DOCSLIB.ORG

Senescence-Associated Ribosome Biogenesis Defects Contributes to Cell Cycle Arrest Through the Rb Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Senescence-Associated Ribosome Biogenesis Defects Contributes to Cell Cycle Arrest Through the Rb Pathway ARTICLES https://doi.org/10.1038/s41556-018-0127-y Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway Frédéric Lessard1, Sebastian Igelmann1, Christian Trahan2, Geneviève Huot1, Emmanuelle Saint-Germain1, Lian Mignacca1, Neylen Del Toro1, Stéphane Lopes-Paciencia1, Benjamin Le Calvé5, Marinieve Montero1, Xavier Deschênes-Simard4, Marina Bury6, Olga Moiseeva7, Marie-Camille Rowell1, Cornelia E. Zorca1, Daniel Zenklusen 1, Léa Brakier-Gingras1, Véronique Bourdeau1, Marlene Oeffinger1,2,3 and Gerardo Ferbeyre 1* Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA pre- cursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accu- mulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells. ellular senescence opposes neoplastic transformation by by cyclin-dependent kinases such as CDK2, CDK4 and CDK618. preventing the proliferation of cells that have experienced Genetic inactivation of CDK4 leads to p53-independent senes- oncogenic stimuli1. Senescence is efficient as a tumour sup- cence18 and CDK4 inhibitors can reactivate a latent senescence pro- C 19,20 pressor mechanism as long as it prevents cell cycle progression. gramme in cancer cells . Here, we show a mechanism that targets Some benign lesions contain senescent cells that remain out of the CDK4/6 kinases in senescent cells. We demonstrate that onco- the cell cycle2,3. Senescent cells also stimulate their own clearance genic signals interfere with rRNA biogenesis via the degradation of by the immune system, thereby strengthening the defenses against multiple ribosome biogenesis factors, leading to a p53-independent tumourigenesis4,5. However, the process is not infallible and lesions but Rb-dependent senescence response. Senescent cells accumu- containing senescent cells can progress into malignant cancers6,7. lated both rRNA precursors and ribosomal proteins in the nucleus To escape from senescence, cells need to increase protein biosyn- and nucleolus. Moreover, we found that the ribosomal protein S14 thesis and, more importantly, the machinery to do so. Indeed, ribo- (uS11) binds and inactivates the cyclin-dependent kinase CDK4, some biogenesis is upregulated in cancer cells8,9. Senescent cells thereby acting as a CKI and linking ribosome biogenesis to cell cycle exhibit reduced ribosome biogenesis and this has been explained control. Since p53 is inactivated in most human cancers, this work by a delay in ribosomal RNA (rRNA) processing eventually lead- provides a rationale to target ribosome biogenesis and restore senes- ing to the accumulation of the ribosomal proteins L5 (uL18) and cence in human tumours in a p53-independent manner. L11 (uL5), which form a complex with the 5S rRNA and disable the E3 ligase MDM2 (or HDM2), thus activating p5310. Conversely, Results drugs that reduce ribosome biogenesis can trigger senescence and Deficient ribosome biogenesis and accumulation of rRNA precur- are considered very promising anticancer therapeutics11–13. sors in senescent cells. Non-dividing cells as well as senescent cells Cellular senescence can be induced in cells in the absence have a limited demand for ribosomes and hence ribosome biogen- of p5314 through a pathway that involves several members of the esis. Paradoxically, induction of senescence by oncogenic Ras or by cyclin-dependent kinase inhibitor (CKI) family, such as p16INK4a telomere shortening (replicative senescence) in normal human fibro- (p16) and p15INK4b (or CDKN2B), and the retinoblastoma (Rb1 blasts induces nucleolar clustering into a single prominent nucleolus or Rb) tumour suppressor15,16. Rb controls cell cycle progression (Fig. 1a), reminiscent of big and abundant nucleoli of aggressive can- by repressing E2F activity, and in senescent cells, by promoting the cer cells9. To determine the relationship between decreased ribosome formation of heterochromatin at E2F target promoters3,17. In pro- biogenesis and the senescence programme, we first used the model of liferating cells or cells that escape from senescence, Rb is inhibited oncogene-induced senescence (OIS). Shortly after the introduction 1Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Quebec, Canada. 2Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada. 3Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. 4Faculty of Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada. 5URBC-NARILIS, University of Namur, Namur, Belgium. 6Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada. 7Generium 601125 Vladimirskaya obl, Petushinsky, Russia. *e-mail: [email protected] NATURE CELL BiologY | www.nature.com/naturecellbiology © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. ARTICLES NATURE CELL BIOLOGY a c FBL DAPI 5′-ETS ITS1 ITS2 3′-ETS 18S 5.8S 28S 01 A0 13EC 24′4b 4a 3′ 02 47S Vector 01 45S A0 43S 41S E 36S C 36S-C RAS 2 32.5S 32S 30S 26S 21S Old 18S-E 4a 12S 5.8S 5520 6512 7564 Starved d e 3 D6 D12 D18 P = 0.0020 2 VectRAS Vect RASVect RAS YoungOld P = 0.0025 P = 0.0106 o 45/47S rati Confluent 41S 1 45-47S/21S 30S 0 d b Day 20 26S 5520 S S S Ol Vect Vect Vect RA RA RA Young 21S D6 D12D18 VectRASPMLYoungOld 18S-E f 7 47S P = 0.0610 36S-C 6512 6 36S 5 32S 7564 o 4 P = 0.0150 rati 3 41S 12S 7564 P = 0.0176 P = 0.0052 2 28S 45-47S/18S-E 1 0 d 18S S Ol Vect Vect Vect RAS RAS RA 32S Young D6 D12D18 28S ghAntisense Sense Antisense Sense Vector RAS RAS Young OldOld ) ) FISH 18S FISH ′ 5.8S(5 ′ 5.8S(5 28S y Overla y (EtBr) Overla Fig. 1 | Senescence involves diminished ribosome biogenesis. a, Indirect immunofluorescence (IF) with a specific anti-fibrillarin (FBL) antibody showing the nucleolus. The nucleus was counterstained with DAPI. Images represent IMR90 cells expressing an empty control vector or H-RASV12 (RAS) at day 12 post-infection, IMR90 cells at replicative senescence (old) (passage 40), serum starved for 6 days or confluent arrested for 4 days (1 out of 3 independent experiments with similar results). Scale bar, 20 µ m. b, Autoradiography for de novo rRNA synthesis after a three-hour pulse labelling with [3H]-uridine. Total RNA was extracted after the pulse from IMR90 cells at day 20 post-infection with H-RASV12 (RAS), PML-IV (PML) or an empty control vector (Vect), or young (passage 24) and old (passage 38) IMR90 cells and compared to total 28S rRNA detected with ethidium bromide (EtBr) under UV light (1 out of 3 independent experiments with similar results). c, Schematic representation of the human 47S rRNA and different rRNA processing intermediates. The regions used for northern probes (yellow, position 5520; blue, position 6512; green, position 7564) and FISH (red) are indicated. d, Northern blots with total RNA extracted from IMR90 cells at day 6, day 12 and day 18 post-infection with H-RASV12 (RAS) or an empty control vector (Vect), or young (passage 24) and old (passage 40) IMR90 cells (1 out of 3 independent experiments with similar results). Precursor rRNAs detected with the probes described in c are indicated (right). e,f, Ratios of 45–47S/21S (e) and 45–47S/18S-E (f) rRNA levels quantified from experiments as in d. All signals were normalized to total 28S rRNA detected with methylene blue staining. Error bars are mean ± s.d., n = 3 independent experiments. P value as indicated, two-sided Student’s t-test. g,h, Fluorescence in situ hybridization (FISH) with an antisense or sense probe overlapping the 5.8S (5′ ) rRNA processing site 2 as shown in c. The nucleus was counterstained with DAPI. Images represent MR90 cells expressing H-RASV12 (RAS) or an empty control vector at day 20 post-infection (g) or young (passage 25) and old (passage 43) IMR90 cells (h) (1 out of 2 independent experiments with similar results). Scale bars (g,h), 10 µ m. See also Supplementary Figs. 1 and 2. of oncogenic Ras, there is an increase in both rRNA synthesis and We conclude that the synthesis of rRNA is largely reduced in senes- cell proliferation (days 2–6, Supplementary Fig. 1a). However, when cent cells irrespective of the stress that triggered the process. cells became senescent (days 8–20 after Ras expression, PML (pro- Next, we used probes complementary to the internal transcribed myelocytic leukaeumia) expression or telomere shortening), rRNA spacers ITS1 and ITS2 (Fig. 1c) to characterize pre-rRNA process- synthesis was dramatically reduced as measured using a three- ing intermediates in senescent cells. We loaded the gels normal- hour pulse of 3H-uridine (Fig. 1b and Supplementary Fig. 1a–d). ized against the amount of mature 28S rRNA as was done for pulse NATURE CELL BiologY | www.nature.com/naturecellbiology © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. NATURE CELL BIOLOGY ARTICLES a Vector RAS PML c Ctrl Camptothecin β -gal - SA β -gal SA- 5.9% 89.5% 72.7% 4.3% 60.6% RPL29 RPL29 4.7% 89.3% 59.3% 13.7% 83.7% FBL FBL Overlay Overlay b Young Old Starved Confluent d Ctrl β-IFN β -gal SA- β -gal SA- 1.5% 86.6% 1.8% 7.1% 5.4% 25.9% 9 RPL2 9 RPL2 4.3% 78.7% 7.0% 8.0% 11.7% 53.3% FBL FBL y Overla y Overla Fig.
Load more

Recommended publications
  • Epigenome-Wide Exploratory Study of Monozygotic Twins Suggests Differentially Methylated Regions to Associate with Hand Grip Strength
    Biogerontology (2019) 20:627–647 https://doi.org/10.1007/s10522-019-09818-1 (0123456789().,-volV)( 0123456789().,-volV) RESEARCH ARTICLE Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength Mette Soerensen . Weilong Li . Birgit Debrabant . Marianne Nygaard . Jonas Mengel-From . Morten Frost . Kaare Christensen . Lene Christiansen . Qihua Tan Received: 15 April 2019 / Accepted: 24 June 2019 / Published online: 28 June 2019 Ó The Author(s) 2019 Abstract Hand grip strength is a measure of mus- significant CpG sites or pathways were found, how- cular strength and is used to study age-related loss of ever two of the suggestive top CpG sites were mapped physical capacity. In order to explore the biological to the COL6A1 and CACNA1B genes, known to be mechanisms that influence hand grip strength varia- related to muscular dysfunction. By investigating tion, an epigenome-wide association study (EWAS) of genomic regions using the comb-p algorithm, several hand grip strength in 672 middle-aged and elderly differentially methylated regions in regulatory monozygotic twins (age 55–90 years) was performed, domains were identified as significantly associated to using both individual and twin pair level analyses, the hand grip strength, and pathway analyses of these latter controlling the influence of genetic variation. regions revealed significant pathways related to the Moreover, as measurements of hand grip strength immune system, autoimmune disorders, including performed over 8 years were available in the elderly diabetes type 1 and viral myocarditis, as well as twins (age 73–90 at intake), a longitudinal EWAS was negative regulation of cell differentiation.
    [Show full text]
  • A Systems Genetics Approach to Revealing the Pdgfb Molecular Network of the Retina
    Molecular Vision 2020; 26:459-471 <http://www.molvis.org/molvis/v26/459> © 2020 Molecular Vision Received 19 November 2019 | Accepted 17 June 2020 | Published 19 June 2020 A systems genetics approach to revealing the Pdgfb molecular network of the retina Shasha Li,1,2 Fuyi Xu,2 Lin Liu,1 Rong Ju,3 Jonas Bergquist,1,4 Qing Yin Zheng,5,6 Jia Mi,1 Lu Lu,2 Xuri Li,3 Geng Tian1 (The first two authors contributed equally to this work.) 1Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, Shandong, China; 2Department of Genetics, Genomics and informatics, University of Tennessee Health Science Center, Memphis, TN; 3State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, China; 4Analytical Chemistry and Neurochemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden; 5Transformative Otology and Neuroscience Center, Case Western Reserve University School of Medicine, Cleveland, OH; 6Departments of Otolaryngology, Case Western Reserve University School of Medicine, Cleveland, OH. Purpose: Platelet-derived growth factor (PDGF) signaling is well known to be involved in vascular retinopathies. Among the PDGF family, the subunit B (PDGFB) protein is considered a promising therapeutic target. This study aimed to identify the genes and potential pathways through which PDGFB affects retinal phenotypes by using a systems genetics approach. Methods: Gene expression data had been previously generated in a laboratory for the retinas of 75 C57BL/6J(B6) X DBA/2J (BXD) recombinant inbred (RI) strains. Using this data, the genetic correlation method was used to identify genes correlated to Pdgfb. A correlation between intraocular pressure (IOP) and Pdgfb was calculated based on the Pearson correlation coefficient.
    [Show full text]
  • HUMAN RIBOSOME BIOGENESIS and the REGULATION of the TUMOUR SUPPRESSOR P53
    HUMAN RIBOSOME BIOGENESIS AND THE REGULATION OF THE TUMOUR SUPPRESSOR p53 Andria Pelava Submitted for Doctor of Philosophy Final submission: December 2016 Institute of Cell and Molecular Biosciences Faculty of Medical Sciences Newcastle University ii Abstract Ribosome production is an energetically expensive and, therefore, highly regulated process. Defects in ribosome biogenesis lead to genetic diseases called Ribosomopathies, such as Dyskeratosis Congenita (DC), and mutations in ribosomal proteins and ribosome biogenesis factors are linked to multiple types of cancer. During ribosome biogenesis, the ribosomal RNAs (rRNAs) are processed and modified, and defects in ribosome biogenesis lead to the activation of p53. This project aimed to investigate the functions of Dyskerin, mutated in X-linked DC, in human ribosome biogenesis and p53 regulation, and to explore the link between ribosome production and p53 homeostasis. Dyskerin is an rRNA pseudouridine synthase and required for telomere maintenance. There is some debate as to whether DC is the result of telomere maintenance or ribosome biogenesis defects. It is shown here that human Dyskerin is required for the production of both LSU and SSU, and knockdown of Dyskerin leads to p53 activation via inhibition of MDM2 via the 5S RNP, an LSU assembly intermediate which accumulates after ribosome biogenesis defects. My data indicate that p53 activation, due to defects in ribosome biogenesis, may contribute to the clinical symptoms seen in patients suffering with DC. In addition, it is shown that defects in early or late stages of SSU or LSU biogenesis, result in activation of p53 via the 5S RNP-MDM2 pathway, and that p53 is induced in less than 12 hours after ribosome biogenesis defects.
    [Show full text]
  • Genome-Wide Association Study Identifies 44 Independent Genomic Loci for Self-Reported Adult Hearing Difficulty in the UK Biobank Cohort
    bioRxiv preprint doi: https://doi.org/10.1101/549071; this version posted February 14, 2019. 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 association study identifies 44 independent genomic loci for self-reported adult hearing difficulty in the UK Biobank cohort Helena RR. Wells1,2, Maxim B. Freidin1, Fatin N. Zainul Abidin2, Antony Payton3, Piers Dawes4, Kevin J. Munro4,5, Cynthia C. Morton4,5,6, David R. Moore4,7, #*Sally J Dawson2, #*Frances MK. Williams1 1Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London 2UCL Ear Institute, University College London 3Division of Informatics, Imaging & Data Sciences, The University of Manchester 4Manchester Centre for Audiology and Deafness, The University of Manchester 5Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre 6Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women’s Hospital, Harvard Medical School 7Cincinnati Children's Hospital Medical Centre, Department of Otolaryngology, University of Cincinnati College of Medicine #Joint senior authors *Corresponding authors 1 bioRxiv preprint doi: https://doi.org/10.1101/549071; this version posted February 14, 2019. 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. Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 651.
    [Show full text]
  • Co-Evolution of B7H6 and Nkp30, Identification of a New B7 Family Member, B7H7, and of B7's Historical Relationship with the MHC
    Immunogenetics (2012) 64:571–590 DOI 10.1007/s00251-012-0616-2 ORIGINAL PAPER Evolution of the B7 family: co-evolution of B7H6 and NKp30, identification of a new B7 family member, B7H7, and of B7's historical relationship with the MHC Martin F. Flajnik & Tereza Tlapakova & Michael F. Criscitiello & Vladimir Krylov & Yuko Ohta Received: 19 January 2012 /Accepted: 20 March 2012 /Published online: 11 April 2012 # Springer-Verlag 2012 Abstract The B7 family of genes is essential in the regula- Furthermore, we identified a Xenopus-specific B7 homolog tion of the adaptive immune system. Most B7 family mem- (B7HXen) and revealed its close linkage to B2M, which we bers contain both variable (V)- and constant (C)-type have demonstrated previously to have been originally domains of the immunoglobulin superfamily (IgSF). encoded in the MHC. Thus, our study provides further proof Through in silico screening of the Xenopus genome and that the B7 precursor was included in the proto MHC. subsequent phylogenetic analysis, we found novel genes Additionally, the comparative analysis revealed a new B7 belonging to the B7 family, one of which is the recently family member, B7H7, which was previously designated in discovered B7H6. Humans and rats have a single B7H6 the literature as an unknown gene, HHLA2. gene; however, many B7H6 genes were detected in a single large cluster in the Xenopus genome. The B7H6 expression Keywords B7 family. MHC . Evolution . Natural killer patterns also varied in a species-specific manner. Human receptors . Genetic linkage . Xenopus B7H6 binds to the activating natural killer receptor, NKp30. While the NKp30 gene is single-copy and maps to the MHC in most vertebrates, many Xenopus NKp30 genes were Introduction found in a cluster on a separate chromosome that does not harbor the MHC.
    [Show full text]
  • Universidade De São Paulo Faculdade De Zootecnia E Engenharia De Alimentos
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE ZOOTECNIA E ENGENHARIA DE ALIMENTOS LAÍS GRIGOLETTO Genomic studies in Montana Tropical Composite cattle Pirassununga 2020 LAIS GRIGOLETTO Genomic studies in Montana Tropical Composite cattle Versão Corrigida Thesis submitted to the College of Animal Science and Food Engineering, University of São Paulo in partial fulfillment of the requirements for the degree of Doctor in Science from the Animal Biosciences program. Concentration area: Genetics, Molecular and Cellular Biology Supervisor: Prof. Dr. José Bento Sterman Ferraz Co-supervisor: Prof. Dr. Fernando Baldi Pirassununga 2020 Ficha catalográfica elaborada pelo Serviço de Biblioteca e Informação, FZEA/USP, com os dados fornecidos pelo(a) autor(a) Grigoletto, Laís G857g Genomic studies in Montana Tropical Composite cattle / Laís Grigoletto ; orientador José Bento Sterman Ferraz ; coorientador Fernando Baldi. -- Pirassununga, 2020. 183 f. Tese (Doutorado - Programa de Pós-Graduação em Biociência Animal) -- Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo. 1. beef cattle. 2. composite. 3. genomics. 4. imputation. 5. genetic progress. I. Ferraz, José Bento Sterman, orient. II. Baldi, Fernando, coorient. III. Título. Permitida a cópia total ou parcial deste documento, desde que citada a fonte - o autor UNIVERSIDADE DE SÃO PAULO Faculdade de Zootecnia e Engenharia de Alimentos Comissão de Ética no Uso de Animais DISPENSA DE ANÁLISE ÉTICA Comunicamos que o projeto de pesquisa abaixo identificado está dispensado da análise ética por utilizar animais oriundos de coleções biológicas formadas anteriormente ao ano de 2008, ano da promulgação da Lei nº 11.794/2008 – lei que estabelece procedimentos para o uso científico de animais. Ressaltamos que atividades realizadas na vigência da referida lei, ou que resulte em incremento do acervo biológico, devem ser submetidas à análise desta CEUA conforme disposto pelo Conselho Nacional de Controle de Experimentação Animal (CONCEA).
    [Show full text]
  • Csde1 Binds Transcripts Involved in Protein Homeostasis and Controls
    www.nature.com/scientificreports OPEN Csde1 binds transcripts involved in protein homeostasis and controls their expression in an erythroid cell Received: 17 August 2017 Accepted: 18 January 2018 line Published: xx xx xxxx Kat S. Moore1, Nurcan Yagci1, Floris van Alphen2, Nahuel A. Paolini1, Rastislav Horos3, Ntsiki M. Held4, Riekelt H. Houtkooper4, Emile van den Akker1, Alexander B. Meijer2,5, Peter A. C. ‘t Hoen 6 & Marieke von Lindern1 Expression of the RNA-binding protein Csde1 (Cold shock domain protein e1) is strongly upregulated during erythropoiesis compared to other hematopoietic lineages. Csde1 expression is impaired in the severe congenital anemia Diamond Blackfan Anemia (DBA), and reduced expression of Csde1 in healthy erythroblasts impaired their proliferation and diferentiation. To investigate the cellular pathways controlled by Csde1 in erythropoiesis, we identifed the transcripts that physically associate with Csde1 in erythroid cells. These mainly encoded proteins involved in ribogenesis, mRNA translation and protein degradation, but also proteins associated with the mitochondrial respiratory chain and mitosis. Crispr/ Cas9-mediated deletion of the frst cold shock domain of Csde1 afected RNA expression and/or protein expression of Csde1-bound transcripts. For instance, protein expression of Pabpc1 was enhanced while Pabpc1 mRNA expression was reduced indicating more efcient translation of Pabpc1 followed by negative feedback on mRNA stability. Overall, the efect of reduced Csde1 function on mRNA stability and translation of Csde1-bound transcripts was modest. Clones with complete loss of Csde1, however, could not be generated. We suggest that Csde1 is involved in feed-back control in protein homeostasis and that it dampens stochastic changes in mRNA expression.
    [Show full text]
  • On the Relationship of Protein and Mrna Dynamics in Vertebrate Embryonic Development
    Resource On the Relationship of Protein and mRNA Dynamics in Vertebrate Embryonic Development Graphical Abstract Authors Leonid Peshkin, Martin Wu¨ hr, Esther Pearl, ..., Marko Horb, Steven P. Gygi, Marc W. Kirschner Correspondence [email protected] (S.P.G.), [email protected] (M.W.K.) In Brief Embryos express proteins at the correct time during development, by balancing the maternal contribution with protein synthesis and degradation. Peshkin et al. determine the absolute concentrations of 10,000 proteins and 28,000 transcripts across Xenopus development, uncovering the relative roles of these three processes across the proteome and revealing global trends. Highlights Accession Numbers d A genome-scale resource of mRNA and protein expression GSE73905 for vertebrate embryogenesis GSE73870 PXD002349 d Temporal patterns of change in mRNA and protein abundance are poorly correlated d A simple kinetic model explains protein expression as a function of mRNA levels d Embryogenesis is driven by maternal protein dowry and tissue-specific transcription Peshkin et al., 2015, Developmental Cell 35, 383–394 November 9, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.devcel.2015.10.010 Developmental Cell Resource On the Relationship of Protein and mRNA Dynamics in Vertebrate Embryonic Development Leonid Peshkin,1,5 Martin Wu¨ hr,1,2,5 Esther Pearl,3 Wilhelm Haas,2 Robert M. Freeman, Jr.,1 John C. Gerhart,4 Allon M. Klein,1 Marko Horb,3 Steven P. Gygi,2,* and Marc W. Kirschner1,* 1Department of Systems Biology 2Department of Cell Biology Harvard Medical School, Boston, MA 02115, USA 3National Xenopus Resource, Marine Biological Laboratory, Woods Hole, MA 02543, USA 4Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 96704, USA 5Co-first author *Correspondence: [email protected] (S.P.G.), [email protected] (M.W.K.) http://dx.doi.org/10.1016/j.devcel.2015.10.010 SUMMARY abundance may also not be the whole story: posttranslational modifications may provide crucial regulatory input.
    [Show full text]
  • Network of Micrornas-Mrnas Interactions in Pancreatic Cancer
    Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 534821, 8 pages http://dx.doi.org/10.1155/2014/534821 Research Article Network of microRNAs-mRNAs Interactions in Pancreatic Cancer Elnaz Naderi,1 Mehdi Mostafaei,2 Akram Pourshams,1 and Ashraf Mohamadkhani1 1 Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran 2 Biotechnology Engineering, Islamic Azad University,Tehran North Branch, Tehran, Iran Correspondence should be addressed to Ashraf Mohamadkhani; [email protected] Received 5 February 2014; Revised 13 April 2014; Accepted 13 April 2014; Published 7 May 2014 Academic Editor: FangXiang Wu Copyright © 2014 Elnaz Naderi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. MicroRNAs are small RNA molecules that regulate the expression of certain genes through interaction with mRNA targets and are mainly involved in human cancer. This study was conducted to make the network of miRNAs-mRNAs interactions in pancreatic cancer as the fourth leading cause of cancer death. Methods. 56 miRNAs that were exclusively expressed and 1176 genes that were downregulated or silenced in pancreas cancer were extracted from beforehand investigations. MiRNA–mRNA interactions data analysis and related networks were explored using MAGIA tool and Cytoscape 3 software. Functional annotations of candidate genes in pancreatic cancer were identified by DAVID annotation tool. Results. This network is made of 217 nodes for mRNA, 15 nodes for miRNA, and 241 edges that show 241 regulations between 15 miRNAs and 217 target genes.
    [Show full text]
  • Identi Cation and Validation of an RNA Binding Proteins-Associated
    Identication and Validation of an RNA Binding Proteins-Associated Prognostic Signature for Non- Small Cell Lung Cancer Ti-wei Miao sichuan university https://orcid.org/0000-0003-3705-1568 Fang-ying Chen Department of Tuberculosis, the Third People's Hospital of Tibet Autonomous Region, Lhasa, China Wei Xiao Respiratory Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China Long-yi Du Respiratory Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China Bing Mao Respiratory Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China Yan Wang Research Core Facility, West China Hospital, Sichuan University, Chengdu, China Juan-juan Fu ( [email protected] ) Respiratory Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China https://orcid.org/0000-0002-7957-1409 Research Keywords: RBPs, NSCLC, prognosis, meta-analysis, bioinformatics Posted Date: November 4th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-100245/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/27 Abstract Background: Non-small cell lung cancer (NSCLC) is a malignancy with relatively high incidence and poor prognosis. RNA-binding proteins (RBPs) were reported to be dysregulated in multiple cancers and were closely associated with tumor initiation and progression. However, the functions of RBPs in NSCLC remain unclear. Method: The RNA sequencing data and corresponding clinical information of NSCLC was downloaded from The Cancer Genome Atlas (TCGA) database.
    [Show full text]
  • Supplemental Table 2
    Supplemental Table 2 probeID geneSymbol geneTitle cox.tt 223518_at DFFA DNA fragmentation factor, 45kDa, alpha polypeptide 4.86807974 212370_x_at FAM21A /// FAM21B /// FAM21C family with sequence similarity 21, member A /// family with sequence similarity 21, member B /// family with sequence similarity 21, member C -4.039911936 228937_at C13orf31 chromosome 13 open reading frame 31 -3.965652752 224217_s_at FAF1 Fas (TNFRSF6) associated factor 1 3.818692986 219066_at PPCDC phosphopantothenoylcysteine decarboxylase 3.812463041 200994_at IPO7 importin 7 3.722967297 203853_s_at GAB2 GRB2-associated binding protein 2 -3.576924648 218118_s_at TIMM23 translocase of inner mitochondrial membrane 23 homolog (yeast) -3.525051556 238662_at ATPBD4 ATP binding domain 4 3.522716621 212905_at CSTF2T cleavage stimulation factor, 3' pre-RNA, subunit 2, 64kDa, tau variant -3.458703211 225075_at PDRG1 p53 and DNA-damage regulated 1 3.437886045 211430_s_at IGH@ /// IGHG1 /// IGHG2 /// IGHM /// IGHV4-31 /// LOC100294459 immunoglobulin heavy locus /// immunoglobulin heavy constant gamma 1 (G1m marker) /// immunoglobulin heavy constant gamma 2 (G2m marker) /// immunoglobulin heavy constant mu /// immunoglobulin heavy variable 4-31 /// similar to immunoglobulin lambda-like polypeptide 1 -3.404297079 244181_at 244181_at --- -3.363118329 202231_at EIF3M eukaryotic translation initiation factor 3, subunit M 3.345657723 201160_s_at CSDA cold shock domain protein A 3.337512802 214946_x_at FAM21A /// FAM21B /// FAM21C /// FAM21D family with sequence similarity 21,
    [Show full text]
  • Translational Profiling Reveals the Transcriptome of Leptin Receptor Neurons and Its Regulation by Leptin
    TRANSLATIONAL PROFILING REVEALS THE TRANSCRIPTOME OF LEPTIN RECEPTOR NEURONS AND ITS REGULATION BY LEPTIN by Margaret B. Allison A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Integrative Physiology) In the University of Michigan 2015 Doctoral Committee: Professor Martin G. Myers Jr., Chair Associate Professor Carol F. Elias Professor Malcolm J. Low Professor Suzanne Moenter Professor Audrey Seasholtz Before you leave these portals To meet less fortunate mortals There's just one final message I would give to you: You all have learned reliance On the sacred teachings of science So I hope, through life, you never will decline In spite of philistine defiance To do what all good scientists do: Experiment! -- Cole Porter There is no cure for curiosity. -- unknown © Margaret Brewster Allison 2015 ACKNOWLEDGEMENTS If it takes a village to raise a child, it takes a research university to raise a graduate student. There are many people who have supported me over the past six years at Michigan, and it is hard to imagine pursuing my PhD without them. First and foremost among all the people I need to thank is my mentor, Martin. Nothing I might say here would ever suffice to cover the depth and breadth of my gratitude to him. Without his patience, his insight, and his at times insufferably positive outlook, I don’t know where I would be today. Martin supported my intellectual curiosity, honed my scientific inquiry, and allowed me to do some really fun research in his lab. It was a privilege and a pleasure to work for him and with him.
    [Show full text]