. Defects in Available online 20 July 2015 the ability to sustain a proper balance of excitatory and inhibitory activity are characteristic of numerous neurological disorders such as schizophrenia, Alzheimer’s disease, and autism. A variety of homeostatic Keywords: mechanisms appear to be critical for balancing excitatory and inhibitory activity in a network. These are Nicotinic operative at the level of individual neurons, regulating their excitability by adjusting the numbers and Homeostasis types of ion channels, and at the level of synaptic connections, determining the relative numbers of Compensation excitatory versus inhibitory connections a neuron receives. Nicotinic cholinergic signaling is well Neural network E/I ratio positioned to contribute at both levels because it appears early in development, extends across much of Circuits the nervous system, and modulates transmission at many kinds of synapses.
    [Show full text]
  • Nicotinic Signaling: Alpha3 Beta4 Heteromers, Alpha5 Subunits, and the Rp Ototoxin Lypd6b Vanessa Ochoa University of Vermont
    University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2015 Nicotinic Signaling: Alpha3 Beta4 Heteromers, Alpha5 Subunits, And The rP ototoxin Lypd6b Vanessa Ochoa University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Part of the Neuroscience and Neurobiology Commons Recommended Citation Ochoa, Vanessa, "Nicotinic Signaling: Alpha3 Beta4 Heteromers, Alpha5 Subunits, And The rP ototoxin Lypd6b" (2015). Graduate College Dissertations and Theses. 472. https://scholarworks.uvm.edu/graddis/472 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. NICOTINIC SIGNALING: ALPHA3 BETA4 HETEROMERS, ALPHA5 SUBUNITS, AND THE PROTOTOXIN LYPD6B A Dissertation Presented by Vanessa Ochoa to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Neuroscience October, 2015 Defense Date: July 15, 2015 Dissertation Examination Committee: Rae Nishi, Ph.D., Advisor Nicholas H. Heintz, Ph.D., Chairperson Victor May, Ph.D. Rodney Parsons, Ph.D. Anthony Morielli, Ph.D. Cynthia J. Forehand, Ph.D., Dean of the Graduate College ABSTRACT Prototoxin proteins have been identified as members of the Ly6/uPAR super family whose three-finger motif resembles that of α-bungarotoxin. Though they are known to modify the function of nAChRs, their specificity is still unclear. Our lab identified three prototoxin proteins in the chicken ciliary ganglion: Ch3ly, Ch5ly, and Ch6ly.
    [Show full text]
  • Prostate Stem Cell Antigen Gene Is Expressed in Islets of Pancreas
    Original Article http://dx.doi.org/10.5115/acb.2012.45.3.149 pISSN 2093-3665 eISSN 2093-3673 Prostate stem cell antigen gene is expressed in islets of pancreas Hiroe Ono*, Kazuyoshi Yanagihara, Hiromi Sakamoto, Teruhiko Yoshida, Norihisa Saeki Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan Abstract: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface antigen with an organ- dependent expression pattern in cancers; e.g., up-regulated in prostate cancer and down-regulated in gastric cancer. Previously it was reported that PSCA is not expressed in the normal pancreas but aberrantly expressed in pancreatic cancer. In this present study, we identified PSCA expression in islets of the pancreas by immunohistochemistry, which was co-localized with four islet- cell markers: insulin, glucagon, somatostatin and pancreatic polypeptide. In our investigation of the transcription start site of PSCA, we found a non-coding splicing variant of PSCA as well as authentic PSCA transcripts in mRNA samples from a normal pancreas. Both the transcripts were also identified in several pancreatic cancer cell lines. We previously reported that PSCA expression is correlated to the methylation status of the enhancer region in gastric and gallbladder cancer cell lines but not in pancreatic cancer cell lines, suggesting that PSCA expression is regulated in a different mode in pancreatic cancer from that in gastric and gallbladder cancers. Key words: GPI-anchored protein, Islet cells, Pancreatic cancer, Splicing variant, Immunohistochemistry Received June 19, 2012; Revised July 19, 2012; Accepted August 14, 2012 Introduction [3]. It is also up-regulated in other tumors including urinary bladder cancer, renal cell carcinoma, hydatidiform mole and The prostate stem cell antigen (PSCA) gene encodes a ovarian mucinous tumor, where PSCA is thought to abet glycosylphosphatidylinositol (GPI)-anchored membrane tumor progression [1].
    [Show full text]
  • NIH Public Access Author Manuscript Gastroenterology
    NIH Public Access Author Manuscript Gastroenterology. Author manuscript; available in PMC 2012 February 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Gastroenterology. 2011 February ; 140(2): 435±441. doi:10.1053/j.gastro.2010.11.001. An association between a variation in the PSCA gene and upper gastrointestinal cancer in Caucasians Paul Lochhead*,1, Bernd Frank‡,1, Georgina L. Hold*, Charles S. Rabkin§, Michael T. H. Ng*, Thomas L. Vaughan∥, Harvey A. Risch¶, Marilie D. Gammon#, Jolanta Lissowska**, Melanie N. Weck‡, Elke Raum‡, Heiko Müller‡, Thomas Illig‡‡, Norman Klopp‡‡, Alan Dawson*, Kenneth E. McColl§§, Hermann Brenner‡, Wong-Ho Chow§, and Emad M. El- Omar* *Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Scotland ‡Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany §Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland ∥Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, and Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington ¶Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut #Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina **Division of Cancer Epidemiology and Prevention, M. Sklodowska- Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland ‡‡Institute of Epidemiology, Research Centre for Environment and Health, Neuherberg, Germany §§Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland Abstract Background & Aims—An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations.
    [Show full text]