DOCSLIB.ORG

Genetic Circuitry of Survival Motor Neuron, the Gene Underlying Spinal

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Genetic circuitry of Survival motor neuron, the gene PNAS PLUS underlying spinal muscular atrophy Anindya Sena,1, Douglas N. Dimlicha,1, K. G. Guruharshaa,1, Mark W. Kankela,1, Kazuya Horia, Takakazu Yokokuraa,3, Sophie Brachatb,c, Delwood Richardsonb, Joseph Loureirob, Rajeev Sivasankaranb, Daniel Curtisb, Lance S. Davidowd, Lee L. Rubind, Anne C. Harte, David Van Vactora, and Spyros Artavanis-Tsakonasa,2 aDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115; bDevelopmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA 02139; cMusculoskeletal Diseases, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland; dDepartment of Stem Cell and Regenerative Biology, Harvard Medical School, Boston, MA 02115; and eDepartment of Neuroscience, Brown University, Providence, RI 02912 Edited by Jeffrey C. Hall, University of Maine, Orono, ME, and approved May 7, 2013 (received for review February 13, 2013) The clinical severity of the neurodegenerative disorder spinal muscu- snRNP biogenesis, the molecular functionality that is most clearly lar atrophy (SMA) is dependent on the levels of functional Survival associated with SMN. Motor Neuron (SMN) protein. Consequently, current strategies for As the human disease state results from partial loss of SMN developing treatments for SMA generally focus on augmenting SMN function, we reasoned that a screening paradigm using a hypo- levels. To identify additional potential therapeutic avenues and morphic Smn background (as opposed to a background that achieve a greater understanding of SMN, we applied in vivo, in vitro, completely eliminates SMN function) would more closely resemble and in silico approaches to identify genetic and biochemical interac- the genetic condition in SMA. Such a screen would therefore en- tors of the Drosophila SMN homolog. We identified more than 300 hance our ability to detect elements of the Smn genetic network candidate genes that alter an Smn-dependent phenotype in vivo. In- and, consequently, add significantly to our efforts to both dissect the tegrating the results from our genetic screens, large-scale protein in- Smn genetic circuitry and identify clinically relevant targets with teraction studies, and bioinformatic analysis, we define a unique mode of action. interactome for SMN that provides a knowledge base for a better This complementary screen proved to be more sensitive than our understanding of SMA. previous screen and led to the identification of over 300 genetic in- GENETICS teractors. Taking advantage of the recently established Drosophila proteomics | disease model | neurodegeneration | Protein Interaction Map (DPiM) (13), we related the newly neuromuscular junction | ALS identified genetic interactors to the SMN protein interactome, producing an integrated Drosophila SMN biological network. Fi- pinal muscular atrophy (SMA), the leading genetic cause of nally, the Drosophila SMN network was evaluated for its relevance Sinfant mortality, results from the partial loss of Survival Motor to human biology by mapping Drosophila SMN network genes to Neuron (SMN) gene activity (1). Numerous studies indicate that their human homologs and analyzing the human network using SMN functions as a central component of a complex that is re- computational biology tools. The projection of the Drosophila sponsible for the assembly of spliceosomal small nuclear ribonu- SMN network derived from this study onto the human network cleoproteins (snRNPs) (reviewed in ref. 2). SMN is also reported derived from prior knowledge provides a rational basis for SMN to play additional roles, including mRNA trafficking in the axon functional hypotheses and network intervention points that carry (3). In humans, SMN is encoded by two nearly identical genes, potential for so-far-unexplored clinical applications. SMN1 and SMN2, which are located on chromosome 5 (4). SMN2 fi differs from SMN1 in that only 10% of SMN2 transcripts produce Signi cance functional SMN due to a single-nucleotide polymorphism that results in inefficient splicing of exon 7 and translation of a trun- Spinal muscular atrophy (SMA), the leading genetic cause of cated, unstable SMN protein (1, 5, 6). The clinical severity of SMA infant mortality, is a devastating neurodegenerative disease correlates with the SMN2 copy number, which varies between caused by reduced levels of Survival Motor Neuron (SMN) gene individuals (7). As the small amount of functional SMN2 protein activity. Despite well-characterized aspects of the involvement produced by each copy of the gene is capable of partially com- of SMN in small nuclear ribonucleoprotein biogenesis, the gene pensating for the loss of the SMN1 gene function, higher copy circuitry affecting SMN activity remains obscure. Here, we use Drosophila as a model system to integrate results from large- numbers of SMN2 typically result in milder forms of SMA. fi scale genetic and proteomic studies and bioinformatic analyses Therefore, genetic modi ers capable of increasing the abundance fi fi to de ne a unique SMN interactome to provide a basis for and/or speci c activity of SMN hold promise as therapeutic targets. a better understanding of SMA. Such efforts not only help The Drosophila genome harbors a single, highly conserved dissect Smn biology but also may point to potential clinically ortholog of SMN1/2, the Smn gene. SMN is essential for cell via- relevant targets. bility in vertebrates and Drosophila (8, 9). In Drosophila, zygotic loss of Smn function results in recessive larval lethality (not em- Author contributions: A.S., D.N.D., M.W.K., D.C., L.L.R., D.V.V., and S.A.-T. designed re- bryonic as might be expected) due to the rescue of early de- search; A.S., D.N.D., K.G.G., M.W.K., K.H., and T.Y. performed research; D.N.D., K.G.G., velopment by maternal contribution of Smn. The larval phenotype S.B., D.R., J.L., R.S., D.C., L.S.D., L.L.R., A.C.H., and D.V.V. contributed new reagents/ana- lytic tools; A.S., D.N.D., K.G.G., M.W.K., S.B., D.R., J.L., R.S., L.S.D., A.C.H., and S.A.-T. includes neuromuscular junction (NMJ) abnormalities that are analyzed data; and A.S., D.N.D., K.G.G., M.W.K., S.B., D.C., and S.A.-T. wrote the paper. reminiscent of those associated with the human disease, rendering The authors declare no conflict of interest. this invertebrate organism an excellent system to model SMN bi- This article is a PNAS Direct Submission. – ology (9 11). We previously described a genetic screen for modi- 1A.S., D.N.D., K.G.G., and M.W.K. contributed equally to this work. fiers of the lethal phenotype resulting from a complete loss- 2To whom correspondence should be addressed. E-mail: [email protected]. of-function Smn allele (12). This screen, although it probed half of 3 fi Present address: Okinawa Science and Technology Graduate University, Onna-son, the Drosophila genome, identi ed only a relatively small number of Okinawa 904-0495, Japan. genes that affected the NMJ phenotype associated with Smn loss This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of function (12). In particular, it did not identify genes involved in 1073/pnas.1301738110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1301738110 PNAS | Published online June 11, 2013 | E2371–E2380 Downloaded by guest on September 30, 2021 Results FL26B genetic background resulted in enhancement or suppres- Genetic Screen for Modifiers of Smn-Dependent Lethality. We ex- sion, respectively (Fig. 1A). In addition, the ability of wild-type amined several Smn-RNAi strains under the control of the yeast Smn (expressed by a UAS-Smn-GFP transgene) to rescue the le- upstream activation sequence (UAS) to identify a hypomorphic thality indicates that this phenotype does not result from off-target Smn allele that could be used to model SMA in Drosophila more RNAi effects. These results were corroborated using an in- faithfully than alleles that completely abolish Smn function. We dependent Smn RNAi strain. Finally, we demonstrated that pre- identified a transgenic strain, UAS-Smn-RNAiFL26B (FL26B), that viously identified Smn modifiers altered the Smn RNAi displays a less severe phenotype than the allele used in our previous phenotype in the expected fashion (Fig. 1A). Together, these screen (12). Specifically, expression of FL26B under the control results demonstrate that the tubGAL4::FL26B phenotype is useful of tubulinGAL4 (tubGAL4::FL26B) results in late pupal le- in detecting changes in Smn functional activity and is thus thality whereby ∼50% of the pupae reach a more mature (pig- asuitableassayonwhichtobaseamodifier screen that will mented) developmental stage before death than their less define and dissect the Smn genetic network. mature, unpigmented siblings (Fig. 1A). Using this assay, we screened the Exelixis collection of ge- We determined that this phenotype, measured by the ratio of nome-wide insertional mutations (http://drosophila.med.harvard. pigmented to unpigmented pupae, is sensitive to Smn gene dosage, edu) (14, 15) for dominant modification of the lethality associ- as reducing or increasing Smn copy number in the tubGAL4:: ated with the tubGAL4::FL26B strain (see Fig. 1B for scheme) A B P{tubP-Gal4}LL7 e 100% w1118 ; P{UAS-Smn-RNAi}FL26B ; TM6B, P{tubP-Gal80}OV3 Hu Tb e 80% 60% w1118 40% ;; TE{Exelixis} F1 20% P{tubP-Gal4}LL7 e w1118 ; P{UAS-Smn-RNAi}FL26B ; 0% TE{Exelixis} Count pigmented and unpigmented Control d02492 d09801 f05549 c05057 Smn pupae (Tb) and adult escaper (Hu) Smn rescue Smn deficiency pigmented
Recommended publications
  • XPO1E571K Mutation Modifies Exportin 1 Localisation And

    XPO1E571K Mutation Modifies Exportin 1 Localisation And

    cancers Article XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma Hadjer Miloudi 1, Élodie Bohers 1,2, François Guillonneau 3 , Antoine Taly 4,5 , Vincent Cabaud Gibouin 6,7 , Pierre-Julien Viailly 1,2 , Gaëtan Jego 6,7 , Luca Grumolato 8 , Fabrice Jardin 1,2 and Brigitte Sola 1,* 1 INSERM U1245, Unicaen, Normandie University, F-14000 Caen, France; [email protected] (H.M.); [email protected] (E.B.); [email protected] (P.-J.V.); [email protected] (F.J.) 2 Centre de lutte contre le Cancer Henri Becquerel, F-76000 Rouen, France 3 Plateforme Protéomique 3P5, Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 Paris, France; [email protected] 4 Laboratoire de Biochimie Théorique, CNRS UPR 9030, Université de Paris, F-75005 Paris, France; [email protected] 5 Institut de Biologie Physico-Chimique, Fondation Edmond de Rothschild, PSL Research University, F-75005 Paris, France 6 INSERM, LNC UMR1231, F-21000 Dijon, France; [email protected] (V.C.G.); [email protected] (G.J.) 7 Team HSP-Pathies, University of Burgundy and Franche-Comtée, F-21000 Dijon, France 8 INSERM U1239, Unirouen, Normandie University, F-76130 Mont-Saint-Aignan, France; [email protected] * Correspondence: [email protected]; Tel.: +33-2-3156-8210 Received: 11 September 2020; Accepted: 28 September 2020; Published: 30 September 2020 Simple Summary: Almost 25% of patients with either primary mediastinal B-cell lymphoma (PMBL) or classical Hodgkin lymphoma (cHL) possess a recurrent mutation of the XPO1 gene encoding the major nuclear export protein.
  • Targeting the Nuclear Import Receptor Kpnb1 As an Anticancer Therapeutic

    Targeting the Nuclear Import Receptor Kpnb1 As an Anticancer Therapeutic

    Published OnlineFirst February 1, 2016; DOI: 10.1158/1535-7163.MCT-15-0052 Small Molecule Therapeutics Molecular Cancer Therapeutics Targeting the Nuclear Import Receptor Kpnb1as an Anticancer Therapeutic Pauline J. van der Watt1, Alicia Chi1, Tamara Stelma1, Catherine Stowell1, Erin Strydom1, Sarah Carden1, Liselotte Angus1, Kate Hadley1, Dirk Lang2, Wei Wei3, Michael J. Birrer3, John O. Trent4, and Virna D. Leaner1 Abstract Karyopherin beta 1 (Kpnb1) is a nuclear transport receptor tissue origins. Minimum effect on the proliferation of non- that imports cargoes into the nucleus. Recently, elevated Kpnb1 cancer cells was observed at the concentration of INI-43 that expression was found in certain cancers and Kpnb1silencing showed a significant cytotoxic effect on various cervical and with siRNA was shown to induce cancer cell death. This study esophageal cancer cell lines. A rescue experiment confirmed aimed to identify novel small molecule inhibitors of Kpnb1, that INI-43 exerted its cell killing effects, in part, by targeting and determine their anticancer activity. An in silico screen Kpnb1. INI-43 treatment elicited a G2–M cell-cycle arrest in identified molecules that potentially bind Kpnb1 and Inhibitor cancer cells and induced the intrinsic apoptotic pathway. Intra- of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3- peritoneal administration of INI-43 significantly inhibited the dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was growth of subcutaneously xenografted esophageal and cervical investigated further as it interfered with the nuclear localization tumor cells. We propose that Kpnb1 inhibitors could have of Kpnb1andknownKpnb1cargoesNFAT,NFkB, AP-1, and therapeutic potential for the treatment of cancer.
  • Molecular Basis for the Distinct Cellular Functions of the Lsm1-7 and Lsm2-8 Complexes

    Molecular Basis for the Distinct Cellular Functions of the Lsm1-7 and Lsm2-8 Complexes

    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.22.055376; this version posted April 23, 2020. 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. Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes Eric J. Montemayor1,2, Johanna M. Virta1, Samuel M. Hayes1, Yuichiro Nomura1, David A. Brow2, Samuel E. Butcher1 1Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. 2Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Correspondence should be addressed to E.J.M. ([email protected]) and S.E.B. ([email protected]). Abstract Eukaryotes possess eight highly conserved Lsm (like Sm) proteins that assemble into circular, heteroheptameric complexes, bind RNA, and direct a diverse range of biological processes. Among the many essential functions of Lsm proteins, the cytoplasmic Lsm1-7 complex initiates mRNA decay, while the nuclear Lsm2-8 complex acts as a chaperone for U6 spliceosomal RNA. It has been unclear how these complexes perform their distinct functions while differing by only one out of seven subunits. Here, we elucidate the molecular basis for Lsm-RNA recognition and present four high-resolution structures of Lsm complexes bound to RNAs. The structures of Lsm2-8 bound to RNA identify the unique 2′,3′ cyclic phosphate end of U6 as a prime determinant of specificity. In contrast, the Lsm1-7 complex strongly discriminates against cyclic phosphates and tightly binds to oligouridylate tracts with terminal purines.
  • Autism Multiplex Family with 16P11.2P12.2 Microduplication Syndrome in Monozygotic Twins and Distal 16P11.2 Deletion in Their Brother

    Autism Multiplex Family with 16P11.2P12.2 Microduplication Syndrome in Monozygotic Twins and Distal 16P11.2 Deletion in Their Brother

    European Journal of Human Genetics (2012) 20, 540–546 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother Anne-Claude Tabet1,2,3,4, Marion Pilorge2,3,4, Richard Delorme5,6,Fre´de´rique Amsellem5,6, Jean-Marc Pinard7, Marion Leboyer6,8,9, Alain Verloes10, Brigitte Benzacken1,11,12 and Catalina Betancur*,2,3,4 The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5–30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5–30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28–30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40–29.25 Mb), inherited from his apparently healthy father.
  • Ingenuity Pathway Analysis of Differentially Expressed Genes Involved in Signaling Pathways and Molecular Networks in Rhoe Gene‑Edited Cardiomyocytes

    Ingenuity Pathway Analysis of Differentially Expressed Genes Involved in Signaling Pathways and Molecular Networks in Rhoe Gene‑Edited Cardiomyocytes

    INTERNATIONAL JOURNAL OF MOleCular meDICine 46: 1225-1238, 2020 Ingenuity pathway analysis of differentially expressed genes involved in signaling pathways and molecular networks in RhoE gene‑edited cardiomyocytes ZHONGMING SHAO1*, KEKE WANG1*, SHUYA ZHANG2, JIANLING YUAN1, XIAOMING LIAO1, CAIXIA WU1, YUAN ZOU1, YANPING HA1, ZHIHUA SHEN1, JUNLI GUO2 and WEI JIE1,2 1Department of Pathology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang, Guangdong 524023; 2Hainan Provincial Key Laboratory for Tropical Cardiovascular Diseases Research and Key Laboratory of Emergency and Trauma of Ministry of Education, Institute of Cardiovascular Research of The First Affiliated Hospital, Hainan Medical University, Haikou, Hainan 571199, P.R. China Received January 7, 2020; Accepted May 20, 2020 DOI: 10.3892/ijmm.2020.4661 Abstract. RhoE/Rnd3 is an atypical member of the Rho super- injury and abnormalities, cell‑to‑cell signaling and interaction, family of proteins, However, the global biological function and molecular transport. In addition, 885 upstream regulators profile of this protein remains unsolved. In the present study, a were enriched, including 59 molecules that were predicated RhoE‑knockout H9C2 cardiomyocyte cell line was established to be strongly activated (Z‑score >2) and 60 molecules that using CRISPR/Cas9 technology, following which differentially were predicated to be significantly inhibited (Z‑scores <‑2). In expressed genes (DEGs) between the knockout and wild‑type particular, 33 regulatory effects and 25 networks were revealed cell lines were screened using whole genome expression gene to be associated with the DEGs. Among them, the most signifi- chips. A total of 829 DEGs, including 417 upregulated and cant regulatory effects were ‘adhesion of endothelial cells’ and 412 downregulated, were identified using the threshold of ‘recruitment of myeloid cells’ and the top network was ‘neuro- fold changes ≥1.2 and P<0.05.
  • Towards a Molecular Understanding of Microrna-Mediated Gene Silencing

    Towards a Molecular Understanding of Microrna-Mediated Gene Silencing

    REVIEWS NON-CODING RNA Towards a molecular understanding of microRNA-mediated gene silencing Stefanie Jonas and Elisa Izaurralde Abstract | MicroRNAs (miRNAs)­ are a conserved class of small non-coding RNAs that assemble with Argonaute proteins into miRNA-induced silencing complexes (miRISCs) to direct post-transcriptional silencing of complementary mRNA targets. Silencing is accomplished through a combination of translational repression and mRNA destabilization, with the latter contributing to most of the steady-state repression in animal cell cultures. Degradation of the mRNA target is initiated by deadenylation, which is followed by decapping and 5ʹ‑to‑3ʹ exonucleolytic decay. Recent work has enhanced our understanding of the mechanisms of silencing, making it possible to describe in molecular terms a continuum of direct interactions from miRNA target recognition to mRNA deadenylation, decapping and 5ʹ‑to‑3ʹ degradation. Furthermore, an intricate interplay between translational repression and mRNA degradation is emerging. Deadenylation MicroRNAs (mi­RNAs) are conserved post-transcriptional recruit additional protein partners to mediate silenc- 5,6 Shortening of mRNA poly(A) regulators of gene expression that are integral to ing . Silencing occurs through a combination of tails. In eukaryotes, this almost all known biological processes, including translational repression, deadenylation, decapping and process is catalysed by the cell growth, proliferation and differentiation, as well 5ʹ‑to‑3ʹ mRNA degradation5,6 (FIG. 1). The GW182 pro- consecutive but partially as organismal metabolism and development1. The teins play a central part in this process and are among redundant action of two 5,6 cytoplasmic deadenylase number of mi­RNAs encoded within the genomes of the most extensively studied AGO partners .
  • In Human Metabolism

    In Human Metabolism

    Supporting Information (SI Appendix) Framework and resource for more than 11,000 gene-transcript- protein-reaction associations (GeTPRA) in human metabolism SI Appendix Materials and Methods Standardization of Metabolite IDs with MNXM IDs Defined in the MNXref Namespace. Information on metabolic contents of the Recon 2Q was standardized using MNXM IDs defined in the MNXref namespace available at MetaNetX (1-3). This standardization was to facilitate the model refinement process described below. Each metabolite ID in the Recon 2Q was converted to MNXM ID accordingly. For metabolite IDs that were not converted to MNXM IDs, they were manually converted to MNXM IDs by comparing their compound structures and synonyms. In the final resulting SBML files, 97 metabolites were assigned with arbitrary IDs (i.e., “MNXMK_” followed by four digits) because they were not covered by the MNXref namespace (i.e., metabolite IDs not converted to MNXM IDs). Refinement or Removal of Biochemically Inconsistent Reactions. Recon 2 was built upon metabolic genes and reactions collected from EHMN (4, 5), the first genome-scale human liver metabolic model HepatoNet1 (6), an acylcarnitine and fatty-acid oxidation model Ac-FAO (7), and a small intestinal enterocyte model hs_eIEC611 (8). Flux variability analysis (9) of the Recon 2Q identified blocked reactions coming from these four sources of metabolic reaction data. The EHMN caused the greatest number of blocked reactions in the Recon 2Q (1,070 reactions corresponding to 69.3% of all the identified blocked reactions). To refine the EHMN reactions, following reactions were initially disregarded: 1) reactions having metabolite IDs not convertible to MNXM IDs; and 2) reactions without genes.
  • Identification of Novel Branch Points Reveals Insights Into RNA Processing

    Identification of Novel Branch Points Reveals Insights Into RNA Processing

    Identification of Novel Branch Points Reveals Insights into RNA Processing by Genevieve Michelle Gould B.A. Molecular and Cell Biology with an emphasis in Genetics, Genomics, and Development University of California, Berkeley (2009) Submitted to the Department of Biology in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY September 2015 © Massachusetts Institute of Technology 2015. All rights reserved. Signature of Author .................................................................................................................................................... Department of Biology August 31, 2015 Certified by .................................................................................................................................................................... Christopher B. Burge Professor of Biology Thesis Supervisor Accepted by.................................................................................................................................................................... Michael Hemann Associate Professor of Biology Co-Chair, Biology Graduate Committee 1 2 Identification of Novel Branch Points Reveals Insights into RNA Processing by Genevieve Michelle Gould Submitted to the Department of Biology on August 31, 2015 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biology Abstract Pre-mRNA splicing is a ubiquitous process necessary for the production of functional eukaryotic mRNAs. The branch
  • Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice

    Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice

    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
  • Table SI. Genes Upregulated ≥ 2-Fold by MIH 2.4Bl Treatment Affymetrix ID

    Table SI. Genes Upregulated ≥ 2-Fold by MIH 2.4Bl Treatment Affymetrix ID

    Table SI. Genes upregulated 2-fold by MIH 2.4Bl treatment Fold UniGene ID Description Affymetrix ID Entrez Gene Change 1558048_x_at 28.84 Hs.551290 231597_x_at 17.02 Hs.720692 238825_at 10.19 93953 Hs.135167 acidic repeat containing (ACRC) 203821_at 9.82 1839 Hs.799 heparin binding EGF like growth factor (HBEGF) 1559509_at 9.41 Hs.656636 202957_at 9.06 3059 Hs.14601 hematopoietic cell-specific Lyn substrate 1 (HCLS1) 202388_at 8.11 5997 Hs.78944 regulator of G-protein signaling 2 (RGS2) 213649_at 7.9 6432 Hs.309090 serine and arginine rich splicing factor 7 (SRSF7) 228262_at 7.83 256714 Hs.127951 MAP7 domain containing 2 (MAP7D2) 38037_at 7.75 1839 Hs.799 heparin binding EGF like growth factor (HBEGF) 224549_x_at 7.6 202672_s_at 7.53 467 Hs.460 activating transcription factor 3 (ATF3) 243581_at 6.94 Hs.659284 239203_at 6.9 286006 Hs.396189 leucine rich single-pass membrane protein 1 (LSMEM1) 210800_at 6.7 1678 translocase of inner mitochondrial membrane 8 homolog A (yeast) (TIMM8A) 238956_at 6.48 1943 Hs.741510 ephrin A2 (EFNA2) 242918_at 6.22 4678 Hs.319334 nuclear autoantigenic sperm protein (NASP) 224254_x_at 6.06 243509_at 6 236832_at 5.89 221442 Hs.374076 adenylate cyclase 10, soluble pseudogene 1 (ADCY10P1) 234562_x_at 5.89 Hs.675414 214093_s_at 5.88 8880 Hs.567380; far upstream element binding protein 1 (FUBP1) Hs.707742 223774_at 5.59 677825 Hs.632377 small nucleolar RNA, H/ACA box 44 (SNORA44) 234723_x_at 5.48 Hs.677287 226419_s_at 5.41 6426 Hs.710026; serine and arginine rich splicing factor 1 (SRSF1) Hs.744140 228967_at 5.37
  • DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy

    DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy

    cells Review DEAD-Box RNA Helicases in Cell Cycle Control and Clinical Therapy Lu Zhang 1,2 and Xiaogang Li 2,3,* 1 Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, China; [email protected] 2 Department of Internal Medicine, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55905, USA 3 Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55905, USA * Correspondence: [email protected]; Tel.: +1-507-266-0110 Abstract: Cell cycle is regulated through numerous signaling pathways that determine whether cells will proliferate, remain quiescent, arrest, or undergo apoptosis. Abnormal cell cycle regula- tion has been linked to many diseases. Thus, there is an urgent need to understand the diverse molecular mechanisms of how the cell cycle is controlled. RNA helicases constitute a large family of proteins with functions in all aspects of RNA metabolism, including unwinding or annealing of RNA molecules to regulate pre-mRNA, rRNA and miRNA processing, clamping protein complexes on RNA, or remodeling ribonucleoprotein complexes, to regulate gene expression. RNA helicases also regulate the activity of specific proteins through direct interaction. Abnormal expression of RNA helicases has been associated with different diseases, including cancer, neurological disorders, aging, and autosomal dominant polycystic kidney disease (ADPKD) via regulation of a diverse range of cellular processes such as cell proliferation, cell cycle arrest, and apoptosis. Recent studies showed that RNA helicases participate in the regulation of the cell cycle progression at each cell cycle phase, including G1-S transition, S phase, G2-M transition, mitosis, and cytokinesis.
  • Rabbit Anti-CDCA5/FITC Conjugated Antibody

    Rabbit Anti-CDCA5/FITC Conjugated Antibody

    SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-CDCA5/FITC Conjugated antibody SL7717R-FITC Product Name: Anti-CDCA5/FITC Chinese Name: FITC标记的细胞分裂周期相关蛋白5抗体 Alias: Cell division cycle associated protein 5; MGC16386; p35; Sororin; CDCA5_HUMAN. Organism Species: Rabbit Clonality: Polyclonal React Species: Human,Mouse,Rat,Dog,Pig,Cow,Horse,Rabbit, Flow-Cyt=1:50-200IF=1:50-200 Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 28kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human CDCA5 Lsotype: IgG Purification: affinity purified by Protein A Storage Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibodywww.sunlongbiotech.com is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: Sororin, also designated cell division cycle-associated protein 5 (CDCA5) or p35, functions as a regulator of sister chromatid cohesion during mitosis. It interacts with the APC/C complex and is found in a complex consisting of cohesion components SCC- 112, MC1L1, SMC3L1, RAD21 and APRIN. The deduced human and mouse Sororin Product Detail: proteins consist of 252 and 264 amino acid residues, respectively, and both contain a KEN box for APC-dependent ubiquitination.