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  • Cell Line  (2,037)
  • Phosphorylation  (1,100)
  • Chemical Engineering
  • American Association for the Advancement of Science (AAAS)  (2,839)
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  • 1
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    RNA splicing is a primary link between genetic variation and disease (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-30
    Description: Noncoding variants play a central role in the genetics of complex traits, but we still lack a full understanding of the molecular pathways through which they act. We quantified the contribution of cis-acting genetic effects at all major stages of gene regulation from chromatin to proteins, in Yoruba lymphoblastoid cell lines (LCLs). About ~65% of expression quantitative trait loci (eQTLs) have primary effects on chromatin, whereas the remaining eQTLs are enriched in transcribed regions. Using a novel method, we also detected 2893 splicing QTLs, most of which have little or no effect on gene-level expression. These splicing QTLs are major contributors to complex traits, roughly on a par with variants that affect gene expression levels. Our study provides a comprehensive view of the mechanisms linking genetic variation to variation in human gene regulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Yang I -- van de Geijn, Bryce -- Raj, Anil -- Knowles, David A -- Petti, Allegra A -- Golan, David -- Gilad, Yoav -- Pritchard, Jonathan K -- R01MH084703/MH/NIMH NIH HHS/ -- R01MH101825/MH/NIMH NIH HHS/ -- U01HG007036/HG/NHGRI NIH HHS/ -- U54CA149145/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):600-4. doi: 10.1126/science.aad9417. Epub 2016 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University, Stanford, CA, USA. ; Department of Human Genetics, University of Chicago, Chicago, IL, USA. ; Department of Computer Science, Stanford University, Stanford, CA, USA. Department of Radiology, Stanford University, Stanford, CA, USA. ; Genome Institute, Washington University in St. Louis, St. Louis, MO, USA. ; Department of Human Genetics, University of Chicago, Chicago, IL, USA. gilad@uchicago.edu pritch@stanford.edu. ; Department of Genetics, Stanford University, Stanford, CA, USA. Department of Biology, Stanford University, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. gilad@uchicago.edu pritch@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27126046" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Chromatin/metabolism ; *Gene Expression Regulation ; *Genetic Variation ; Genome-Wide Association Study ; Humans ; Immune System Diseases/*genetics ; Lymphocytes/immunology ; Phenotype ; Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; RNA Splicing/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    RNA biochemistry. Transcriptome-wide distribution and function of RNA hydroxymethylcytosine (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-28
    Description: Hydroxymethylcytosine, well described in DNA, occurs also in RNA. Here, we show that hydroxymethylcytosine preferentially marks polyadenylated RNAs and is deposited by Tet in Drosophila. We map the transcriptome-wide hydroxymethylation landscape, revealing hydroxymethylcytosine in the transcripts of many genes, notably in coding sequences, and identify consensus sites for hydroxymethylation. We found that RNA hydroxymethylation can favor mRNA translation. Tet and hydroxymethylated RNA are found to be most abundant in the Drosophila brain, and Tet-deficient fruitflies suffer impaired brain development, accompanied by decreased RNA hydroxymethylation. This study highlights the distribution, localization, and function of cytosine hydroxymethylation and identifies central roles for this modification in Drosophila.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delatte, Benjamin -- Wang, Fei -- Ngoc, Long Vo -- Collignon, Evelyne -- Bonvin, Elise -- Deplus, Rachel -- Calonne, Emilie -- Hassabi, Bouchra -- Putmans, Pascale -- Awe, Stephan -- Wetzel, Collin -- Kreher, Judith -- Soin, Romuald -- Creppe, Catherine -- Limbach, Patrick A -- Gueydan, Cyril -- Kruys, Veronique -- Brehm, Alexander -- Minakhina, Svetlana -- Defrance, Matthieu -- Steward, Ruth -- Fuks, Francois -- R01 GM089992/GM/NIGMS NIH HHS/ -- T32 CA117846/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 15;351(6270):282-5. doi: 10.1126/science.aac5253.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB Cancer Research Center (U-CRC), Universite Libre de Bruxelles (ULB), Brussels, Belgium. ; Waksman Institute, Department of Molecular Biology and Biochemistry, Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ, USA. ; Laboratory of Molecular Biology of the Gene, Faculty of Sciences, Universite Libre de Bruxelles, Gosselies, Belgium. ; Institut fur Molekularbiologie und Tumorforschung, Philipps-Universitat Marburg, Marburg, Germany. ; Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA. ; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB Cancer Research Center (U-CRC), Universite Libre de Bruxelles (ULB), Brussels, Belgium. ffuks@ulb.ac.be.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26816380" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/*abnormalities/metabolism ; Cell Line ; Cytosine/*analogs & derivatives/metabolism ; Dioxygenases/genetics/metabolism ; Drosophila melanogaster/genetics/*growth & development/metabolism ; Methylation ; RNA, Messenger/genetics/*metabolism ; Transcriptome
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 3
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    Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-28
    Description: Genes encoding human beta-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal gamma-globin genes and maintains the nucleosome density necessary for gamma-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778394/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Masuda, Takeshi -- Wang, Xin -- Maeda, Manami -- Canver, Matthew C -- Sher, Falak -- Funnell, Alister P W -- Fisher, Chris -- Suciu, Maria -- Martyn, Gabriella E -- Norton, Laura J -- Zhu, Catherine -- Kurita, Ryo -- Nakamura, Yukio -- Xu, Jian -- Higgs, Douglas R -- Crossley, Merlin -- Bauer, Daniel E -- Orkin, Stuart H -- Kharchenko, Peter V -- Maeda, Takahiro -- R01 AI084905/AI/NIAID NIH HHS/ -- R01 HL032259/HL/NHLBI NIH HHS/ -- R56 DK105001/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 15;351(6270):285-9. doi: 10.1126/science.aad3312.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. ; Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. ; Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK. ; Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan. ; Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan. Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. ; Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Boston, MA 02115, USA. ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. peter.kharchenko@post.harvard.edu tmaeda@partners.org. ; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. peter.kharchenko@post.harvard.edu tmaeda@partners.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26816381" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia, Sickle Cell/genetics ; Animals ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Chromatin/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Erythroblasts/cytology ; Erythropoiesis/genetics ; Fetal Hemoglobin/*genetics ; *Gene Silencing ; Humans ; Mice ; Mice, Knockout ; Nuclear Proteins/genetics/*metabolism ; Repressor Proteins/genetics/*metabolism ; Sequence Deletion ; Thalassemia/genetics ; Transcription Factors/genetics/*metabolism ; gamma-Globins/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 4
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    Phase separation of signaling molecules promotes T cell receptor signal transduction (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-09
    Description: Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Xiaolei -- Ditlev, Jonathon A -- Hui, Enfu -- Xing, Wenmin -- Banjade, Sudeep -- Okrut, Julia -- King, David S -- Taunton, Jack -- Rosen, Michael K -- Vale, Ronald D -- 5-F32-DK101188/DK/NIDDK NIH HHS/ -- F32 DK101188/DK/NIDDK NIH HHS/ -- R01 GM056322/GM/NIGMS NIH HHS/ -- R01-GM56322/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):595-9. doi: 10.1126/science.aad9964. Epub 2016 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; HHMI Mass Spectrometry Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27056844" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*metabolism ; Adaptor Proteins, Signal Transducing/*metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Jurkat Cells ; Membrane Proteins/*metabolism ; Mitogen-Activated Protein Kinase Kinases ; Phosphorylation ; Polymerization ; Receptors, Antigen, T-Cell/*agonists ; Signal Transduction ; T-Lymphocytes/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 5
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    Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-16
    Description: Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goodman, Christopher D -- Siregar, Josephine E -- Mollard, Vanessa -- Vega-Rodriguez, Joel -- Syafruddin, Din -- Matsuoka, Hiroyuki -- Matsuzaki, Motomichi -- Toyama, Tomoko -- Sturm, Angelika -- Cozijnsen, Anton -- Jacobs-Lorena, Marcelo -- Kita, Kiyoshi -- Marzuki, Sangkot -- McFadden, Geoffrey I -- AI031478/AI/NIAID NIH HHS/ -- RR00052/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):349-53. doi: 10.1126/science.aad9279.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. gim@unimelb.edu.au deang@unimelb.edu.au. ; School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia. Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. ; Johns Hopkins University Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Malaria Research Institute, Baltimore, MD 21205, USA. ; Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia. Department of Parasitology, Faculty of Medicine, Hasanuddin University, Jalan Perintis Kemerdekaan Km10, Makassar 90245, Indonesia. ; Division of Medical Zoology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. ; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan. ; Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27081071" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles/*parasitology ; Antimalarials/*pharmacology/therapeutic use ; Atovaquone/*pharmacology/therapeutic use ; Cell Line ; Cytochromes b/*genetics ; Drug Resistance/*genetics ; Genes, Mitochondrial/genetics ; Humans ; Life Cycle Stages/drug effects/genetics ; Malaria/drug therapy/*parasitology/transmission ; Male ; Mice ; Mitochondria/*genetics ; Mutation ; Plasmodium berghei/*drug effects/genetics/growth & development ; Selection, Genetic
    Print ISSN: 0036-8075
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  • 6
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    Designer protein delivery: From natural to engineered affinity-controlled release systems (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-19
    Description: Exploiting binding affinities between molecules is an established practice in many fields, including biochemical separations, diagnostics, and drug development; however, using these affinities to control biomolecule release is a more recent strategy. Affinity-controlled release takes advantage of the reversible nature of noncovalent interactions between a therapeutic protein and a binding partner to slow the diffusive release of the protein from a vehicle. This process, in contrast to degradation-controlled sustained-release formulations such as poly(lactic-co-glycolic acid) microspheres, is controlled through the strength of the binding interaction, the binding kinetics, and the concentration of binding partners. In the context of affinity-controlled release--and specifically the discovery or design of binding partners--we review advances in in vitro selection and directed evolution of proteins, peptides, and oligonucleotides (aptamers), aided by computational design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pakulska, Malgosia M -- Miersch, Shane -- Shoichet, Molly S -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):aac4750. doi: 10.1126/science.aac4750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, and Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. ; Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, and Donnelly Centre, University of Toronto, Toronto, Ontario, Canada. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26989257" target="_blank"〉PubMed〈/a〉
    Keywords: Chemical Engineering ; Combinatorial Chemistry Techniques ; Delayed-Action Preparations/*chemistry ; Directed Molecular Evolution ; *Drug Design ; Humans ; Lactic Acid/*chemistry ; Microspheres ; Polyglycolic Acid/*chemistry ; Proteins/*administration & dosage
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  • 7
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    mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2alpha eIF2alpha phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ben-Sahra, Issam -- Hoxhaj, Gerta -- Ricoult, Stephane J H -- Asara, John M -- Manning, Brendan D -- K99-CA194192/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01-CA120964/CA/NCI NIH HHS/ -- P30-CA006516/CA/NCI NIH HHS/ -- R01 CA181390/CA/NCI NIH HHS/ -- R01-CA181390/CA/NCI NIH HHS/ -- R35 CA197459/CA/NCI NIH HHS/ -- R35-CA197459/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):728-33. doi: 10.1126/science.aad0489.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. ; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. ; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. bmanning@hsph.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912861" target="_blank"〉PubMed〈/a〉
    Keywords: Activating Transcription Factor 4/genetics/metabolism ; Animals ; Eukaryotic Initiation Factor-2/metabolism ; HEK293 Cells ; Humans ; Methenyltetrahydrofolate Cyclohydrolase/genetics ; Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics ; Mice ; Mitochondria/*metabolism ; Multiprotein Complexes/genetics/*metabolism ; Phosphorylation ; Protein Biosynthesis ; Purines/*biosynthesis ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Tetrahydrofolates/*metabolism ; Transcription, Genetic
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  • 8
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    CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-06
    Description: SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56beta, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bidinosti, Michael -- Botta, Paolo -- Kruttner, Sebastian -- Proenca, Catia C -- Stoehr, Natacha -- Bernhard, Mario -- Fruh, Isabelle -- Mueller, Matthias -- Bonenfant, Debora -- Voshol, Hans -- Carbone, Walter -- Neal, Sarah J -- McTighe, Stephanie M -- Roma, Guglielmo -- Dolmetsch, Ricardo E -- Porter, Jeffrey A -- Caroni, Pico -- Bouwmeester, Tewis -- Luthi, Andreas -- Galimberti, Ivan -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1199-203. doi: 10.1126/science.aad5487. Epub 2016 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Friedrich Miescher Institute, Basel, Switzerland. ; Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA. ; Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ivan.galimberti@novartis.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26847545" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autism Spectrum Disorder/*drug therapy/enzymology/genetics ; Chromosome Deletion ; Chromosome Disorders/genetics ; Chromosomes, Human, Pair 22/genetics ; Disease Models, Animal ; Down-Regulation ; Gene Knockdown Techniques ; Humans ; Insulin-Like Growth Factor I/metabolism ; Mice ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/*genetics ; Neurons/enzymology ; Phosphorylation ; Protein Phosphatase 2/metabolism ; Protein-Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism ; Proteomics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
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  • 9
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    Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-04-11
    Description: Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das, Indrajit -- Krzyzosiak, Agnieszka -- Schneider, Kim -- Wrabetz, Lawrence -- D'Antonio, Maurizio -- Barry, Nicholas -- Sigurdardottir, Anna -- Bertolotti, Anne -- 309516/European Research Council/International -- MC_U105185860/Medical Research Council/United Kingdom -- R01-NS55256/NS/NINDS NIH HHS/ -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 10;348(6231):239-42. doi: 10.1126/science.aaa4484.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. aberto@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25859045" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Cells, Cultured ; Charcot-Marie-Tooth Disease/drug therapy/metabolism/pathology ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Inhibitors/metabolism/pharmacokinetics/*pharmacology/toxicity ; Guanabenz/*analogs & derivatives/chemical ; synthesis/metabolism/pharmacology/toxicity ; HeLa Cells ; Humans ; Mice ; Mice, Transgenic ; Molecular Targeted Therapy ; Phosphorylation ; Protein Folding ; Protein Phosphatase 1/*antagonists & inhibitors ; Proteostasis Deficiencies/*drug therapy/*prevention & control ; Signal Transduction
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Circadian rhythms. Decoupling circadian clock protein turnover from circadian period determination (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-01-31
    Description: The mechanistic basis of eukaryotic circadian oscillators in model systems as diverse as Neurospora, Drosophila, and mammalian cells is thought to be a transcription-and-translation-based negative feedback loop, wherein progressive and controlled phosphorylation of one or more negative elements ultimately elicits their own proteasome-mediated degradation, thereby releasing negative feedback and determining circadian period length. The Neurospora crassa circadian negative element FREQUENCY (FRQ) exemplifies such proteins; it is progressively phosphorylated at more than 100 sites, and strains bearing alleles of frq with anomalous phosphorylation display abnormal stability of FRQ that is well correlated with altered periods or apparent arrhythmicity. Unexpectedly, we unveiled normal circadian oscillations that reflect the allelic state of frq but that persist in the absence of typical degradation of FRQ. This manifest uncoupling of negative element turnover from circadian period length determination is not consistent with the consensus eukaryotic circadian model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Larrondo, Luis F -- Olivares-Yanez, Consuelo -- Baker, Christopher L -- Loros, Jennifer J -- Dunlap, Jay C -- P01 GM68087/GM/NIGMS NIH HHS/ -- R01 GM034985/GM/NIGMS NIH HHS/ -- R01 GM083336/GM/NIGMS NIH HHS/ -- R01 GM34985/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):1257277. doi: 10.1126/science.1257277.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl. ; Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635104" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/analogs & derivatives/pharmacology ; Alleles ; *Circadian Clocks ; *Circadian Rhythm ; Feedback, Physiological ; Fungal Proteins/biosynthesis/*genetics/*metabolism ; Half-Life ; Neurospora crassa/*physiology ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Stability ; Proteolysis ; Signal Transduction
    Print ISSN: 0036-8075
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  • 11
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    Proteomics. Tissue-based map of the human proteome (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-01-24
    Description: Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Uhlen, Mathias -- Fagerberg, Linn -- Hallstrom, Bjorn M -- Lindskog, Cecilia -- Oksvold, Per -- Mardinoglu, Adil -- Sivertsson, Asa -- Kampf, Caroline -- Sjostedt, Evelina -- Asplund, Anna -- Olsson, IngMarie -- Edlund, Karolina -- Lundberg, Emma -- Navani, Sanjay -- Szigyarto, Cristina Al-Khalili -- Odeberg, Jacob -- Djureinovic, Dijana -- Takanen, Jenny Ottosson -- Hober, Sophia -- Alm, Tove -- Edqvist, Per-Henrik -- Berling, Holger -- Tegel, Hanna -- Mulder, Jan -- Rockberg, Johan -- Nilsson, Peter -- Schwenk, Jochen M -- Hamsten, Marica -- von Feilitzen, Kalle -- Forsberg, Mattias -- Persson, Lukas -- Johansson, Fredric -- Zwahlen, Martin -- von Heijne, Gunnar -- Nielsen, Jens -- Ponten, Fredrik -- New York, N.Y. -- Science. 2015 Jan 23;347(6220):1260419. doi: 10.1126/science.1260419.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 21 Stockholm, Sweden. Department of Proteomics, KTH-Royal Institute of Technology, SE-106 91 Stockholm, Sweden. Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2970 Horsholm, Denmark. mathias.uhlen@scilifelab.se. ; Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 21 Stockholm, Sweden. ; Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 21 Stockholm, Sweden. Department of Proteomics, KTH-Royal Institute of Technology, SE-106 91 Stockholm, Sweden. ; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden. ; Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden. ; Science for Life Laboratory, KTH-Royal Institute of Technology, SE-171 21 Stockholm, Sweden. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden. ; Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, D-44139 Dortmund, Germany. ; Lab Surgpath, Mumbai, India. ; Department of Proteomics, KTH-Royal Institute of Technology, SE-106 91 Stockholm, Sweden. ; Science for Life Laboratory, Department of Neuroscience, Karolinska Institute, SE-171 77 Stockholm, Sweden. ; Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. ; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2970 Horsholm, Denmark. Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25613900" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Cell Line ; *Databases, Protein ; Female ; Genes ; Genetic Code ; Humans ; Internet ; Male ; Membrane Proteins/genetics/metabolism ; Mitochondrial Proteins/genetics/metabolism ; Neoplasms/genetics/metabolism ; Protein Array Analysis ; Protein Isoforms/genetics/metabolism ; Proteome/genetics/*metabolism ; Tissue Distribution ; Transcription, Genetic
    Print ISSN: 0036-8075
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  • 12
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    ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-01
    Description: The actin cross-linking domain (ACD) is an actin-specific toxin produced by several pathogens, including life-threatening spp. of Vibrio cholerae, Vibrio vulnificus, and Aeromonas hydrophila. Actin cross-linking by ACD is thought to lead to slow cytoskeleton failure owing to a gradual sequestration of actin in the form of nonfunctional oligomers. Here, we found that ACD converted cytoplasmic actin into highly toxic oligomers that potently "poisoned" the ability of major actin assembly proteins, formins, to sustain actin polymerization. Thus, ACD can target the most abundant cellular protein by using actin oligomers as secondary toxins to efficiently subvert cellular functions of actin while functioning at very low doses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648357/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648357/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heisler, David B -- Kudryashova, Elena -- Grinevich, Dmitry O -- Suarez, Cristian -- Winkelman, Jonathan D -- Birukov, Konstantin G -- Kotha, Sainath R -- Parinandi, Narasimham L -- Vavylonis, Dimitrios -- Kovar, David R -- Kudryashov, Dmitri S -- R01 GM079265/GM/NIGMS NIH HHS/ -- R01 GM098430/GM/NIGMS NIH HHS/ -- R01 GM114666/GM/NIGMS NIH HHS/ -- R01 HL076259/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 31;349(6247):535-9. doi: 10.1126/science.aab4090.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA. ; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. kudryashov.1@osu.edu kudryashova.1@osu.edu. ; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. ; Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA. ; Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. ; Lipid Signaling and Lipidomics Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. ; Department of Physics, Lehigh University, Bethlehem, PA 18015, USA. ; Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. ; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA. The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA. kudryashov.1@osu.edu kudryashova.1@osu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26228148" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*metabolism ; Animals ; Antigens, Bacterial/*chemistry/genetics/*toxicity ; Bacterial Toxins/*chemistry/genetics/*toxicity ; Cell Line ; Fetal Proteins/*antagonists & inhibitors ; Intestinal Mucosa/drug effects/metabolism ; Microfilament Proteins/*antagonists & inhibitors ; Nuclear Proteins/*antagonists & inhibitors ; Polymerization/drug effects ; Protein Structure, Tertiary ; Rats
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  • 13
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    CELL DIVISION CYCLE. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-13
    Description: Cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules through kinetochores and the spindle assembly checkpoint (SAC) is satisfied. We show that the amino-terminal localization module of the SAC protein kinase MPS1 (monopolar spindle 1) directly interacts with the HEC1 (highly expressed in cancer 1) calponin homology domain in the NDC80 (nuclear division cycle 80) kinetochore complex in vitro, in a phosphorylation-dependent manner. Microtubule polymers disrupted this interaction. In cells, MPS1 binding to kinetochores or to ectopic NDC80 complexes was prevented by end-on microtubule attachment, independent of known kinetochore protein-removal mechanisms. Competition for kinetochore binding between SAC proteins and microtubules provides a direct and perhaps evolutionarily conserved way to detect a properly organized spindle ready for cell division.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hiruma, Yoshitaka -- Sacristan, Carlos -- Pachis, Spyridon T -- Adamopoulos, Athanassios -- Kuijt, Timo -- Ubbink, Marcellus -- von Castelmur, Eleonore -- Perrakis, Anastassis -- Kops, Geert J P L -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1264-7. doi: 10.1126/science.aaa4055. Epub 2015 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Leiden Institute of Chemistry, Leiden University, Post Office Box 9502, 2300 RA Leiden, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068855" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Binding, Competitive ; Calcium-Binding Proteins/genetics/metabolism ; *Cell Cycle Checkpoints ; Cell Cycle Proteins/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microfilament Proteins/genetics/metabolism ; Microtubules/*metabolism ; Nuclear Proteins/chemistry/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Signal Transduction ; Spindle Apparatus/*metabolism
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  • 14
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    Circadian rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-27
    Description: Organisms are adapted to the relentless cycles of day and night, because they evolved timekeeping systems called circadian clocks, which regulate biological activities with ~24-hour rhythms. The clock of cyanobacteria is driven by a three-protein oscillator composed of KaiA, KaiB, and KaiC, which together generate a circadian rhythm of KaiC phosphorylation. We show that KaiB flips between two distinct three-dimensional folds, and its rare transition to an active state provides a time delay that is required to match the timing of the oscillator to that of Earth's rotation. Once KaiB switches folds, it binds phosphorylated KaiC and captures KaiA, which initiates a phase transition of the circadian cycle, and it regulates components of the clock-output pathway, which provides the link that joins the timekeeping and signaling functions of the oscillator.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506712/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Yong-Gang -- Cohen, Susan E -- Phong, Connie -- Myers, William K -- Kim, Yong-Ick -- Tseng, Roger -- Lin, Jenny -- Zhang, Li -- Boyd, Joseph S -- Lee, Yvonne -- Kang, Shannon -- Lee, David -- Li, Sheng -- Britt, R David -- Rust, Michael J -- Golden, Susan S -- LiWang, Andy -- AI081982/AI/NIAID NIH HHS/ -- AI101436/AI/NIAID NIH HHS/ -- GM062419/GM/NIGMS NIH HHS/ -- GM100116/GM/NIGMS NIH HHS/ -- GM107521/GM/NIGMS NIH HHS/ -- R01 GM062419/GM/NIGMS NIH HHS/ -- R01 GM100116/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):324-8. doi: 10.1126/science.1260031. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Natural Sciences, University of California, Merced, CA 95343, USA. ; Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA. ; Department of Chemistry, University of California, Davis, CA 95616, USA. ; School of Natural Sciences, University of California, Merced, CA 95343, USA. Quantitative and Systems Biology, University of California, Merced, CA 95343, USA. ; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. ; Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA. Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. ; School of Natural Sciences, University of California, Merced, CA 95343, USA. Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA. Quantitative and Systems Biology, University of California, Merced, CA 95343, USA. Chemistry and Chemical Biology, University of California, Merced, CA 95343, USA. Health Sciences Research Institute, University of California, Merced, CA 95343, USA. aliwang@ucmerced.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113641" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics/*metabolism ; *Circadian Rhythm ; Circadian Rhythm Signaling Peptides and Proteins/*chemistry/genetics/*metabolism ; Phosphorylation ; Protein Folding ; Protein Structure, Secondary ; Synechococcus/metabolism/*physiology
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  • 15
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    ADVANCED IMAGING. Extended-resolution structured illumination imaging of endocytic and cytoskeletal dynamics (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-01
    Description: Super-resolution fluorescence microscopy is distinct among nanoscale imaging tools in its ability to image protein dynamics in living cells. Structured illumination microscopy (SIM) stands out in this regard because of its high speed and low illumination intensities, but typically offers only a twofold resolution gain. We extended the resolution of live-cell SIM through two approaches: ultrahigh numerical aperture SIM at 84-nanometer lateral resolution for more than 100 multicolor frames, and nonlinear SIM with patterned activation at 45- to 62-nanometer resolution for approximately 20 to 40 frames. We applied these approaches to image dynamics near the plasma membrane of spatially resolved assemblies of clathrin and caveolin, Rab5a in early endosomes, and alpha-actinin, often in relationship to cortical actin. In addition, we examined mitochondria, actin, and the Golgi apparatus dynamics in three dimensions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659358/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659358/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Dong -- Shao, Lin -- Chen, Bi-Chang -- Zhang, Xi -- Zhang, Mingshu -- Moses, Brian -- Milkie, Daniel E -- Beach, Jordan R -- Hammer, John A 3rd -- Pasham, Mithun -- Kirchhausen, Tomas -- Baird, Michelle A -- Davidson, Michael W -- Xu, Pingyong -- Betzig, Eric -- GM-075252/GM/NIGMS NIH HHS/ -- R01 GM075252/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):aab3500. doi: 10.1126/science.aab3500.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. ; Key Laboratory of RNA Biology and Beijing Key Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. College of Life Sciences, Central China Normal University, Wuhan 430079, Hubei, China. ; Key Laboratory of RNA Biology and Beijing Key Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. ; Coleman Technologies, 5131 West Chester Pike, Newtown Square, PA 19073, USA. ; Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. ; Department of Cell Biology and Pediatrics, Harvard Medical School and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. ; Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, FL 32310, USA. ; National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, FL 32310, USA. ; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. betzige@janelia.hhmi.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315442" target="_blank"〉PubMed〈/a〉
    Keywords: Actinin/analysis ; Actins/analysis ; Animals ; Cell Line ; Clathrin/analysis ; Clathrin-Coated Vesicles/chemistry/ultrastructure ; Coated Pits, Cell-Membrane/chemistry/ultrastructure ; Cytoskeleton/chemistry/metabolism/*ultrastructure ; *Endocytosis ; Endosomes/chemistry/ultrastructure ; Golgi Apparatus/ultrastructure ; Image Processing, Computer-Assisted ; Imaging, Three-Dimensional/instrumentation/*methods ; Microscopy, Fluorescence/instrumentation/*methods ; Mitochondria/chemistry/ultrastructure ; Organelles/chemistry/metabolism/*ultrastructure ; rab5 GTP-Binding Proteins/analysis
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  • 16
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    Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-02-01
    Description: During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Siqi -- Cai, Xin -- Wu, Jiaxi -- Cong, Qian -- Chen, Xiang -- Li, Tuo -- Du, Fenghe -- Ren, Junyao -- Wu, You-Tong -- Grishin, Nick V -- Chen, Zhijian J -- AI-93967/AI/NIAID NIH HHS/ -- GM-094575/GM/NIGMS NIH HHS/ -- GM-63692/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25636800" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/*metabolism ; Adaptor Proteins, Vesicular Transport/chemistry/*metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; Humans ; I-kappa B Kinase/metabolism ; Interferon Regulatory Factor-3/chemistry/*metabolism ; Interferon-alpha/biosynthesis ; Interferon-beta/biosynthesis ; Membrane Proteins/chemistry/*metabolism ; Mice ; Molecular Sequence Data ; Phosphorylation ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/metabolism ; Recombinant Proteins/metabolism ; Sendai virus/physiology ; Serine/metabolism ; Signal Transduction ; Ubiquitination ; Vesiculovirus/physiology
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 17
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    Transcription factor trapping by RNA in gene regulatory elements (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-10-31
    Description: Transcription factors (TFs) bind specific sequences in promoter-proximal and -distal DNA elements to regulate gene transcription. RNA is transcribed from both of these DNA elements, and some DNA binding TFs bind RNA. Hence, RNA transcribed from regulatory elements may contribute to stable TF occupancy at these sites. We show that the ubiquitously expressed TF Yin-Yang 1 (YY1) binds to both gene regulatory elements and their associated RNA species across the entire genome. Reduced transcription of regulatory elements diminishes YY1 occupancy, whereas artificial tethering of RNA enhances YY1 occupancy at these elements. We propose that RNA makes a modest but important contribution to the maintenance of certain TFs at gene regulatory elements and suggest that transcription of regulatory elements produces a positive-feedback loop that contributes to the stability of gene expression programs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720525/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sigova, Alla A -- Abraham, Brian J -- Ji, Xiong -- Molinie, Benoit -- Hannett, Nancy M -- Guo, Yang Eric -- Jangi, Mohini -- Giallourakis, Cosmas C -- Sharp, Phillip A -- Young, Richard A -- HG002668/HG/NHGRI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 20;350(6263):978-81. doi: 10.1126/science.aad3346. Epub 2015 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. ; Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02140, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. young@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26516199" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Binding Sites ; Cell Line ; Consensus Sequence ; DNA/metabolism ; Embryonic Stem Cells/metabolism ; *Enhancer Elements, Genetic ; *Gene Expression Regulation ; Mice ; *Promoter Regions, Genetic ; RNA, Messenger/*metabolism ; *Transcription, Genetic ; YY1 Transcription Factor/*metabolism
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    Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-01-09
    Description: Naive and primed pluripotent states retain distinct molecular properties, yet limited knowledge exists on how their state transitions are regulated. Here, we identify Mettl3, an N(6)-methyladenosine (m(6)A) transferase, as a regulator for terminating murine naive pluripotency. Mettl3 knockout preimplantation epiblasts and naive embryonic stem cells are depleted for m(6)A in mRNAs, yet are viable. However, they fail to adequately terminate their naive state and, subsequently, undergo aberrant and restricted lineage priming at the postimplantation stage, which leads to early embryonic lethality. m(6)A predominantly and directly reduces mRNA stability, including that of key naive pluripotency-promoting transcripts. This study highlights a critical role for an mRNA epigenetic modification in vivo and identifies regulatory modules that functionally influence naive and primed pluripotency in an opposing manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geula, Shay -- Moshitch-Moshkovitz, Sharon -- Dominissini, Dan -- Mansour, Abed AlFatah -- Kol, Nitzan -- Salmon-Divon, Mali -- Hershkovitz, Vera -- Peer, Eyal -- Mor, Nofar -- Manor, Yair S -- Ben-Haim, Moshe Shay -- Eyal, Eran -- Yunger, Sharon -- Pinto, Yishay -- Jaitin, Diego Adhemar -- Viukov, Sergey -- Rais, Yoach -- Krupalnik, Vladislav -- Chomsky, Elad -- Zerbib, Mirie -- Maza, Itay -- Rechavi, Yoav -- Massarwa, Rada -- Hanna, Suhair -- Amit, Ido -- Levanon, Erez Y -- Amariglio, Ninette -- Stern-Ginossar, Noam -- Novershtern, Noa -- Rechavi, Gideon -- Hanna, Jacob H -- New York, N.Y. -- Science. 2015 Feb 27;347(6225):1002-6. doi: 10.1126/science.1261417. Epub 2015 Jan 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. ; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA. ; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. ; The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. The Department of Pediatrics and the Pediatric Immunology Unit, Rambam Medical Center, and the B. Rappaport Faculty of Medicine, Technion, Haifa, Israel. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il. ; Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. jacob.hanna@weizmann.ac.il noa.novershtern@weizmann.ac.il gidi.rechavi@sheba.health.gov.il.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25569111" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*analogs & derivatives/metabolism ; Animals ; Blastocyst/enzymology ; Cell Differentiation/genetics/*physiology ; Cell Line ; Embryo Loss/genetics ; Epigenesis, Genetic ; Female ; Gene Knockout Techniques ; Male ; Methylation ; Methyltransferases/genetics/*physiology ; Mice ; Mice, Knockout ; Pluripotent Stem Cells/*cytology/enzymology ; RNA, Messenger/*metabolism
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    Structural biology. Structural basis for Notch1 engagement of Delta-like 4 (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-24
    Description: Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445638/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445638/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luca, Vincent C -- Jude, Kevin M -- Pierce, Nathan W -- Nachury, Maxence V -- Fischer, Suzanne -- Garcia, K Christopher -- 1R01-GM097015/GM/NIGMS NIH HHS/ -- R01 GM097015/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):847-53. doi: 10.1126/science.1261093.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700513" target="_blank"〉PubMed〈/a〉
    Keywords: Alagille Syndrome/genetics ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cell Line ; Conserved Sequence ; Crystallography, X-Ray ; Fucose/chemistry ; Glucose/chemistry ; Glycosylation ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics ; Ligands ; Membrane Proteins/*chemistry/genetics/ultrastructure ; Molecular Sequence Data ; Molecular Targeted Therapy ; Polysaccharides/chemistry ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Notch1/*chemistry/genetics/ultrastructure ; Serine/chemistry/genetics ; Threonine/chemistry/genetics
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    Centrosomes. Regulated assembly of a supramolecular centrosome scaffold in vitro (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-05-16
    Description: The centrosome organizes microtubule arrays within animal cells and comprises two centrioles surrounded by an amorphous protein mass called the pericentriolar material (PCM). Despite the importance of centrosomes as microtubule-organizing centers, the mechanism and regulation of PCM assembly are not well understood. In Caenorhabditis elegans, PCM assembly requires the coiled-coil protein SPD-5. We found that recombinant SPD-5 could polymerize to form micrometer-sized porous networks in vitro. Network assembly was accelerated by two conserved regulators that control PCM assembly in vivo, Polo-like kinase-1 and SPD-2/Cep192. Only the assembled SPD-5 networks, and not unassembled SPD-5 protein, functioned as a scaffold for other PCM proteins. Thus, PCM size and binding capacity emerge from the regulated polymerization of one coiled-coil protein to form a porous network.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Woodruff, Jeffrey B -- Wueseke, Oliver -- Viscardi, Valeria -- Mahamid, Julia -- Ochoa, Stacy D -- Bunkenborg, Jakob -- Widlund, Per O -- Pozniakovsky, Andrei -- Zanin, Esther -- Bahmanyar, Shirin -- Zinke, Andrea -- Hong, Sun Hae -- Decker, Marcus -- Baumeister, Wolfgang -- Andersen, Jens S -- Oegema, Karen -- Hyman, Anthony A -- R01-GM074207/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 May 15;348(6236):808-12. doi: 10.1126/science.aaa3923.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. ; Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsried 82152, Germany. ; Department of Clinical Biochemistry, Copenhagen University Hospital, Hvidovre 2650, Denmark. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. ; Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. hyman@mpi-cbg.de koegema@ucsd.edu. ; Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. hyman@mpi-cbg.de koegema@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25977552" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/*genetics/*metabolism ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Centrosome/*metabolism/ultrasonography ; Metabolic Networks and Pathways ; Phosphorylation ; Polymerization ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism
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    ENDOCYTOSIS. Endocytic sites mature by continuous bending and remodeling of the clathrin coat (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-06-20
    Description: During clathrin-mediated endocytosis (CME), plasma membrane regions are internalized to retrieve extracellular molecules and cell surface components. Whether endocytosis occurs by direct clathrin assembly into curved lattices on the budding vesicle or by initial recruitment to flat membranes and subsequent reshaping has been controversial. To distinguish between these models, we combined fluorescence microscopy and electron tomography to locate endocytic sites and to determine their coat and membrane shapes during invagination. The curvature of the clathrin coat increased, whereas the coated surface area remained nearly constant. Furthermore, clathrin rapidly exchanged at all stages of CME. Thus, coated vesicle budding appears to involve bending of a dynamic preassembled clathrin coat.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Avinoam, Ori -- Schorb, Martin -- Beese, Carsten J -- Briggs, John A G -- Kaksonen, Marko -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1369-72. doi: 10.1126/science.aaa9555.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology and Biophysics Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. Structural and Computational Biology Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. ; Structural and Computational Biology Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. Electron Microscopy Core Facility, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. ; Cell Biology and Biophysics Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. ; Structural and Computational Biology Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. Cell Biology and Biophysics Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. marko.kaksonen@unige.ch john.briggs@embl.de. ; Cell Biology and Biophysics Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. Structural and Computational Biology Unit, The European Molecular Biology Laboratory, Heidelberg 69117, Germany. marko.kaksonen@unige.ch john.briggs@embl.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089517" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Clathrin/*chemistry ; Coated Pits, Cell-Membrane/*chemistry ; Electron Microscope Tomography ; *Endocytosis ; Fluorescence Recovery After Photobleaching ; Humans ; Microscopy, Fluorescence
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    Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-04-04
    Description: By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405120/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Katajisto, Pekka -- Dohla, Julia -- Chaffer, Christine L -- Pentinmikko, Nalle -- Marjanovic, Nemanja -- Iqbal, Sharif -- Zoncu, Roberto -- Chen, Walter -- Weinberg, Robert A -- Sabatini, David M -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Apr 17;348(6232):340-3. doi: 10.1126/science.1260384. Epub 2015 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Institute of Biotechnology, University of Helsinki, P.O. Box 00014, Helsinki, Finland. pekka.katajisto@helsinki.fi sabatini@wi.mit.edu. ; Institute of Biotechnology, University of Helsinki, P.O. Box 00014, Helsinki, Finland. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. ; Whitehead Institute for Biomedical Research, Boston, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA. Broad Institute, Cambridge, MA 02142, USA. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. pekka.katajisto@helsinki.fi sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25837514" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Aging/genetics/*physiology ; Cell Division/genetics/*physiology ; Cell Line ; Humans ; Mitochondria/*physiology/ultrastructure ; Stem Cells/*physiology/*ultrastructure
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    Genome-wide inactivation of porcine endogenous retroviruses (PERVs) (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-10-13
    Description: The shortage of organs for transplantation is a major barrier to the treatment of organ failure. Although porcine organs are considered promising, their use has been checked by concerns about the transmission of porcine endogenous retroviruses (PERVs) to humans. Here we describe the eradication of all PERVs in a porcine kidney epithelial cell line (PK15). We first determined the PK15 PERV copy number to be 62. Using CRISPR-Cas9, we disrupted all copies of the PERV pol gene and demonstrated a 〉1000-fold reduction in PERV transmission to human cells, using our engineered cells. Our study shows that CRISPR-Cas9 multiplexability can be as high as 62 and demonstrates the possibility that PERVs can be inactivated for clinical application of porcine-to-human xenotransplantation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Luhan -- Guell, Marc -- Niu, Dong -- George, Haydy -- Lesha, Emal -- Grishin, Dennis -- Aach, John -- Shrock, Ellen -- Xu, Weihong -- Poci, Jurgen -- Cortazio, Rebeca -- Wilkinson, Robert A -- Fishman, Jay A -- Church, George -- P50 HG005550/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1101-4. doi: 10.1126/science.aad1191. Epub 2015 Oct 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA. eGenesis Biosciences, Boston, MA 02115, USA. gchurch@genetics.med.harvard.edu luhan.yang@egenesisbio.com. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA. eGenesis Biosciences, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. College of Animal Sciences, Zhejiang University, Hangzhou 310058, China. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. ; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ; Transplant Infectious Disease and Compromised Host Program, Massachusetts General Hospital, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26456528" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; CRISPR-Cas Systems ; Cell Line ; Endogenous Retroviruses/*genetics ; Epithelial Cells/virology ; Gene Dosage ; Gene Targeting/*methods ; Genes, pol ; HEK293 Cells ; Humans ; Kidney/virology ; Molecular Sequence Data ; Retroviridae Infections/*prevention & control/transmission/virology ; Swine/*virology ; Transplantation, Heterologous/*methods ; *Virus Inactivation
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    Genomic variation. Impact of regulatory variation from RNA to protein (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-02-07
    Description: The phenotypic consequences of expression quantitative trait loci (eQTLs) are presumably due to their effects on protein expression levels. Yet the impact of genetic variation, including eQTLs, on protein levels remains poorly understood. To address this, we mapped genetic variants that are associated with eQTLs, ribosome occupancy (rQTLs), or protein abundance (pQTLs). We found that most QTLs are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, eQTLs tend to have significantly reduced effect sizes on protein levels, which suggests that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we identified a class of cis QTLs that affect protein abundance with little or no effect on messenger RNA or ribosome levels, which suggests that they may arise from differences in posttranslational regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507520/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507520/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Battle, Alexis -- Khan, Zia -- Wang, Sidney H -- Mitrano, Amy -- Ford, Michael J -- Pritchard, Jonathan K -- Gilad, Yoav -- F32 HG006972/HG/NHGRI NIH HHS/ -- F32HG006972/HG/NHGRI NIH HHS/ -- GM077959/GM/NIGMS NIH HHS/ -- HG007036/HG/NHGRI NIH HHS/ -- MH084703/MH/NIMH NIH HHS/ -- R01 GM077959/GM/NIGMS NIH HHS/ -- R01 MH084703/MH/NIMH NIH HHS/ -- U01 HG007036/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 6;347(6222):664-7. doi: 10.1126/science.1260793. Epub 2014 Dec 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. ; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. ; MS Bioworks, LLC, 3950 Varsity Drive, Ann Arbor, MI 48108, USA. ; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Department of Biology, Stanford University, Stanford, CA 94305, USA. pritch@stanford.edu gilad@uchicago.edu. ; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. pritch@stanford.edu gilad@uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25657249" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Flanking Region ; 5' Flanking Region ; Cell Line ; Exons ; *Gene Expression Regulation ; *Genetic Variation ; Humans ; Phenotype ; Protein Biosynthesis/*genetics ; *Quantitative Trait Loci ; RNA, Messenger/*genetics ; Ribosomes/metabolism ; *Transcription, Genetic
    Print ISSN: 0036-8075
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    RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-12-15
    Description: Release of promoter-proximal paused RNA polymerase II (Pol II) during early elongation is a critical step in transcriptional regulation in metazoan cells. Paused Pol II release is thought to require the kinase activity of cyclin-dependent kinase 9 (CDK9) for the phosphorylation of DRB sensitivity-inducing factor, negative elongation factor, and C-terminal domain (CTD) serine-2 of Pol II. We found that Pol II-associated factor 1 (PAF1) is a critical regulator of paused Pol II release, that positive transcription elongation factor b (P-TEFb) directly regulates the initial recruitment of PAF1 complex (PAF1C) to genes, and that the subsequent recruitment of CDK12 is dependent on PAF1C. These findings reveal cooperativity among P-TEFb, PAF1C, and CDK12 in pausing release and Pol II CTD phosphorylation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Ming -- Yang, Wenjing -- Ni, Ting -- Tang, Zhanyun -- Nakadai, Tomoyoshi -- Zhu, Jun -- Roeder, Robert G -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1383-6. doi: 10.1126/science.aad2338.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. ; Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. ; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China. ; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. roeder@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26659056" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cyclin-Dependent Kinase 9/metabolism ; Cyclin-Dependent Kinases/metabolism ; *Gene Expression Regulation ; Humans ; Nuclear Proteins/genetics/*metabolism ; Phosphorylation ; Positive Transcriptional Elongation Factor B/metabolism ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; RNA Polymerase II/chemistry/genetics/*metabolism ; *Transcription Elongation, Genetic ; Transcription Factors/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-kappaB activation (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-05-17
    Description: A switchlike response in nuclear factor-kappaB (NF-kappaB) activity implies the existence of a threshold in the NF-kappaB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)-TAK1 (MAP3K7)-inhibitor of NF-kappaB (IkappaB) kinase-beta (IKKbeta) module is a switch mechanism for NF-kappaB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKbeta to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKbeta target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-kappaB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinohara, Hisaaki -- Behar, Marcelo -- Inoue, Kentaro -- Hiroshima, Michio -- Yasuda, Tomoharu -- Nagashima, Takeshi -- Kimura, Shuhei -- Sanjo, Hideki -- Maeda, Shiori -- Yumoto, Noriko -- Ki, Sewon -- Akira, Shizuo -- Sako, Yasushi -- Hoffmann, Alexander -- Kurosaki, Tomohiro -- Okada-Hatakeyama, Mariko -- 5R01CA141722/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 May 16;344(6185):760-4. doi: 10.1126/science.1250020.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ; Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center (QBiC), 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Graduate School of Engineering, Tottori University 4-101, Koyama-minami, Tottori 680-8552, Japan. ; Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ; Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833394" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/metabolism ; CARD Signaling Adaptor Proteins/genetics/*metabolism ; Cell Line ; Chickens ; Feedback, Physiological ; Guanylate Cyclase/genetics/*metabolism ; I-kappa B Kinase/*metabolism ; MAP Kinase Kinase Kinases/genetics/*metabolism ; Mice ; Mice, Knockout ; Mutation ; NF-kappa B/*agonists ; Phosphorylation ; Receptors, Antigen, B-Cell/genetics/*metabolism ; Serine/genetics/metabolism ; Signal Transduction
    Print ISSN: 0036-8075
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    A cascade of histone modifications induces chromatin condensation in mitosis (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-01-05
    Description: Metaphase chromosomes are visible hallmarks of mitosis, yet our understanding of their structure and of the forces shaping them is rudimentary. Phosphorylation of histone H3 serine 10 (H3 S10) by Aurora B kinase is a signature event of mitosis, but its function in chromatin condensation is unclear. Using genetically encoded ultraviolet light-inducible cross-linkers, we monitored protein-protein interactions with spatiotemporal resolution in living yeast to identify the molecular details of the pathway downstream of H3 S10 phosphorylation. This modification leads to the recruitment of the histone deacetylase Hst2p that subsequently removes an acetyl group from histone H4 lysine 16, freeing the H4 tail to interact with the surface of neighboring nucleosomes and promoting fiber condensation. This cascade of events provides a condensin-independent driving force of chromatin hypercondensation during mitosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilkins, Bryan J -- Rall, Nils A -- Ostwal, Yogesh -- Kruitwagen, Tom -- Hiragami-Hamada, Kyoko -- Winkler, Marco -- Barral, Yves -- Fischle, Wolfgang -- Neumann, Heinz -- New York, N.Y. -- Science. 2014 Jan 3;343(6166):77-80. doi: 10.1126/science.1244508.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Free Floater (Junior) Research Group "Applied Synthetic Biology," Institute for Microbiology and Genetics, Georg-August University Gottingen, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24385627" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Chromatin/*metabolism ; Chromosomes, Fungal/genetics/metabolism ; Cross-Linking Reagents/chemistry/radiation effects ; DNA-Binding Proteins/metabolism ; Histones/*metabolism ; Lysine/metabolism ; *Mitosis ; Multiprotein Complexes/metabolism ; Phosphorylation ; Protein Interaction Mapping ; *Protein Processing, Post-Translational ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Serine/*metabolism ; Sirtuin 2/metabolism
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Enzyme regulation. IRBIT is a novel regulator of ribonucleotide reductase in higher eukaryotes (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-09-23
    Description: Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme. Formation of the RNR-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We demonstrate a mechanism for RNR regulation in higher eukaryotes that acts by enhancing allosteric RNR inhibition by dATP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnaoutov, Alexei -- Dasso, Mary -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1512-5. doi: 10.1126/science.1251550.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. arnaouta@mail.nih.gov. ; Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237103" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalytic Domain ; Deoxyadenine Nucleotides/*metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Lectins, C-Type/genetics/*metabolism ; Membrane Proteins/genetics/*metabolism ; Molecular Sequence Data ; Phosphorylation ; Ribonucleotide Reductases/*antagonists & inhibitors/metabolism
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    FoxP influences the speed and accuracy of a perceptual decision in Drosophila (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-05-24
    Description: Decisions take time if information gradually accumulates to a response threshold, but the neural mechanisms of integration and thresholding are unknown. We characterized a decision process in Drosophila that bears the behavioral signature of evidence accumulation. As stimulus contrast in trained odor discriminations decreased, reaction times increased and perceptual accuracy declined, in quantitative agreement with a drift-diffusion model. FoxP mutants took longer than wild-type flies to form decisions of similar or reduced accuracy, especially in difficult, low-contrast tasks. RNA interference with FoxP expression in alphabeta core Kenyon cells, or the overexpression of a potassium conductance in these neurons, recapitulated the FoxP mutant phenotype. A mushroom body subdomain whose development or function require the transcription factor FoxP thus supports the progression of a decision toward commitment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206523/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206523/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DasGupta, Shamik -- Ferreira, Clara Howcroft -- Miesenbock, Gero -- 090309/Wellcome Trust/United Kingdom -- G0700888/Medical Research Council/United Kingdom -- G0701225/Medical Research Council/United Kingdom -- R01 DA030601/DA/NIDA NIH HHS/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 May 23;344(6186):901-4. doi: 10.1126/science.1252114.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Neural Circuits and Behaviour, University of Oxford, Tinsley Building, Mansfield Road, Oxford, OX1 3SR, UK. ; Centre for Neural Circuits and Behaviour, University of Oxford, Tinsley Building, Mansfield Road, Oxford, OX1 3SR, UK. gero.miesenboeck@cncb.ox.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24855268" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Behavior, Animal ; Cell Line ; *Decision Making ; Drosophila Proteins/genetics/*physiology ; Drosophila melanogaster/genetics/*physiology ; Forkhead Transcription Factors/genetics/*physiology ; Mushroom Bodies/growth & development/metabolism ; Mutation ; Neurons/physiology ; Odors ; *Psychomotor Performance ; RNA Interference ; Reaction Time/genetics/*physiology ; Smell
    Print ISSN: 0036-8075
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    Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-01
    Description: Epigenetic gene silencing is seen in several repeat-expansion diseases. In fragile X syndrome, the most common genetic form of mental retardation, a CGG trinucleotide-repeat expansion adjacent to the fragile X mental retardation 1 (FMR1) gene promoter results in its epigenetic silencing. Here, we show that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5' untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA.DNA duplex. Disrupting the interaction of the mRNA with the CGG-repeat portion of the FMR1 gene prevents promoter silencing. Thus, our data link trinucleotide-repeat expansion to a form of RNA-directed gene silencing mediated by direct interactions of the trinucleotide-repeat RNA and DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357282/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357282/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colak, Dilek -- Zaninovic, Nikica -- Cohen, Michael S -- Rosenwaks, Zev -- Yang, Wang-Yong -- Gerhardt, Jeannine -- Disney, Matthew D -- Jaffrey, Samie R -- R01 GM079235/GM/NIGMS NIH HHS/ -- R01 MH80420/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Feb 28;343(6174):1002-5. doi: 10.1126/science.1245831.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24578575" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; DNA Methylation ; Embryonic Stem Cells/metabolism ; Fragile X Mental Retardation Protein/*genetics ; Fragile X Syndrome/*genetics ; *Gene Silencing ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neurons/metabolism ; Nuclear Proteins/genetics ; Promoter Regions, Genetic/genetics ; RNA, Messenger/*genetics ; RNA, Small Interfering/genetics ; Trinucleotide Repeats/*genetics
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-06-28
    Description: Dynamin superfamily molecular motors use guanosine triphosphate (GTP) as a source of energy for membrane-remodeling events. We found that knockdown of nucleoside diphosphate kinases (NDPKs) NM23-H1/H2, which produce GTP through adenosine triphosphate (ATP)-driven conversion of guanosine diphosphate (GDP), inhibited dynamin-mediated endocytosis. NM23-H1/H2 localized at clathrin-coated pits and interacted with the proline-rich domain of dynamin. In vitro, NM23-H1/H2 were recruited to dynamin-induced tubules, stimulated GTP-loading on dynamin, and triggered fission in the presence of ATP and GDP. NM23-H4, a mitochondria-specific NDPK, colocalized with mitochondrial dynamin-like OPA1 involved in mitochondria inner membrane fusion and increased GTP-loading on OPA1. Like OPA1 loss of function, silencing of NM23-H4 but not NM23-H1/H2 resulted in mitochondrial fragmentation, reflecting fusion defects. Thus, NDPKs interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601533/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601533/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boissan, Mathieu -- Montagnac, Guillaume -- Shen, Qinfang -- Griparic, Lorena -- Guitton, Jerome -- Romao, Maryse -- Sauvonnet, Nathalie -- Lagache, Thibault -- Lascu, Ioan -- Raposo, Graca -- Desbourdes, Celine -- Schlattner, Uwe -- Lacombe, Marie-Lise -- Polo, Simona -- van der Bliek, Alexander M -- Roux, Aurelien -- Chavrier, Philippe -- 311536/European Research Council/International -- New York, N.Y. -- Science. 2014 Jun 27;344(6191):1510-5. doi: 10.1126/science.1253768.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, Research Center, Paris, France. Membrane and Cytoskeleton Dynamics, CNRS UMR 144, Paris, France. Universite Pierre et Marie Curie, University Paris 06, Paris, France. Saint-Antoine Research Center, INSERM UMR-S 938, Paris, France. mathieu.boissan@inserm.fr philippe.chavrier@curie.fr. ; Institut Curie, Research Center, Paris, France. Membrane and Cytoskeleton Dynamics, CNRS UMR 144, Paris, France. ; Department of Biological Chemistry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA. ; Hospices Civils de Lyon, Pierre Benite, France. Universite de Lyon, Lyon, France. ; Institut Curie, Research Center, Paris, France. Structure and Membrane Compartments, CNRS UMR 144, Paris, France. ; Institut Pasteur, Unite de Biologie des Interactions Cellulaires, Paris, France. ; Quantitative Image Analysis Unit, Institut Pasteur, Paris, France. ; Institut de Biochimie et Genetique Cellulaires-CNRS, Universite Bordeaux 2, Bordeaux, France. ; Universite Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics, Grenoble, France. Inserm, U1055, Grenoble, France. ; Universite Pierre et Marie Curie, University Paris 06, Paris, France. Saint-Antoine Research Center, INSERM UMR-S 938, Paris, France. ; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. Dipartimento di Scienze della Salute, Universita' degli Studi di Milano, Milan, Italy. ; Biochemistry Department, University of Geneva, & Swiss National Center for Competence in Research Program Chemical Biology, Geneva, Switzerland. ; Institut Curie, Research Center, Paris, France. Membrane and Cytoskeleton Dynamics, CNRS UMR 144, Paris, France. mathieu.boissan@inserm.fr philippe.chavrier@curie.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24970086" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Cell Line ; Cell Membrane/*metabolism ; Coated Pits, Cell-Membrane/metabolism ; Dynamins/*metabolism ; Endocytosis ; GTP Phosphohydrolases/metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/*metabolism ; Humans ; Intracellular Membranes/metabolism ; Membrane Fusion ; Mitochondria/metabolism ; NM23 Nucleoside Diphosphate Kinases/genetics/*metabolism ; Nucleoside Diphosphate Kinase D/metabolism
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    A mutually assured destruction mechanism attenuates light signaling in Arabidopsis (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-06-07
    Description: After light-induced nuclear translocation, phytochrome photoreceptors interact with and induce rapid phosphorylation and degradation of basic helix-loop-helix transcription factors, such as PHYTOCHROME-INTERACTING FACTOR 3 (PIF3), to regulate gene expression. Concomitantly, this interaction triggers feedback reduction of phytochrome B (phyB) levels. Light-induced phosphorylation of PIF3 is necessary for the degradation of both proteins. We report that this PIF3 phosphorylation induces, and is necessary for, recruitment of LRB [Light-Response Bric-a-Brack/Tramtrack/Broad (BTB)] E3 ubiquitin ligases to the PIF3-phyB complex. The recruited LRBs promote concurrent polyubiqutination and degradation of both PIF3 and phyB in vivo. These data reveal a linked signal-transmission and attenuation mechanism involving mutually assured destruction of the receptor and its immediate signaling partner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414656/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414656/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ni, Weimin -- Xu, Shou-Ling -- Tepperman, James M -- Stanley, David J -- Maltby, Dave A -- Gross, John D -- Burlingame, Alma L -- Wang, Zhi-Yong -- Quail, Peter H -- 2R01 GM-047475/GM/NIGMS NIH HHS/ -- 5R01GM066258/GM/NIGMS NIH HHS/ -- 8P41GM103481/GM/NIGMS NIH HHS/ -- P41 GM103481/GM/NIGMS NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- R01 GM047475/GM/NIGMS NIH HHS/ -- R01 GM066258/GM/NIGMS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1160-4. doi: 10.1126/science.1250778.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Plant Gene Expression Center, Agriculture Research Service (ARS), U.S. Department of Agriculture (USDA), Albany, CA 94710, USA. ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Plant Biology, Carnegie Institution for Science, Stanford, CA 94305, USA. ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA. ; Department of Plant Biology, Carnegie Institution for Science, Stanford, CA 94305, USA. ; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Plant Gene Expression Center, Agriculture Research Service (ARS), U.S. Department of Agriculture (USDA), Albany, CA 94710, USA. quail@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904166" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Arabidopsis/genetics/*growth & development/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Cell Nucleus/metabolism ; Cullin Proteins/*metabolism ; Gene Expression Regulation, Plant ; HeLa Cells ; Humans ; *Light Signal Transduction ; Nuclear Proteins/genetics/metabolism ; Phosphorylation ; Phytochrome B/*metabolism ; Polyubiquitin/metabolism ; Proteolysis ; *Ubiquitination
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    Optical control of muscle function by transplantation of stem cell-derived motor neurons in mice (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-04-05
    Description: Damage to the central nervous system caused by traumatic injury or neurological disorders can lead to permanent loss of voluntary motor function and muscle paralysis. Here, we describe an approach that circumvents central motor circuit pathology to restore specific skeletal muscle function. We generated murine embryonic stem cell-derived motor neurons that express the light-sensitive ion channel channelrhodopsin-2, which we then engrafted into partially denervated branches of the sciatic nerve of adult mice. These engrafted motor neurons not only reinnervated lower hind-limb muscles but also enabled their function to be restored in a controllable manner using optogenetic stimulation. This synthesis of regenerative medicine and optogenetics may be a successful strategy to restore muscle function after traumatic injury or disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bryson, J Barney -- Machado, Carolina Barcellos -- Crossley, Martin -- Stevenson, Danielle -- Bros-Facer, Virginie -- Burrone, Juan -- Greensmith, Linda -- Lieberam, Ivo -- 095589/Wellcome Trust/United Kingdom -- G0900585/Medical Research Council/United Kingdom -- G1001234/Biotechnology and Biological Sciences Research Council/United Kingdom -- MR/K000608/1/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Apr 4;344(6179):94-7. doi: 10.1126/science.1248523.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24700859" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/physiology ; Cell Line ; Electric Stimulation ; Embryonic Stem Cells/cytology/physiology ; Female ; Hindlimb ; Isometric Contraction ; *Light ; Mice ; Mice, Inbred C57BL ; Motor Neurons/cytology/*physiology/*transplantation ; Muscle Denervation ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/*innervation/*physiology ; Nerve Regeneration ; *Optogenetics ; Rhodopsin/genetics/metabolism ; Sciatic Nerve/physiology ; Transfection ; Transgenes
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    Highly multiplexed subcellular RNA sequencing in situ (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-01
    Description: Understanding the spatial organization of gene expression with single-nucleotide resolution requires localizing the sequences of expressed RNA transcripts within a cell in situ. Here, we describe fluorescent in situ RNA sequencing (FISSEQ), in which stably cross-linked complementary DNA (cDNA) amplicons are sequenced within a biological sample. Using 30-base reads from 8102 genes in situ, we examined RNA expression and localization in human primary fibroblasts with a simulated wound-healing assay. FISSEQ is compatible with tissue sections and whole-mount embryos and reduces the limitations of optical resolution and noisy signals on single-molecule detection. Our platform enables massively parallel detection of genetic elements, including gene transcripts and molecular barcodes, and can be used to investigate cellular phenotype, gene regulation, and environment in situ.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140943/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140943/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Je Hyuk -- Daugharthy, Evan R -- Scheiman, Jonathan -- Kalhor, Reza -- Yang, Joyce L -- Ferrante, Thomas C -- Terry, Richard -- Jeanty, Sauveur S F -- Li, Chao -- Amamoto, Ryoji -- Peters, Derek T -- Turczyk, Brian M -- Marblestone, Adam H -- Inverso, Samuel A -- Bernard, Amy -- Mali, Prashant -- Rios, Xavier -- Aach, John -- Church, George M -- GM080177/GM/NIGMS NIH HHS/ -- MH098977/MH/NIMH NIH HHS/ -- P50 HG005550/HG/NHGRI NIH HHS/ -- RC2 HL102815/HL/NHLBI NIH HHS/ -- RC2HL102815/HL/NHLBI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32 GM080177/GM/NIGMS NIH HHS/ -- U01 MH098977/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1360-3. doi: 10.1126/science.1250212. Epub 2014 Feb 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wyss Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24578530" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Line ; Cells, Cultured ; DNA, Complementary ; Fluorescence ; Gene Expression Profiling/*methods ; Humans ; Induced Pluripotent Stem Cells ; RNA, Messenger/genetics/metabolism ; Sequence Analysis, RNA/*methods ; Single-Cell Analysis ; Transcription Initiation Site ; *Transcriptome ; Wound Healing
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    Structures of PI4KIIIbeta complexes show simultaneous recruitment of Rab11 and its effectors (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-05-31
    Description: Phosphatidylinositol 4-kinases (PI4Ks) and small guanosine triphosphatases (GTPases) are essential for processes that require expansion and remodeling of phosphatidylinositol 4-phosphate (PI4P)-containing membranes, including cytokinesis, intracellular development of malarial pathogens, and replication of a wide range of RNA viruses. However, the structural basis for coordination of PI4K, GTPases, and their effectors is unknown. Here, we describe structures of PI4Kbeta (PI4KIIIbeta) bound to the small GTPase Rab11a without and with the Rab11 effector protein FIP3. The Rab11-PI4KIIIbeta interface is distinct compared with known structures of Rab complexes and does not involve switch regions used by GTPase effectors. Our data provide a mechanism for how PI4KIIIbeta coordinates Rab11 and its effectors on PI4P-enriched membranes and also provide strategies for the design of specific inhibitors that could potentially target plasmodial PI4KIIIbeta to combat malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046302/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046302/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burke, John E -- Inglis, Alison J -- Perisic, Olga -- Masson, Glenn R -- McLaughlin, Stephen H -- Rutaganira, Florentine -- Shokat, Kevan M -- Williams, Roger L -- MC_U105184308/Medical Research Council/United Kingdom -- PG/11/109/29247/British Heart Foundation/United Kingdom -- PG11/109/29247/British Heart Foundation/United Kingdom -- R01AI099245/AI/NIAID NIH HHS/ -- T32 GM064337/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 May 30;344(6187):1035-8. doi: 10.1126/science.1253397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. jeburke@uvic.ca rlw@mrc-lmb.cam.ac.uk. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ; Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24876499" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antimalarials/chemistry/pharmacology ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Drug Design ; Humans ; I-kappa B Kinase/*chemistry ; Molecular Sequence Data ; Mutation ; Phosphotransferases (Alcohol Group Acceptor)/*chemistry/genetics ; Plasmodium/drug effects/growth & development ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; rab GTP-Binding Proteins/*chemistry
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    Nucleocytoplasmic shuttling of a GATA transcription factor functions as a development timer (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-22
    Description: Biological oscillations are observed at many levels of cellular organization. In the social amoeba Dictyostelium discoideum, starvation-triggered multicellular development is organized by periodic cyclic adenosine 3',5'-monophosphate (cAMP) waves, which provide both chemoattractant gradients and developmental signals. We report that GtaC, a GATA transcription factor, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of a nuclear localization signal and reversible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor-mediated phosphorylation. Although both are required for developmental gene expression, receptor occupancy promotes nuclear exit of GtaC, which leads to a transient burst of transcription at each cAMP cycle. We demonstrate that this biological circuit filters out high-frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061987/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061987/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cai, Huaqing -- Katoh-Kurasawa, Mariko -- Muramoto, Tetsuya -- Santhanam, Balaji -- Long, Yu -- Li, Lei -- Ueda, Masahiro -- Iglesias, Pablo A -- Shaulsky, Gad -- Devreotes, Peter N -- GM 28007/GM/NIGMS NIH HHS/ -- GM 34933/GM/NIGMS NIH HHS/ -- HD 039691/HD/NICHD NIH HHS/ -- P01 HD039691/HD/NICHD NIH HHS/ -- R01 GM028007/GM/NIGMS NIH HHS/ -- R01 GM034933/GM/NIGMS NIH HHS/ -- R37 GM028007/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1249531. doi: 10.1126/science.1249531.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24653039" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Cell Nucleus/*metabolism ; Cyclic AMP/metabolism/pharmacology ; Cytoplasm/*metabolism ; Dictyostelium/growth & development/*metabolism ; GATA Transcription Factors/chemistry/genetics/*metabolism ; Gene Expression Regulation ; Heterotrimeric GTP-Binding Proteins/metabolism ; Nuclear Localization Signals ; Phosphorylation ; Protozoan Proteins/chemistry/genetics/*metabolism ; Receptors, G-Protein-Coupled/metabolism
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    PCP and septins compartmentalize cortical actomyosin to direct collective cell movement (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-02-08
    Description: Despite our understanding of actomyosin function in individual migrating cells, we know little about the mechanisms by which actomyosin drives collective cell movement in vertebrate embryos. The collective movements of convergent extension drive both global reorganization of the early embryo and local remodeling during organogenesis. We report here that planar cell polarity (PCP) proteins control convergent extension by exploiting an evolutionarily ancient function of the septin cytoskeleton. By directing septin-mediated compartmentalization of cortical actomyosin, PCP proteins coordinate the specific shortening of mesenchymal cell-cell contacts, which in turn powers cell interdigitation. These data illuminate the interface between developmental signaling systems and the fundamental machinery of cell behavior and should provide insights into the etiology of human birth defects, such as spina bifida and congenital kidney cysts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167615/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167615/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shindo, Asako -- Wallingford, John B -- R01 GM074104/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Feb 7;343(6171):649-52. doi: 10.1126/science.1243126.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and University of Texas at Austin, Austin, TX 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24503851" target="_blank"〉PubMed〈/a〉
    Keywords: Actomyosin/*metabolism ; Animals ; *Cell Movement ; *Cell Polarity ; Embryo, Nonmammalian/cytology/metabolism ; Female ; Gastrula/cytology/metabolism ; Gene Knockdown Techniques ; Humans ; Mesoderm/cytology/metabolism ; Organogenesis ; Phosphorylation ; Septins/genetics/*metabolism ; Xenopus Proteins/genetics/*metabolism ; Xenopus laevis
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    Btk29A promotes Wnt4 signaling in the niche to terminate germ cell proliferation in Drosophila (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-01-18
    Description: Btk29A is the Drosophila ortholog of the mammalian Bruton's tyrosine kinase (Btk), mutations of which in humans cause a heritable immunodeficiency disease. Btk29A mutations stabilized the proliferating cystoblast fate, leading to an ovarian tumor. This phenotype was rescued by overexpression of wild-type Btk29A and phenocopied by the interference of Wnt4-beta-catenin signaling or its putative downstream nuclear protein Piwi in somatic escort cells. Btk29A and mammalian Btk directly phosphorylated tyrosine residues of beta-catenin, leading to the up-regulation of its transcriptional activity. Thus, we identify a transcriptional switch involving the kinase Btk29A/Btk and its phosphorylation target, beta-catenin, which functions downstream of Wnt4 in escort cells to terminate Drosophila germ cell proliferation through up-regulation of piwi expression. This signaling mechanism likely represents a versatile developmental switch.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamada-Kawaguchi, Noriko -- Nore, Beston F -- Kuwada, Yusuke -- Smith, C I Edvard -- Yamamoto, Daisuke -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):294-7. doi: 10.1126/science.1244512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology and Neurosciences, Tohoku University Graduate School of Life Sciences, Sendai 980-8577, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24436419" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/*biosynthesis ; *Cell Proliferation ; DNA Breaks, Double-Stranded ; Drosophila Proteins/*biosynthesis/genetics/*metabolism ; Drosophila melanogaster/genetics/metabolism/*physiology ; Gene Knockdown Techniques ; Genomic Instability ; Germ Cells/cytology/metabolism/*physiology ; Glycoproteins/genetics/*metabolism ; Phosphorylation ; Protein-Tyrosine Kinases/genetics/*metabolism ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Transcription, Genetic ; Tyrosine/genetics/metabolism ; Up-Regulation ; Wnt Proteins/genetics/*metabolism ; beta Catenin/genetics/*metabolism
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    Mitochondria. Cell cycle-dependent regulation of mitochondrial preprotein translocase (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-11-08
    Description: Mitochondria play central roles in cellular energy conversion, metabolism, and apoptosis. Mitochondria import more than 1000 different proteins from the cytosol. It is unknown if the mitochondrial protein import machinery is connected to the cell division cycle. We found that the cyclin-dependent kinase Cdk1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. The molecular mechanism involved phosphorylation of the cytosolic precursor of Tom6 by cyclin Clb3-activated Cdk1, leading to enhanced import of Tom6 into mitochondria. Tom6 phosphorylation promoted assembly of the protein import channel Tom40 and import of fusion proteins, thus stimulating the respiratory activity of mitochondria in mitosis. Tom6 phosphorylation provides a direct means for regulating mitochondrial biogenesis and activity in a cell cycle-specific manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harbauer, Angelika B -- Opalinska, Magdalena -- Gerbeth, Carolin -- Herman, Josip S -- Rao, Sanjana -- Schonfisch, Birgit -- Guiard, Bernard -- Schmidt, Oliver -- Pfanner, Nikolaus -- Meisinger, Chris -- New York, N.Y. -- Science. 2014 Nov 28;346(6213):1109-13. doi: 10.1126/science.1261253. Epub 2014 Nov 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. Trinationales Graduiertenkolleg 1478, Universitat Freiburg, 79104 Freiburg, Germany. Faculty of Biology, Universitat Freiburg, 79104 Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. Trinationales Graduiertenkolleg 1478, Universitat Freiburg, 79104 Freiburg, Germany. Faculty of Biology, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. Faculty of Biology, Universitat Freiburg, 79104 Freiburg, Germany. Spemann Graduate School of Biology and Medicine, Universitat Freiburg, 79104 Freiburg, Germany. ; Centre de Genetique Moleculaire, CNRS, 91190 Gif-sur-Yvette, France. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. nikolaus.pfanner@biochemie.uni-freiburg.de chris.meisinger@biochemie.uni-freiburg.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25378463" target="_blank"〉PubMed〈/a〉
    Keywords: CDC2 Protein Kinase/metabolism ; *Cell Cycle ; Cyclin B/metabolism ; Cytosol/metabolism ; Mitochondria/*metabolism ; Mitochondrial Membrane Transport Proteins/*metabolism ; Phosphorylation ; Protein Precursors/*metabolism ; Protein Transport ; Saccharomyces cerevisiae/*cytology/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism
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    Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-02
    Description: Many RNA regulatory proteins controlling pre-messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459787/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwon, Ilmin -- Xiang, Siheng -- Kato, Masato -- Wu, Leeju -- Theodoropoulos, Pano -- Wang, Tao -- Kim, Jiwoong -- Yun, Jonghyun -- Xie, Yang -- McKnight, Steven L -- U01 GM107623/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 5;345(6201):1139-45. doi: 10.1126/science.1254917. Epub 2014 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. ; Quantitative Biomedical Research Center, Department of Clinical Sciences, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. ; Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. steven.mcknight@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25081482" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Astrocytes/*metabolism/pathology ; Cell Death ; Cell Nucleolus/*metabolism ; Cells, Cultured ; Dipeptides/genetics/*metabolism/pharmacology ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Glutamate Plasma Membrane Transport Proteins/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism ; Humans ; Hydrogel ; Phosphorylation ; Protein Biosynthesis ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Proteins/*genetics ; RNA, Antisense/antagonists & inhibitors/biosynthesis ; RNA, Messenger/antagonists & inhibitors/biosynthesis ; RNA, Ribosomal/antagonists & inhibitors/biosynthesis ; Repetitive Sequences, Amino Acid ; Transcription, Genetic
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    A peptide hormone and its receptor protein kinase regulate plant cell expansion (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-01-25
    Description: Plant cells are immobile; thus, plant growth and development depend on cell expansion rather than cell migration. The molecular mechanism by which the plasma membrane initiates changes in the cell expansion rate remains elusive. We found that a secreted peptide, RALF (rapid alkalinization factor), suppresses cell elongation of the primary root by activating the cell surface receptor FERONIA in Arabidopsis thaliana. A direct peptide-receptor interaction is supported by specific binding of RALF to FERONIA and reduced binding and insensitivity to RALF-induced growth inhibition in feronia mutants. Phosphoproteome measurements demonstrate that the RALF-FERONIA interaction causes phosphorylation of plasma membrane H(+)-adenosine triphosphatase 2 at Ser(899), mediating the inhibition of proton transport. The results reveal a molecular mechanism for RALF-induced extracellular alkalinization and a signaling pathway that regulates cell expansion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672726/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672726/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haruta, Miyoshi -- Sabat, Grzegorz -- Stecker, Kelly -- Minkoff, Benjamin B -- Sussman, Michael R -- 5T32HG002760/HG/NHGRI NIH HHS/ -- U54 GM074901/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 24;343(6169):408-11. doi: 10.1126/science.1244454.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biotechnology Center, University of Wisconsin, Madison, WI 53706, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24458638" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*cytology/metabolism ; Arabidopsis Proteins/*agonists/genetics/*metabolism ; *Cell Enlargement ; Cell Membrane/*enzymology ; Molecular Sequence Data ; Peptide Hormones/genetics/*metabolism ; Phosphorylation ; Phosphotransferases/genetics/metabolism ; Plant Cells/metabolism/physiology ; Plant Roots/cytology/metabolism ; Protein Binding ; Proteome/metabolism ; Proton-Translocating ATPases/*metabolism ; Serine/metabolism
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    Biofuels. Engineering alcohol tolerance in yeast (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-10-04
    Description: Ethanol toxicity in the yeast Saccharomyces cerevisiae limits titer and productivity in the industrial production of transportation bioethanol. We show that strengthening the opposing potassium and proton electrochemical membrane gradients is a mechanism that enhances general resistance to multiple alcohols. The elevation of extracellular potassium and pH physically bolsters these gradients, increasing tolerance to higher alcohols and ethanol fermentation in commercial and laboratory strains (including a xylose-fermenting strain) under industrial-like conditions. Production per cell remains largely unchanged, with improvements deriving from heightened population viability. Likewise, up-regulation of the potassium and proton pumps in the laboratory strain enhances performance to levels exceeding those of industrial strains. Although genetically complex, alcohol tolerance can thus be dominated by a single cellular process, one controlled by a major physicochemical component but amenable to biological augmentation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401034/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401034/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lam, Felix H -- Ghaderi, Adel -- Fink, Gerald R -- Stephanopoulos, Gregory -- R01 GM035010/GM/NIGMS NIH HHS/ -- R01-GM035010/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):71-5. doi: 10.1126/science.1257859. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. Whitehead Institute for Biomedical Research, Cambridge, MA, USA. ; Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA, USA. gfink@wi.mit.edu gregstep@mit.edu. ; Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. gfink@wi.mit.edu gregstep@mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278607" target="_blank"〉PubMed〈/a〉
    Keywords: *Biofuels ; Cation Transport Proteins/genetics ; Cell Culture Techniques ; Cell Membrane/metabolism ; Chemical Engineering ; *Drug Resistance, Fungal/genetics ; Ethanol/*metabolism/pharmacology ; Fermentation ; Genetic Engineering ; Glucose/metabolism ; Hydrogen-Ion Concentration ; Phosphates/*metabolism ; Potassium Compounds/*metabolism ; Proton Pumps/genetics ; Proton-Translocating ATPases/genetics ; Saccharomyces cerevisiae/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Up-Regulation ; Xylose/metabolism
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    Chromatin decondensation is sufficient to alter nuclear organization in embryonic stem cells (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-12-06
    Description: During differentiation, thousands of genes are repositioned toward or away from the nuclear envelope. These movements correlate with changes in transcription and replication timing. Using synthetic (TALE) transcription factors, we found that transcriptional activation of endogenous genes by a viral trans-activator is sufficient to induce gene repositioning toward the nuclear interior in embryonic stem cells. However, gene relocation was also induced by recruitment of an acidic peptide that decondenses chromatin without affecting transcription, indicating that nuclear reorganization is driven by chromatin remodeling rather than transcription. We identified an epigenetic inheritance of chromatin decondensation that maintained central nuclear positioning through mitosis even after the TALE transcription factor was lost. Our results also demonstrate that transcriptional activation, but not chromatin decondensation, is sufficient to change replication timing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Therizols, Pierre -- Illingworth, Robert S -- Courilleau, Celine -- Boyle, Shelagh -- Wood, Andrew J -- Bickmore, Wendy A -- 102560/Wellcome Trust/United Kingdom -- MC_PC_U127527202/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Dec 5;346(6214):1238-42. doi: 10.1126/science.1259587.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. wendy.bickmore@igmm.ed.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25477464" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/*genetics ; Cell Line ; Cell Nucleus/*genetics/metabolism/ultrastructure ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; DNA Replication ; Embryonic Stem Cells/*cytology/metabolism ; *Epigenesis, Genetic ; Mice ; Nuclear Envelope/genetics/metabolism/ultrastructure ; Trans-Activators/*metabolism ; *Transcriptional Activation
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    The art of entrepreneurship (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-11-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Langer, Robert S -- Gura, Trisha -- New York, N.Y. -- Science. 2014 Nov 28;346(6213):1146. doi: 10.1126/science.346.6213.1146.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Trisha Gura is a freelance writer who lives in Boston. For more on life and careers visit www.sciencecareers.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25430772" target="_blank"〉PubMed〈/a〉
    Keywords: Biotechnology ; *Career Choice ; Chemical Engineering ; *Entrepreneurship ; *Science
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    Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-06-07
    Description: Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an "eat me" signal.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Segawa, Katsumori -- Kurata, Sachiko -- Yanagihashi, Yuichi -- Brummelkamp, Thijn R -- Matsuda, Fumihiko -- Nagata, Shigekazu -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1164-8. doi: 10.1126/science.1252809.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. ; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan. ; Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Kyoto 606-8501, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kyoto 606-8501, Japan. snagata@mfour.med.kyoto-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904167" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/genetics/*metabolism ; *Apoptosis ; Caspases/*metabolism ; Cell Line ; Cell Membrane/*enzymology ; Genetic Testing ; Humans ; Membrane Proteins/*metabolism ; Membrane Transport Proteins ; Phosphatidylserines/*metabolism ; Phospholipid Transfer Proteins/genetics/*metabolism ; Protein Transport
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    Systems biology. Accurate information transmission through dynamic biochemical signaling networks (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-12-17
    Description: Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation--that is, dynamics--to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2+)), and nuclear factor kappa-B (NF-kappaB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Selimkhanov, Jangir -- Taylor, Brooks -- Yao, Jason -- Pilko, Anna -- Albeck, John -- Hoffmann, Alexander -- Tsimring, Lev -- Wollman, Roy -- P50 GM085764/GM/NIGMS NIH HHS/ -- P50-GM085764/GM/NIGMS NIH HHS/ -- R01 GM089976/GM/NIGMS NIH HHS/ -- R01-GM071573/GM/NIGMS NIH HHS/ -- R01-GM089976/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Dec 12;346(6215):1370-3. doi: 10.1126/science.1254933.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, University of California-San Diego, La Jolla, CA 92093, USA. ; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA 92093, USA. ; Department of Molecular and Cellular Biology, University of California-Davis, Davis 95616, USA. ; San Diego Center for Systems Biology, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90025, USA. ; San Diego Center for Systems Biology, La Jolla, CA 92093, USA. BioCircuits Institute, University of California-San Diego, La Jolla, CA 92093, USA. ; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA 92093, USA. San Diego Center for Systems Biology, La Jolla, CA 92093, USA. Cell and Developmental Biology Section, Division of Biological Sciences, University of California-San Diego, La Jolla, CA 92093, USA. rwollman@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25504722" target="_blank"〉PubMed〈/a〉
    Keywords: *Calcium Signaling ; Cell Line ; Computer Simulation ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; *MAP Kinase Signaling System ; NF-kappa B/*metabolism ; *Signal Transduction ; Signal-To-Noise Ratio ; Single-Cell Analysis ; Systems Biology
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    Virus entry. Lassa virus entry requires a trigger-induced receptor switch (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-06-28
    Description: Lassa virus spreads from a rodent to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported 30 years ago to resist infection. We found that Lassa virus readily engaged its cell-surface receptor alpha-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this receptor switch in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239993/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239993/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jae, Lucas T -- Raaben, Matthijs -- Herbert, Andrew S -- Kuehne, Ana I -- Wirchnianski, Ariel S -- Soh, Timothy K -- Stubbs, Sarah H -- Janssen, Hans -- Damme, Markus -- Saftig, Paul -- Whelan, Sean P -- Dye, John M -- Brummelkamp, Thijn R -- AI081842/AI/NIAID NIH HHS/ -- AI109740/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI109740/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 27;344(6191):1506-10. doi: 10.1126/science.1252480.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ; U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. ; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ; Biochemisches Institut, Christian Albrechts-Universitat Kiel, 24118 Kiel, Germany. ; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu. ; U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Cancer Genomics Center (CGC.nl), Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24970085" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; Cell Membrane/metabolism/virology ; Cells, Cultured ; Chickens ; Dystroglycans/genetics/metabolism ; Glycosylation ; Humans ; Hydrogen-Ion Concentration ; Lassa Fever/virology ; Lassa virus/*physiology ; Lysosomal-Associated Membrane Protein 1/chemistry/*metabolism ; Lysosomes/metabolism/virology ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Protein Binding ; Receptors, Virus/*metabolism ; Sialyltransferases/metabolism ; Viral Envelope Proteins/*metabolism ; *Virus Internalization
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    Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-02-22
    Description: Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-alpha treatment can clear HBV but is limited by systemic side effects. We describe how interferon-alpha can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-beta receptor activation as a therapeutic alternative. Interferon-alpha and lymphotoxin-beta receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases-for example, by lymphotoxin-beta receptor activation-allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lucifora, Julie -- Xia, Yuchen -- Reisinger, Florian -- Zhang, Ke -- Stadler, Daniela -- Cheng, Xiaoming -- Sprinzl, Martin F -- Koppensteiner, Herwig -- Makowska, Zuzanna -- Volz, Tassilo -- Remouchamps, Caroline -- Chou, Wen-Min -- Thasler, Wolfgang E -- Huser, Norbert -- Durantel, David -- Liang, T Jake -- Munk, Carsten -- Heim, Markus H -- Browning, Jeffrey L -- Dejardin, Emmanuel -- Dandri, Maura -- Schindler, Michael -- Heikenwalder, Mathias -- Protzer, Ulrike -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1221-8. doi: 10.1126/science.1243462. Epub 2014 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Virology, Technische Universitat Munchen-Helmholtz Zentrum Munchen, 81675 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24557838" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal ; Antiviral Agents/*pharmacology/therapeutic use ; Cell Line ; Cell Nucleus/virology ; Cytidine/metabolism ; Cytidine Deaminase/biosynthesis ; DNA, Circular/*metabolism ; DNA, Viral/*metabolism ; Hepatitis B/*drug therapy ; Hepatitis B virus/*drug effects/metabolism ; Hepatocytes/*drug effects/metabolism/virology ; Humans ; Interferon-alpha/*pharmacology/therapeutic use ; Liver/drug effects/metabolism/virology ; Lymphotoxin beta Receptor/*agonists/antagonists & inhibitors ; Mice, SCID ; Proteins ; Up-Regulation
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    Feedback control of chromosome separation by a midzone Aurora B gradient (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-06-14
    Description: Accurate chromosome segregation during mitosis requires the physical separation of sister chromatids before nuclear envelope reassembly (NER). However, how these two processes are coordinated remains unknown. Here, we identified a conserved feedback control mechanism that delays chromosome decondensation and NER in response to incomplete chromosome separation during anaphase. A midzone-associated Aurora B gradient was found to monitor chromosome position along the division axis and to prevent premature chromosome decondensation by retaining Condensin I. PP1/PP2A phosphatases counteracted this gradient and promoted chromosome decondensation and NER. Thus, an Aurora B gradient appears to mediate a surveillance mechanism that prevents chromosome decondensation and NER until effective separation of sister chromatids is achieved. This allows the correction and reintegration of lagging chromosomes in the main nuclei before completion of NER.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Afonso, Olga -- Matos, Irina -- Pereira, Antonio J -- Aguiar, Paulo -- Lampson, Michael A -- Maiato, Helder -- New York, N.Y. -- Science. 2014 Jul 18;345(6194):332-6. doi: 10.1126/science.1251121. Epub 2014 Jun 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. ; Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. Center for Mathematics, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal. ; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. Cell Division Unit, Department of Experimental Biology, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal. maiato@ibmc.up.pt.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24925910" target="_blank"〉PubMed〈/a〉
    Keywords: *Anaphase ; Animals ; Aurora Kinase B/antagonists & inhibitors/genetics/*metabolism ; Cell Line ; Cell Line, Tumor ; Chromosome Segregation/genetics/*physiology ; Drosophila ; *Feedback, Physiological ; Humans ; Nuclear Envelope/genetics/*metabolism ; Protein Phosphatase 1/metabolism ; Protein Phosphatase 2/metabolism
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    Controlling low rates of cell differentiation through noise and ultrahigh feedback (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-06-21
    Description: Mammalian tissue size is maintained by slow replacement of de-differentiating and dying cells. For adipocytes, key regulators of glucose and lipid metabolism, the renewal rate is only 10% per year. We used computational modeling, quantitative mass spectrometry, and single-cell microscopy to show that cell-to-cell variability, or noise, in protein abundance acts within a network of more than six positive feedbacks to permit pre-adipocytes to differentiate at very low rates. This reconciles two fundamental opposing requirements: High cell-to-cell signal variability is needed to generate very low differentiation rates, whereas low signal variability is needed to prevent differentiated cells from de-differentiating. Higher eukaryotes can thus control low rates of near irreversible cell fate decisions through a balancing act between noise and ultrahigh feedback connectivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733388/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733388/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahrends, Robert -- Ota, Asuka -- Kovary, Kyle M -- Kudo, Takamasa -- Park, Byung Ouk -- Teruel, Mary N -- P50 GM107615/GM/NIGMS NIH HHS/ -- P50GM107615/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 20;344(6190):1384-9. doi: 10.1126/science.1252079.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA. ; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA. mteruel@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24948735" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/*cytology ; *Adipogenesis ; Animals ; CCAAT-Enhancer-Binding Proteins/genetics/metabolism ; Cell Communication ; Cell Differentiation ; Cell Line ; Computer Simulation ; Feedback, Physiological ; Mass Spectrometry ; Mice ; *Models, Biological ; PPAR gamma/genetics/metabolism ; RNA, Small Interfering/genetics ; Single-Cell Analysis ; Stem Cells/cytology
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    The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-04-20
    Description: Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however, few have been identified that regulate immune cell differentiation and function. Here, we identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs). Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation. lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the known mechanisms of lncRNA action.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Pin -- Xue, Yiquan -- Han, Yanmei -- Lin, Li -- Wu, Cong -- Xu, Sheng -- Jiang, Zhengping -- Xu, Junfang -- Liu, Qiuyan -- Cao, Xuetao -- New York, N.Y. -- Science. 2014 Apr 18;344(6181):310-3. doi: 10.1126/science.1251456.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24744378" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Cell Differentiation ; Chromatin/metabolism ; Cytoplasm/metabolism ; Dendritic Cells/*cytology/*immunology/physiology ; Epigenesis, Genetic ; Gene Expression Regulation ; Histones/metabolism ; Humans ; Lymphocyte Activation ; Mice ; Monocytes/cytology ; Nucleic Acid Conformation ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; RNA, Long Noncoding/*metabolism ; STAT3 Transcription Factor/*metabolism ; T-Lymphocytes/immunology
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    Enteric bacteria promote human and mouse norovirus infection of B cells (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-08
    Description: The cell tropism of human noroviruses and the development of an in vitro infection model remain elusive. Although susceptibility to individual human norovirus strains correlates with an individual's histo-blood group antigen (HBGA) profile, the biological basis of this restriction is unknown. We demonstrate that human and mouse noroviruses infected B cells in vitro and likely in vivo. Human norovirus infection of B cells required the presence of HBGA-expressing enteric bacteria. Furthermore, mouse norovirus replication was reduced in vivo when the intestinal microbiota was depleted by means of oral antibiotic administration. Thus, we have identified B cells as a cellular target of noroviruses and enteric bacteria as a stimulatory factor for norovirus infection, leading to the development of an in vitro infection model for human noroviruses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401463/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401463/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, Melissa K -- Watanabe, Makiko -- Zhu, Shu -- Graves, Christina L -- Keyes, Lisa R -- Grau, Katrina R -- Gonzalez-Hernandez, Mariam B -- Iovine, Nicole M -- Wobus, Christiane E -- Vinje, Jan -- Tibbetts, Scott A -- Wallet, Shannon M -- Karst, Stephanie M -- R01 AI080611/AI/NIAID NIH HHS/ -- R21 AI103961/AI/NIAID NIH HHS/ -- T90 DE021990/DE/NIDCR NIH HHS/ -- T90 DE021990-02/DE/NIDCR NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 7;346(6210):755-9. doi: 10.1126/science.1257147.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics and Microbiology, Emerging Pathogens Institute, College of Medicine, University of Florida, Gainesville, FL, USA. ; Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA. Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA. ; Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. ; Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, FL, USA. ; Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. ; Department of Molecular Genetics and Microbiology, Emerging Pathogens Institute, College of Medicine, University of Florida, Gainesville, FL, USA. skarst@ufl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25378626" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; B-Lymphocytes/immunology/*virology ; Caliciviridae Infections/*immunology/microbiology/virology ; Cell Line ; Enterobacteriaceae/drug effects/*physiology ; Gastroenteritis/*immunology/microbiology/virology ; Genome, Viral/genetics/physiology ; Homeodomain Proteins/genetics ; Humans ; Intestines/immunology/*microbiology ; Mice ; Mice, Mutant Strains ; Norovirus/*physiology ; Peyer's Patches/immunology/virology ; *Virus Replication
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    A bacterial tyrosine phosphatase inhibits plant pattern recognition receptor activation (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-15
    Description: Innate immunity relies on the perception of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) located on the host cell's surface. Many plant PRRs are kinases. Here, we report that the Arabidopsis receptor kinase EF-TU RECEPTOR (EFR), which perceives the elf18 peptide derived from bacterial elongation factor Tu, is activated upon ligand binding by phosphorylation on its tyrosine residues. Phosphorylation of a single tyrosine residue, Y836, is required for activation of EFR and downstream immunity to the phytopathogenic bacterium Pseudomonas syringae. A tyrosine phosphatase, HopAO1, secreted by P. syringae, reduces EFR phosphorylation and prevents subsequent immune responses. Thus, host and pathogen compete to take control of PRR tyrosine phosphorylation used to initiate antibacterial immunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macho, Alberto P -- Schwessinger, Benjamin -- Ntoukakis, Vardis -- Brutus, Alexandre -- Segonzac, Cecile -- Roy, Sonali -- Kadota, Yasuhiro -- Oh, Man-Ho -- Sklenar, Jan -- Derbyshire, Paul -- Lozano-Duran, Rosa -- Malinovsky, Frederikke Gro -- Monaghan, Jacqueline -- Menke, Frank L -- Huber, Steven C -- He, Sheng Yang -- Zipfel, Cyril -- BB/G024944/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- R01AI060761/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Mar 28;343(6178):1509-12. doi: 10.1126/science.1248849. Epub 2014 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Sainsbury Laboratory, Norwich Research Park, Norwich NR4 7UH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24625928" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*immunology/*microbiology ; Arabidopsis Proteins/agonists/*metabolism ; Bacterial Proteins/*metabolism ; Peptide Elongation Factor Tu/*metabolism ; Peptides/metabolism/pharmacology ; Phosphorylation ; Protein Tyrosine Phosphatases/*metabolism ; Pseudomonas syringae/enzymology/*pathogenicity ; Receptors, Pattern Recognition/agonists/*metabolism ; Tyrosine/metabolism
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    RNA interference functions as an antiviral immunity mechanism in mammals (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-10-12
    Description: Diverse eukaryotic hosts produce virus-derived small interfering RNAs (siRNAs) to direct antiviral immunity by RNA interference (RNAi). However, it remains unknown whether the mammalian RNAi pathway has a natural antiviral function. Here, we show that infection of hamster cells and suckling mice by Nodamura virus (NoV), a mosquito-transmissible RNA virus, requires RNAi suppression by its B2 protein. Loss of B2 expression or its suppressor activity leads to abundant production of viral siRNAs and rapid clearance of the mutant viruses in mice. However, viral small RNAs detected during virulent infection by NoV do not have the properties of canonical siRNAs. These findings have parallels with the induction and suppression of antiviral RNAi by the related Flock house virus in fruit flies and nematodes and reveal a mammalian antiviral immunity mechanism mediated by RNAi.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875315/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875315/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Yang -- Lu, Jinfeng -- Han, Yanhong -- Fan, Xiaoxu -- Ding, Shou-Wei -- AI52447/AI/NIAID NIH HHS/ -- GM94396/GM/NIGMS NIH HHS/ -- R01 AI052447/AI/NIAID NIH HHS/ -- R01 GM094396/GM/NIGMS NIH HHS/ -- RC1 GM091896/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Oct 11;342(6155):231-4. doi: 10.1126/science.1241911.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Pathology and Microbiology, University of California, Riverside, CA 92521, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24115437" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cricetinae ; Mice ; Nodaviridae/genetics/*pathogenicity ; RNA Interference/*immunology ; RNA Virus Infections/*immunology ; RNA, Small Interfering/*immunology ; RNA, Viral/genetics/*immunology ; Viral Nonstructural Proteins/genetics/*immunology
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    Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-03-23
    Description: Glycosylated alpha-dystroglycan (alpha-DG) serves as cellular entry receptor for multiple pathogens, and defects in its glycosylation cause hereditary Walker-Warburg syndrome (WWS). At least eight proteins are critical to glycosylate alpha-DG, but many genes mutated in WWS remain unknown. To identify modifiers of alpha-DG, we performed a haploid screen for Lassa virus entry, a hemorrhagic fever virus causing thousands of deaths annually that hijacks glycosylated alpha-DG to enter cells. In complementary screens, we profiled cells for absence of alpha-DG carbohydrate chains or biochemically related glycans. This revealed virus host factors and a suite of glycosylation units, including all known Walker-Warburg genes and five additional factors critical for the modification of alpha-DG. Our findings accentuate the complexity of this posttranslational feature and point out genes defective in dystroglycanopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919138/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jae, Lucas T -- Raaben, Matthijs -- Riemersma, Moniek -- van Beusekom, Ellen -- Blomen, Vincent A -- Velds, Arno -- Kerkhoven, Ron M -- Carette, Jan E -- Topaloglu, Haluk -- Meinecke, Peter -- Wessels, Marja W -- Lefeber, Dirk J -- Whelan, Sean P -- van Bokhoven, Hans -- Brummelkamp, Thijn R -- AI057159/AI/NIAID NIH HHS/ -- AI081842/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 26;340(6131):479-83. doi: 10.1126/science.1233675. Epub 2013 Mar 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23519211" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Line ; Dystroglycans/*metabolism ; Female ; Glycosylation ; Haploidy ; Host-Pathogen Interactions/*genetics ; Humans ; Infant ; Lassa Fever/*genetics/virology ; Lassa virus/*physiology ; Male ; Membrane Proteins/*genetics ; Molecular Sequence Data ; Mutation ; Pedigree ; Proteome/*metabolism ; *Virus Internalization ; Walker-Warburg Syndrome/*genetics
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    ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-05-21
    Description: Evidence for transcriptional feedback in circadian timekeeping is abundant, yet little is known about the mechanisms underlying translational control. We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in neurodegenerative disease, is a translational activator of the rate-limiting clock component PERIOD (PER) in Drosophila. ATX2 specifically interacted with TWENTY-FOUR (TYF), an activator of PER translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant ATX2 protein that does not associate with polyadenylate-binding protein (PABP) suppressed behavioral rhythms and decreased abundance of PER. Although ATX2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered TYF and disrupted the association between TYF and PABP. Thus, ATX2 coordinates an active translation complex important for PER expression and circadian rhythms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, Chunghun -- Allada, Ravi -- R01NS059042/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2013 May 17;340(6134):875-9. doi: 10.1126/science.1234785.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23687047" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxins ; Cell Line ; *Circadian Rhythm ; Drosophila Proteins/*biosynthesis/genetics/metabolism ; Drosophila melanogaster/metabolism/*physiology ; Mutation ; Nerve Tissue Proteins/genetics/*metabolism ; Period Circadian Proteins/*biosynthesis ; Poly(A)-Binding Proteins/metabolism ; Protein Biosynthesis ; RNA Interference
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    A long noncoding RNA mediates both activation and repression of immune response genes (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-08-03
    Description: An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carpenter, Susan -- Aiello, Daniel -- Atianand, Maninjay K -- Ricci, Emiliano P -- Gandhi, Pallavi -- Hall, Lisa L -- Byron, Meg -- Monks, Brian -- Henry-Bezy, Meabh -- Lawrence, Jeanne B -- O'Neill, Luke A J -- Moore, Melissa J -- Caffrey, Daniel R -- Fitzgerald, Katherine A -- AI067497/AI/NIAID NIH HHS/ -- GM053234/GM/NIGMS NIH HHS/ -- R01 AI067497/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Aug 16;341(6147):789-92. doi: 10.1126/science.1240925. Epub 2013 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23907535" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Nucleus/metabolism ; Cyclooxygenase 2/genetics ; Cytokines/genetics/metabolism ; Cytosol/metabolism ; *Gene Expression Regulation ; Heterogeneous-Nuclear Ribonucleoproteins/metabolism ; Immunity, Innate/*genetics ; Inflammation/*genetics ; Macrophage Activation ; Macrophages/*immunology/*metabolism ; Mice ; Models, Immunological ; RNA Interference ; RNA, Long Noncoding/*genetics/metabolism ; Toll-Like Receptors/genetics/metabolism ; Transcription Factors/genetics/metabolism ; Transcription, Genetic ; Transcriptional Activation
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    2013 Runners-Up. Human cloning at last (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-12-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉New York, N.Y. -- Science. 2013 Dec 20;342(6165):1436. doi: 10.1126/science.342.6165.1436-a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24357287" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Separation ; Cloning, Organism/*methods ; Female ; Humans ; *Induced Pluripotent Stem Cells ; Nuclear Transfer Techniques ; Pregnancy ; *Research Embryo Creation ; Surrogate Mothers
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    PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-04-27
    Description: Senescent and damaged mitochondria undergo selective mitophagic elimination through mechanisms requiring two Parkinson's disease factors, the mitochondrial kinase PINK1 (PTEN-induced putative kinase protein 1; PTEN is phosphatase and tensin homolog) and the cytosolic ubiquitin ligase Parkin. The nature of the PINK-Parkin interaction and the identity of key factors directing Parkin to damaged mitochondria are unknown. We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. Parkin bound to Mfn2 in a PINK1-dependent manner; PINK1 phosphorylated Mfn2 and promoted its Parkin-mediated ubiqitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of Parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in Parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774525/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Yun -- Dorn, Gerald W 2nd -- R01 HL059888/HL/NHLBI NIH HHS/ -- R21 HL107276/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 26;340(6131):471-5. doi: 10.1126/science.1231031.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23620051" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autophagy ; Cardiomyopathies/enzymology ; Drosophila melanogaster ; Fibroblasts/ultrastructure ; GTP Phosphohydrolases/genetics/*metabolism ; HEK293 Cells ; Humans ; Mice ; Mice, Mutant Strains ; Mitochondria/enzymology ; Mitochondria, Heart/*enzymology ; Molecular Sequence Data ; Myocytes, Cardiac/*enzymology/ultrastructure ; Phosphorylation ; Protein Kinases/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; Ubiquitination
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    Interferon-epsilon protects the female reproductive tract from viral and bacterial infection (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-03-02
    Description: The innate immune system senses pathogens through pattern-recognition receptors (PRRs) that signal to induce effector cytokines, such as type I interferons (IFNs). We characterized IFN-epsilon as a type I IFN because it signaled via the Ifnar1 and Ifnar2 receptors to induce IFN-regulated genes. In contrast to other type I IFNs, IFN-epsilon was not induced by known PRR pathways; instead, IFN-epsilon was constitutively expressed by epithelial cells of the female reproductive tract (FRT) and was hormonally regulated. Ifn-epsilon-deficient mice had increased susceptibility to infection of the FRT by the common sexually transmitted infections (STIs) herpes simplex virus 2 and Chlamydia muridarum. Thus, IFN-epsilon is a potent antipathogen and immunoregulatory cytokine that may be important in combating STIs that represent a major global health and socioeconomic burden.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617553/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617553/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fung, Ka Yee -- Mangan, Niamh E -- Cumming, Helen -- Horvat, Jay C -- Mayall, Jemma R -- Stifter, Sebastian A -- De Weerd, Nicole -- Roisman, Laila C -- Rossjohn, Jamie -- Robertson, Sarah A -- Schjenken, John E -- Parker, Belinda -- Gargett, Caroline E -- Nguyen, Hong P T -- Carr, Daniel J -- Hansbro, Philip M -- Hertzog, Paul J -- R01 AI053108/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 1;339(6123):1088-92. doi: 10.1126/science.1233321.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23449591" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Chlamydia Infections/genetics/*immunology ; *Chlamydia muridarum ; Estrogens/administration & dosage/immunology ; Female ; HEK293 Cells ; Herpes Genitalis/genetics/*immunology ; *Herpesvirus 2, Human ; Humans ; Interferons/genetics/*immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Oligodeoxyribonucleotides/immunology ; Poly I-C/immunology ; Poly dA-dT/immunology ; Toll-Like Receptors/*immunology ; Uterus/immunology ; Vagina/*immunology/microbiology/virology
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    Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-08-10
    Description: Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-beta induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860819/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860819/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Daxing -- Wu, Jiaxi -- Wu, You-Tong -- Du, Fenghe -- Aroh, Chukwuemika -- Yan, Nan -- Sun, Lijun -- Chen, Zhijian J -- R01 AI093967/AI/NIAID NIH HHS/ -- R01 AI098569/AI/NIAID NIH HHS/ -- R01-AI093967/AI/NIAID NIH HHS/ -- R01-AI098569/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Aug 23;341(6148):903-6. doi: 10.1126/science.1240933. Epub 2013 Aug 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23929945" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Gene Knockdown Techniques ; HEK293 Cells ; HIV/drug effects/enzymology/*immunology ; HIV Infections/enzymology/*immunology/virology ; HIV Reverse Transcriptase/antagonists & inhibitors ; Humans ; *Immunity, Innate ; Interferon-beta/biosynthesis ; Membrane Proteins/metabolism ; Mice ; Nucleotidyltransferases/genetics/*metabolism ; Retroviridae/immunology ; Retroviridae Infections/enzymology/immunology/virology ; Reverse Transcriptase Inhibitors/pharmacology
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    Antiviral RNA interference in mammalian cells (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-10-12
    Description: In antiviral RNA interference (RNAi), the DICER enzyme processes virus-derived double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that guide ARGONAUTE proteins to silence complementary viral RNA. As a counterdefense, viruses deploy viral suppressors of RNAi (VSRs). Well-established in plants and invertebrates, the existence of antiviral RNAi remains unknown in mammals. Here, we show that undifferentiated mouse cells infected with encephalomyocarditis virus (EMCV) or Nodamura virus (NoV) accumulate ~22-nucleotide RNAs with all the signature features of siRNAs. These derive from viral dsRNA replication intermediates, incorporate into AGO2, are eliminated in Dicer knockout cells, and decrease in abundance upon cell differentiation. Furthermore, genetically ablating a NoV-encoded VSR that antagonizes DICER during authentic infections reduces NoV accumulation, which is rescued in RNAi-deficient mouse cells. We conclude that antiviral RNAi operates in mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853215/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853215/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maillard, P V -- Ciaudo, C -- Marchais, A -- Li, Y -- Jay, F -- Ding, S W -- Voinnet, Olivier -- R01 AI052447/AI/NIAID NIH HHS/ -- R01 GM094396/GM/NIGMS NIH HHS/ -- RC1 GM091896/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Oct 11;342(6155):235-8. doi: 10.1126/science.1241930.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Swiss Federal Institute of Technology Zurich (ETH-Z), Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24115438" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/genetics/metabolism ; Base Sequence ; Cardiovirus Infections/*immunology ; Cell Line ; DEAD-box RNA Helicases/genetics/metabolism ; Encephalomyocarditis virus/genetics/*physiology ; Gene Knockout Techniques ; Mice ; Molecular Sequence Data ; Nodaviridae/genetics/*physiology ; RNA Interference/*immunology ; RNA Virus Infections/*immunology ; RNA, Double-Stranded/genetics/*immunology/metabolism ; RNA, Small Interfering/genetics/*immunology/metabolism ; RNA, Viral/genetics/*immunology/metabolism ; Ribonuclease III/genetics/metabolism ; Virus Replication
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    The human THAP9 gene encodes an active P-element DNA transposase (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-01-26
    Description: The human genome contains ~50 genes that were derived from transposable elements or transposons, and many are now integral components of cellular gene expression programs. The human THAP9 gene is related to the Drosophila P-element transposase. Here, we show that human THAP9 can mobilize Drosophila P-elements in both Drosophila and human cells. Chimeric proteins formed between the Drosophila P-element transposase N-terminal THAP DNA binding domain and the C-terminal regions of human THAP9 can also mobilize Drosophila P elements. Our results indicate that human THAP9 is an active DNA transposase that, although "domesticated," still retains the catalytic activity to mobilize P transposable elements across species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779457/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779457/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Majumdar, Sharmistha -- Singh, Anita -- Rio, Donald C -- R01 GM048862/GM/NIGMS NIH HHS/ -- R01 GM094890/GM/NIGMS NIH HHS/ -- R01 GM097352/GM/NIGMS NIH HHS/ -- R01 GM104385/GM/NIGMS NIH HHS/ -- R01GM094890/GM/NIGMS NIH HHS/ -- R01GM104385/GM/NIGMS NIH HHS/ -- R01GM48862/GM/NIGMS NIH HHS/ -- R01GM61987/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jan 25;339(6118):446-8. doi: 10.1126/science.1231789.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3204, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23349291" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; *DNA Transposable Elements ; Drosophila/genetics ; Genome, Human ; HEK293 Cells ; Humans ; Molecular Sequence Data ; Recombinant Fusion Proteins/metabolism ; Sequence Analysis, DNA ; Transfection ; Transposases/chemistry/*genetics/*metabolism
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    Tunable signal processing through modular control of transcription factor translocation (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-01-26
    Description: Signaling pathways can induce different dynamics of transcription factor (TF) activation. We explored how TFs process signaling inputs to generate diverse dynamic responses. The budding yeast general stress-responsive TF Msn2 acted as a tunable signal processor that could track, filter, or integrate signals in an input-dependent manner. This tunable signal processing appears to originate from dual regulation of both nuclear import and export by phosphorylation, as mutants with one form of regulation sustained only one signal-processing function. Versatile signal processing by Msn2 is crucial for generating distinct dynamic responses to different natural stresses. Our findings reveal how complex signal-processing functions are integrated into a single molecule and provide a guide for the design of TFs with "programmable" signal-processing functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746486/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746486/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hao, Nan -- Budnik, Bogdan A -- Gunawardena, Jeremy -- O'Shea, Erin K -- R01 GM081578/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jan 25;339(6118):460-4. doi: 10.1126/science.1227299.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University Faculty of Arts and Sciences Center for Systems Biology, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23349292" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Cell Nucleus/*metabolism ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/genetics/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/*metabolism ; Models, Biological ; Nuclear Export Signals ; Nuclear Localization Signals ; Osmotic Pressure ; Oxidative Stress ; Phosphorylation ; Proteins/pharmacology ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; *Signal Transduction ; Stress, Physiological ; Transcription Factors/*metabolism
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    A secreted PTEN phosphatase that enters cells to alter signaling and survival (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-06-08
    Description: Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935617/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935617/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hopkins, Benjamin D -- Fine, Barry -- Steinbach, Nicole -- Dendy, Meaghan -- Rapp, Zachary -- Shaw, Jacquelyn -- Pappas, Kyrie -- Yu, Jennifer S -- Hodakoski, Cindy -- Mense, Sarah -- Klein, Joshua -- Pegno, Sarah -- Sulis, Maria-Luisa -- Goldstein, Hannah -- Amendolara, Benjamin -- Lei, Liang -- Maurer, Matthew -- Bruce, Jeffrey -- Canoll, Peter -- Hibshoosh, Hanina -- Parsons, Ramon -- 2T32 CA09503/CA/NCI NIH HHS/ -- CA082783/CA/NCI NIH HHS/ -- CA097403/CA/NCI NIH HHS/ -- P01 CA097403/CA/NCI NIH HHS/ -- R01 CA082783/CA/NCI NIH HHS/ -- R01 CA155117/CA/NCI NIH HHS/ -- R01 NS066955/NS/NINDS NIH HHS/ -- R01 NS073610/NS/NINDS NIH HHS/ -- R01NS066955/NS/NINDS NIH HHS/ -- T32 CA009503/CA/NCI NIH HHS/ -- T32 GM008224/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):399-402. doi: 10.1126/science.1234907. Epub 2013 Jun 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23744781" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line, Tumor ; *Cell Survival ; Embryonic Stem Cells ; Glioblastoma/drug therapy/metabolism/pathology ; HEK293 Cells ; Humans ; Mice ; Mice, Nude ; Molecular Sequence Data ; Mutation ; PTEN Phosphohydrolase/*chemistry/genetics/*metabolism/pharmacology ; Peptide Chain Initiation, Translational ; Phosphatidylinositol 3-Kinase/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics/metabolism ; *Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
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    Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-01-12
    Description: DNA double-strand breaks (DSBs) represent a threat to the genome because they can lead to the loss of genetic information and chromosome rearrangements. The DNA repair protein p53 binding protein 1 (53BP1) protects the genome by limiting nucleolytic processing of DSBs by a mechanism that requires its phosphorylation, but whether 53BP1 does so directly is not known. Here, we identify Rap1-interacting factor 1 (Rif1) as an ATM (ataxia-telangiectasia mutated) phosphorylation-dependent interactor of 53BP1 and show that absence of Rif1 results in 5'-3' DNA-end resection in mice. Consistent with enhanced DNA resection, Rif1 deficiency impairs DNA repair in the G(1) and S phases of the cell cycle, interferes with class switch recombination in B lymphocytes, and leads to accumulation of chromosome DSBs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815530/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815530/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Virgilio, Michela -- Callen, Elsa -- Yamane, Arito -- Zhang, Wenzhu -- Jankovic, Mila -- Gitlin, Alexander D -- Feldhahn, Niklas -- Resch, Wolfgang -- Oliveira, Thiago Y -- Chait, Brian T -- Nussenzweig, Andre -- Casellas, Rafael -- Robbiani, Davide F -- Nussenzweig, Michel C -- AI037526/AI/NIAID NIH HHS/ -- GM007739/GM/NIGMS NIH HHS/ -- GM103314/GM/NIGMS NIH HHS/ -- R01 AI037526/AI/NIAID NIH HHS/ -- RR00862/RR/NCRR NIH HHS/ -- RR022220/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 Feb 8;339(6120):711-5. doi: 10.1126/science.1230624. Epub 2013 Jan 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23306439" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; B-Lymphocytes/immunology/metabolism ; Cell Cycle Proteins/antagonists & inhibitors/metabolism ; Cells, Cultured ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA/*metabolism ; *DNA Breaks, Double-Stranded ; DNA Repair ; DNA-Binding Proteins/antagonists & inhibitors/*metabolism ; G1 Phase ; G2 Phase ; Genomic Instability ; *Immunoglobulin Class Switching ; Mice ; Phosphorylation ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; S Phase ; Telomere-Binding Proteins/*metabolism ; Tumor Suppressor Proteins/antagonists & inhibitors/metabolism
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    Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-05-25
    Description: The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system-related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haruki, Hirohito -- Pedersen, Miriam Gronlund -- Gorska, Katarzyna Irena -- Pojer, Florence -- Johnsson, Kai -- New York, N.Y. -- Science. 2013 May 24;340(6135):987-91. doi: 10.1126/science.1232972.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉EPFL, Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research in Chemical Biology, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23704574" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Hydroxytryptophan/biosynthesis ; Adult ; Alcohol Oxidoreductases/*antagonists & inhibitors/*chemistry ; Anti-Infective Agents/adverse effects/*pharmacology/therapeutic use ; Biopterin/*analogs & derivatives/biosynthesis ; Cell Line ; Central Nervous System/drug effects ; Crystallography, X-Ray ; Fibroblasts/drug effects/metabolism ; Humans ; Levodopa/biosynthesis ; NADP/chemistry ; Nausea/chemically induced ; Pneumonia, Pneumocystis/drug therapy ; Protein Conformation ; Structure-Activity Relationship ; Sulfamethoxazole/adverse effects/*pharmacology/therapeutic use ; Trimethoprim, Sulfamethoxazole Drug Combination/pharmacology/therapeutic use ; Vomiting/chemically induced
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    RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-beta-catenin signaling (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-02-16
    Description: Casein kinase 1 (CK1) members play key roles in numerous biological processes. They are considered "rogue" kinases, because their enzymatic activity appears unregulated. Contrary to this notion, we have identified the DEAD-box RNA helicase DDX3 as a regulator of the Wnt-beta-catenin network, where it acts as a regulatory subunit of CK1epsilon: In a Wnt-dependent manner, DDX3 binds CK1epsilon and directly stimulates its kinase activity, and promotes phosphorylation of the scaffold protein dishevelled. DDX3 is required for Wnt-beta-catenin signaling in mammalian cells and during Xenopus and Caenorhabditis elegans development. The results also suggest that the kinase-stimulatory function extends to other DDX and CK1 members, opening fresh perspectives for one of the longest-studied protein kinase families.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cruciat, Cristina-Maria -- Dolde, Christine -- de Groot, Reinoud E A -- Ohkawara, Bisei -- Reinhard, Carmen -- Korswagen, Hendrik C -- Niehrs, Christof -- New York, N.Y. -- Science. 2013 Mar 22;339(6126):1436-41. doi: 10.1126/science.1231499. Epub 2013 Feb 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23413191" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Caenorhabditis elegans/genetics/growth & development/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; Casein Kinase Iepsilon/chemistry/*metabolism ; DEAD-box RNA Helicases/chemistry/genetics/*metabolism ; HEK293 Cells ; Humans ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; RNA Helicases/chemistry/genetics/*metabolism ; Wnt Proteins/metabolism ; *Wnt Signaling Pathway ; Xenopus/embryology/genetics/metabolism ; Xenopus Proteins/chemistry/genetics/*metabolism ; beta Catenin/metabolism
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    Phosphorylation of Dishevelled by protein kinase RIPK4 regulates Wnt signaling (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-02-02
    Description: Receptor-interacting protein kinase 4 (RIPK4) is required for epidermal differentiation and is mutated in Bartsocas-Papas syndrome. RIPK4 binds to protein kinase C, but its signaling mechanisms are largely unknown. Ectopic RIPK4, but not catalytically inactive or Bartsocas-Papas RIPK4 mutants, induced accumulation of cytosolic beta-catenin and a transcriptional program similar to that caused by Wnt3a. In Xenopus embryos, Ripk4 synergized with coexpressed Xwnt8, whereas Ripk4 morpholinos or catalytic inactive Ripk4 antagonized Wnt signaling. RIPK4 interacted constitutively with the adaptor protein DVL2 and, after Wnt3a stimulation, with the co-receptor LRP6. Phosphorylation of DVL2 by RIPK4 favored canonical Wnt signaling. Wnt-dependent growth of xenografted human tumor cells was suppressed by RIPK4 knockdown, suggesting that RIPK4 overexpression may contribute to the growth of certain tumor types.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094295/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094295/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, XiaoDong -- McGann, James C -- Liu, Bob Y -- Hannoush, Rami N -- Lill, Jennie R -- Pham, Victoria -- Newton, Kim -- Kakunda, Michael -- Liu, Jinfeng -- Yu, Christine -- Hymowitz, Sarah G -- Hongo, Jo-Anne -- Wynshaw-Boris, Anthony -- Polakis, Paul -- Harland, Richard M -- Dixit, Vishva M -- R01 GM042341/GM/NIGMS NIH HHS/ -- R01 NS073159/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 22;339(6126):1441-5. doi: 10.1126/science.1232253. Epub 2013 Jan 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23371553" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*metabolism ; Animals ; Cell Line ; Cell Line, Tumor ; Cytosol/metabolism ; Female ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Low Density Lipoprotein Receptor-Related Protein-6/metabolism ; Neoplasm Transplantation ; Neoplasms/metabolism ; Ovarian Neoplasms/metabolism ; Phosphoproteins/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Transplantation, Heterologous ; *Wnt Signaling Pathway ; Wnt3A Protein/metabolism ; Xenopus Proteins/genetics/*metabolism ; Xenopus laevis/embryology/metabolism ; beta Catenin/metabolism
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    Functional lysine modification by an intrinsically reactive primary glycolytic metabolite (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-08-03
    Description: The posttranslational modification of proteins and their regulation by metabolites represent conserved mechanisms in biology. At the confluence of these two processes, we report that the primary glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) reacts with select lysine residues in proteins to form 3-phosphoglyceryl-lysine (pgK). This reaction, which does not require enzyme catalysis, but rather exploits the electrophilicity of 1,3-BPG, was found by proteomic profiling to be enriched on diverse classes of proteins and prominently in or around the active sites of glycolytic enzymes. pgK modifications inhibit glycolytic enzymes and, in cells exposed to high glucose, accumulate on these enzymes to create a potential feedback mechanism that contributes to the buildup and redirection of glycolytic intermediates to alternate biosynthetic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005992/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005992/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moellering, Raymond E -- Cravatt, Benjamin F -- CA087660/CA/NCI NIH HHS/ -- R37 CA087660/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2013 Aug 2;341(6145):549-53. doi: 10.1126/science.1238327.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA. rmoeller@scripps.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23908237" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Biomarkers, Tumor/chemistry/metabolism ; Catalysis ; Cell Line ; DNA-Binding Proteins/chemistry/metabolism ; Diphosphoglyceric Acids/*metabolism ; Glucose/metabolism ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/chemistry/metabolism ; Glycerophosphates/*metabolism ; *Glycolysis ; Humans ; Lysine/*analogs & derivatives/*metabolism ; Mice ; Molecular Sequence Data ; Phosphopyruvate Hydratase/chemistry/metabolism ; *Protein Processing, Post-Translational ; Proteins/chemistry/*metabolism ; Tumor Suppressor Proteins/chemistry/metabolism
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    The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-07-06
    Description: Many large noncoding RNAs (lncRNAs) regulate chromatin, but the mechanisms by which they localize to genomic targets remain unexplored. We investigated the localization mechanisms of the Xist lncRNA during X-chromosome inactivation (XCI), a paradigm of lncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the three-dimensional conformation of the X chromosome. Xist requires its silencing domain to spread across actively transcribed regions and thereby access the entire chromosome. These findings suggest a model in which Xist coats the X chromosome by searching in three dimensions, modifying chromosome structure, and spreading to newly accessible locations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778663/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778663/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Engreitz, Jesse M -- Pandya-Jones, Amy -- McDonel, Patrick -- Shishkin, Alexander -- Sirokman, Klara -- Surka, Christine -- Kadri, Sabah -- Xing, Jeffrey -- Goren, Alon -- Lander, Eric S -- Plath, Kathrin -- Guttman, Mitchell -- 1F32GM103139-01/GM/NIGMS NIH HHS/ -- DP5 OD012190/OD/NIH HHS/ -- DP5OD012190/OD/NIH HHS/ -- P01 GM099134/GM/NIGMS NIH HHS/ -- P01GM099134/GM/NIGMS NIH HHS/ -- P50HG006193/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2013 Aug 16;341(6147):1237973. doi: 10.1126/science.1237973. Epub 2013 Jul 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23828888" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Line ; Chromatin/chemistry/metabolism ; Female ; *Genome ; Male ; Mice ; Models, Genetic ; RNA, Long Noncoding/chemistry/*metabolism ; Transcription, Genetic ; X Chromosome/*metabolism/ultrastructure ; *X Chromosome Inactivation
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    H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-05-04
    Description: In the past, avian influenza viruses have crossed species barriers to trigger human pandemics by reassorting with mammal-infective viruses in intermediate livestock hosts. H5N1 viruses are able to infect pigs, and some of them have affinity for the mammalian type alpha-2,6-linked sialic acid airway receptor. Using reverse genetics, we systematically created 127 reassortant viruses between a duck isolate of H5N1, specifically retaining its hemagglutinin (HA) gene throughout, and a highly transmissible, human-infective H1N1 virus. We tested the virulence of the reassortants in mice as a correlate for virulence in humans and tested transmissibility in guinea pigs, which have both avian and mammalian types of airway receptor. Transmission studies showed that the H1N1 virus genes encoding acidic polymerase and nonstructural protein made the H5N1 virus transmissible by respiratory droplet between guinea pigs without killing them. Further experiments implicated other H1N1 genes in the enhancement of mammal-to-mammal transmission, including those that encode nucleoprotein, neuraminidase, and matrix, as well as mutations in H5 HA that improve affinity for humanlike airway receptors. Hence, avian H5N1 subtype viruses do have the potential to acquire mammalian transmissibility by reassortment in current agricultural scenarios.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Ying -- Zhang, Qianyi -- Kong, Huihui -- Jiang, Yongping -- Gao, Yuwei -- Deng, Guohua -- Shi, Jianzhong -- Tian, Guobin -- Liu, Liling -- Liu, Jinxiong -- Guan, Yuntao -- Bu, Zhigao -- Chen, Hualan -- New York, N.Y. -- Science. 2013 Jun 21;340(6139):1459-63. doi: 10.1126/science.1229455. Epub 2013 May 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23641061" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Brain/virology ; Cell Line ; Ferrets ; Genes, Viral ; Guinea Pigs ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry/genetics ; Humans ; Influenza A Virus, H1N1 Subtype/*genetics/pathogenicity ; Influenza A Virus, H5N1 Subtype/*genetics/pathogenicity ; Influenza, Human/transmission/virology ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Mutation ; Orthomyxoviridae Infections/*transmission/*virology ; Reassortant Viruses/*genetics/*pathogenicity ; Receptors, Cell Surface/metabolism ; Receptors, Virus/metabolism ; Respiratory System/*virology ; Reverse Genetics ; Ribonucleoproteins/metabolism ; Viral Proteins/genetics/metabolism ; Virus Replication
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    Activation of the yeast Hippo pathway by phosphorylation-dependent assembly of signaling complexes (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-04-13
    Description: Scaffold-assisted signaling cascades guide cellular decision-making. In budding yeast, one such signal transduction pathway called the mitotic exit network (MEN) governs the transition from mitosis to the G1 phase of the cell cycle. The MEN is conserved and in metazoans is known as the Hippo tumor-suppressor pathway. We found that signaling through the MEN kinase cascade was mediated by an unusual two-step process. The MEN kinase Cdc15 first phosphorylated the scaffold Nud1. This created a phospho-docking site on Nud1, to which the effector kinase complex Dbf2-Mob1 bound through a phosphoserine-threonine binding domain, in order to be activated by Cdc15. This mechanism of pathway activation has implications for signal transmission through other kinase cascades and might represent a general principle in scaffold-assisted signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884217/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rock, Jeremy M -- Lim, Daniel -- Stach, Lasse -- Ogrodowicz, Roksana W -- Keck, Jamie M -- Jones, Michele H -- Wong, Catherine C L -- Yates, John R 3rd -- Winey, Mark -- Smerdon, Stephen J -- Yaffe, Michael B -- Amon, Angelika -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- F32 GM086038/GM/NIGMS NIH HHS/ -- GM056800/GM/NIGMS NIH HHS/ -- GM51312/GM/NIGMS NIH HHS/ -- MC_U117584228/Medical Research Council/United Kingdom -- P30 CA014051/CA/NCI NIH HHS/ -- P41 GM103533/GM/NIGMS NIH HHS/ -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 ES015339/ES/NIEHS NIH HHS/ -- R01 GM051312/GM/NIGMS NIH HHS/ -- R01 GM056800/GM/NIGMS NIH HHS/ -- R29 GM056800/GM/NIGMS NIH HHS/ -- U117584228/Medical Research Council/United Kingdom -- U54 CA112967/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 May 17;340(6134):871-5. doi: 10.1126/science.1235822. Epub 2013 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23579499" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Cell Cycle Proteins/chemistry/*metabolism ; Deoxyribonucleases/chemistry/*metabolism ; Enzyme Activation ; GTP-Binding Proteins/*metabolism ; *Mitosis ; Phosphoproteins/chemistry/*metabolism ; Phosphorylation ; Protein Conformation ; Protein-Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/cytology/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Signal Transduction ; tRNA Methyltransferases/chemistry/*metabolism
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    RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-10-12
    Description: Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles telomere loops (T loops) and suppresses telomere fragility to maintain the integrity of chromosome ends. We established that RTEL1 also associates with the replisome through binding to proliferating cell nuclear antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction (PIP mutant) exhibited accelerated senescence, replication fork instability, reduced replication fork extension rates, and increased origin usage. Although T-loop disassembly at telomeres was unaffected in the mutant cells, telomere replication was compromised, leading to fragile sites at telomeres. RTEL1-PIP mutant mice were viable, but loss of the RTEL1-PCNA interaction accelerated the onset of tumorigenesis in p53-deficient mice. We propose that RTEL1 plays a critical role in both telomere and genome-wide replication, which is crucial for genetic stability and tumor avoidance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vannier, Jean-Baptiste -- Sandhu, Sumit -- Petalcorin, Mark I R -- Wu, Xiaoli -- Nabi, Zinnatun -- Ding, Hao -- Boulton, Simon J -- Canadian Institutes of Health Research/Canada -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2013 Oct 11;342(6155):239-42. doi: 10.1126/science.1241779.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24115439" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Transformation, Neoplastic/genetics/*metabolism ; DNA Helicases/genetics/*metabolism ; *DNA Replication ; Genome/*genetics ; Mice ; Mice, Mutant Strains ; Proliferating Cell Nuclear Antigen/*metabolism ; Telomere/*genetics ; Tumor Suppressor Protein p53/genetics
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    Crosstalk between microtubule attachment complexes ensures accurate chromosome segregation (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-11-16
    Description: The microtubule-based mitotic spindle segregates chromosomes during cell division. During chromosome segregation, the centromeric regions of chromosomes build kinetochores that establish end-coupled attachments to spindle microtubules. Here, we used the Caenorhabditis elegans embryo as a model system to examine the crosstalk between two kinetochore protein complexes implicated in temporally distinct stages of attachment formation. The kinetochore dynein module, which mediates initial lateral microtubule capture, inhibited microtubule binding by the Ndc80 complex, which ultimately forms the end-coupled attachments that segregate chromosomes. The kinetochore dynein module directly regulated Ndc80, independently of phosphorylation by Aurora B kinase, and this regulation was required for accurate segregation. Thus, the conversion from initial dynein-mediated, lateral attachments to correctly oriented, Ndc80-mediated end-coupled attachments is actively controlled.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885540/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheerambathur, Dhanya K -- Gassmann, Reto -- Cook, Brian -- Oegema, Karen -- Desai, Arshad -- GM074215/GM/NIGMS NIH HHS/ -- R01 GM074215/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1239-42. doi: 10.1126/science.1246232. Epub 2013 Nov 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24231804" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Aurora Kinase B/metabolism ; Caenorhabditis elegans/embryology ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Cell Cycle Proteins/chemistry/genetics/metabolism ; *Chromosome Segregation ; Dyneins/*metabolism ; Embryo, Nonmammalian/metabolism ; Kinetochores/*metabolism ; Microtubule-Associated Proteins/genetics/*metabolism ; Microtubules/*metabolism ; Multiprotein Complexes/metabolism ; Phenotype ; Phosphorylation ; Protein Binding ; Spindle Apparatus/*metabolism ; Transgenes
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    Actin-propelled invasive membrane protrusions promote fusogenic protein engagement during cell-cell fusion (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-03-09
    Description: Cell-cell fusion is critical for the conception, development, and physiology of multicellular organisms. Although cellular fusogenic proteins and the actin cytoskeleton are implicated in cell-cell fusion, it remains unclear whether and how they coordinate to promote plasma membrane fusion. We reconstituted a high-efficiency, inducible cell fusion culture system in the normally nonfusing Drosophila S2R+ cells. Both fusogenic proteins and actin cytoskeletal rearrangements were necessary for cell fusion, and in combination they were sufficient to impart fusion competence. Localized actin polymerization triggered by specific cell-cell or cell-matrix adhesion molecules propelled invasive cell membrane protrusions, which in turn promoted fusogenic protein engagement and plasma membrane fusion. This de novo cell fusion culture system reveals a general role for actin-propelled invasive membrane protrusions in driving fusogenic protein engagement during cell-cell fusion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631436/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631436/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shilagardi, Khurts -- Li, Shuo -- Luo, Fengbao -- Marikar, Faiz -- Duan, Rui -- Jin, Peng -- Kim, Ji Hoon -- Murnen, Katherine -- Chen, Elizabeth H -- R01 GM098816/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 19;340(6130):359-63. doi: 10.1126/science.1234781. Epub 2013 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23470732" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*metabolism ; Animals ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Cell Adhesion Molecules/genetics/*metabolism ; *Cell Communication ; Cell Culture Techniques ; *Cell Fusion ; Cell Line ; Cell Surface Extensions/metabolism/physiology ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/cytology ; Immunoglobulins/genetics/metabolism ; Membrane Glycoproteins/genetics/*metabolism ; Membrane Proteins/genetics/metabolism ; Muscle Proteins/genetics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-07-28
    Description: The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seong A -- Pacold, Michael E -- Cervantes, Christopher L -- Lim, Daniel -- Lou, Hua Jane -- Ottina, Kathleen -- Gray, Nathanael S -- Turk, Benjamin E -- Yaffe, Michael B -- Sabatini, David M -- AI047389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- GM59281/GM/NIGMS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):1236566. doi: 10.1126/science.1236566.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888043" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acids/metabolism ; Animals ; Cell Line ; Culture Media ; Humans ; Mice ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Peptides/chemistry/*metabolism ; Phosphorylation ; Proteins/antagonists & inhibitors/*chemistry/*metabolism ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism
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    Cell biology. Does cloning produce better embryonic stem cells? (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-06-22
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gura, Trisha -- New York, N.Y. -- Science. 2013 Jun 21;340(6139):1390. doi: 10.1126/science.340.6139.1390.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23788774" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; *Cloning, Organism ; DNA Methylation ; *Embryonic Stem Cells/physiology ; Humans ; Induced Pluripotent Stem Cells/physiology ; Nuclear Transfer Techniques ; *Stem Cell Research
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    Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-07-28
    Description: Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bassi, C -- Ho, J -- Srikumar, T -- Dowling, R J O -- Gorrini, C -- Miller, S J -- Mak, T W -- Neel, B G -- Raught, B -- Stambolic, V -- R37 CA49152/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):395-9. doi: 10.1126/science.1236188.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888040" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Aminopyridines/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Nucleus/*enzymology/metabolism ; Cisplatin/pharmacology ; DNA Breaks, Double-Stranded ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Doxorubicin/pharmacology ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Morpholines/pharmacology ; Neoplasm Transplantation ; PTEN Phosphohydrolase/genetics/*metabolism ; Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; Sumoylation ; Transplantation, Heterologous ; Tumor Suppressor Proteins/metabolism
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    Wnt stabilization of beta-catenin reveals principles for morphogen receptor-scaffold assemblies (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-04-13
    Description: Wnt signaling stabilizes beta-catenin through the LRP6 receptor signaling complex, which antagonizes the beta-catenin destruction complex. The Axin scaffold and associated glycogen synthase kinase-3 (GSK3) have central roles in both assemblies, but the transduction mechanism from the receptor to the destruction complex is contentious. We report that Wnt signaling is governed by phosphorylation regulation of the Axin scaffolding function. Phosphorylation by GSK3 kept Axin activated ("open") for beta-catenin interaction and poised for engagement of LRP6. Formation of the Wnt-induced LRP6-Axin signaling complex promoted Axin dephosphorylation by protein phosphatase-1 and inactivated ("closed") Axin through an intramolecular interaction. Inactivation of Axin diminished its association with beta-catenin and LRP6, thereby inhibiting beta-catenin phosphorylation and enabling activated LRP6 to selectively recruit active Axin for inactivation reiteratively. Our findings reveal mechanisms for scaffold regulation and morphogen signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788643/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788643/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Sung-Eun -- Huang, He -- Zhao, Ming -- Zhang, Xinjun -- Zhang, Aili -- Semonov, Mikhail V -- MacDonald, Bryan T -- Zhang, Xiaowu -- Garcia Abreu, Jose -- Peng, Leilei -- He, Xi -- P30 HD-18655/HD/NICHD NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- R00EB008737/EB/NIBIB NIH HHS/ -- R01 AR060359/AR/NIAMS NIH HHS/ -- R01 GM074241/GM/NIGMS NIH HHS/ -- R01EB015481/EB/NIBIB NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 May 17;340(6134):867-70. doi: 10.1126/science.1232389. Epub 2013 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉F. M. Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23579495" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Axin Protein/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Low Density Lipoprotein Receptor-Related Protein-6/*metabolism ; Molecular Sequence Data ; Phosphorylation ; Protein Stability ; Signal Transduction ; Wnt Proteins/*metabolism ; Xenopus ; beta Catenin/*metabolism
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    Biomedicine. Review of cloning paper prompts questions (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-06-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Couzin-Frankel, Jennifer -- Vogel, Gretchen -- New York, N.Y. -- Science. 2013 May 31;340(6136):1026-7. doi: 10.1126/science.340.6136.1026.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23723209" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Culture Techniques ; Cell Line ; *Cloning, Organism ; Embryonic Stem Cells/*cytology ; Humans ; Oregon ; Peer Review, Research/*standards ; Scientific Misconduct ; Skin/*cytology ; Software ; *Stem Cell Research
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-08-10
    Description: Phosphorylated O-mannosyl trisaccharide [N-acetylgalactosamine-beta3-N-acetylglucosamine-beta4-(phosphate-6-)mannose] is required for dystroglycan to bind laminin-G domain-containing extracellular proteins with high affinity in muscle and brain. However, the enzymes that produce this structure have not been fully elucidated. We found that glycosyltransferase-like domain-containing 2 (GTDC2) is a protein O-linked mannose beta 1,4-N-acetylglucosaminyltransferase whose product could be extended by beta 1,3-N-acetylgalactosaminyltransferase2 (B3GALNT2) to form the O-mannosyl trisaccharide. Furthermore, we identified SGK196 as an atypical kinase that phosphorylated the 6-position of O-mannose, specifically after the mannose had been modified by both GTDC2 and B3GALNT2. These findings suggest how mutations in GTDC2, B3GALNT2, and SGK196 disrupt dystroglycan receptor function and lead to congenital muscular dystrophy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848040/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshida-Moriguchi, Takako -- Willer, Tobias -- Anderson, Mary E -- Venzke, David -- Whyte, Tamieka -- Muntoni, Francesco -- Lee, Hane -- Nelson, Stanley F -- Yu, Liping -- Campbell, Kevin P -- 1U54NS053672/NS/NINDS NIH HHS/ -- MR/K000608/1/Medical Research Council/United Kingdom -- P30 AR057230/AR/NIAMS NIH HHS/ -- R01 HL079031/HL/NHLBI NIH HHS/ -- U54 NS053672/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Aug 23;341(6148):896-9. doi: 10.1126/science.1239951. Epub 2013 Aug 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23929950" target="_blank"〉PubMed〈/a〉
    Keywords: Dystroglycans/*metabolism ; Glycosylation ; Glycosyltransferases/genetics/metabolism ; HEK293 Cells ; Humans ; N-Acetylgalactosaminyltransferases/genetics/metabolism ; N-Acetylglucosaminyltransferases/genetics/metabolism ; Phosphorylation ; Protein Kinases/genetics/*metabolism ; *Protein Processing, Post-Translational ; Trisaccharides/metabolism
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    Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-07-13
    Description: A classic feature of apoptotic cells is the cell-surface exposure of phosphatidylserine (PtdSer) as an "eat me" signal for engulfment. We show that the Xk-family protein Xkr8 mediates PtdSer exposure in response to apoptotic stimuli. Mouse Xkr8(-/-) cells or human cancer cells in which Xkr8 expression was repressed by hypermethylation failed to expose PtdSer during apoptosis and were inefficiently engulfed by phagocytes. Xkr8 was activated directly by caspases and required a caspase-3 cleavage site for its function. CED-8, the only Caenorhabditis elegans Xk-family homolog, also promoted apoptotic PtdSer exposure and cell-corpse engulfment. Thus, Xk-family proteins have evolutionarily conserved roles in promoting the phagocytosis of dying cells by altering the phospholipid distribution in the plasma membrane.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suzuki, Jun -- Denning, Daniel P -- Imanishi, Eiichi -- Horvitz, H Robert -- Nagata, Shigekazu -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):403-6. doi: 10.1126/science.1236758. Epub 2013 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23845944" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Apoptosis ; Apoptosis Regulatory Proteins/chemistry/genetics/*metabolism ; Caenorhabditis elegans Proteins/*metabolism ; Calcium/metabolism ; Caspases/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Membrane/*metabolism ; CpG Islands ; Humans ; Macrophages/physiology ; Membrane Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Knockout ; Molecular Sequence Data ; *Phagocytosis ; Phosphatidylserines/*metabolism ; Recombinant Fusion Proteins/metabolism
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    Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-12-07
    Description: The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8(+) T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4(+) and CD8(+) T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048998/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Khan, Nooruddin -- Nakaya, Helder I -- Li, Shuzhao -- Loebbermann, Jens -- Maddur, Mohan S -- Park, Youngja -- Jones, Dean P -- Chappert, Pascal -- Davoust, Jean -- Weiss, David S -- Virgin, Herbert W -- Ron, David -- Pulendran, Bali -- 084812/Wellcome Trust/United Kingdom -- 084812/Z/08/Z/Wellcome Trust/United Kingdom -- N01 AI50019/AI/NIAID NIH HHS/ -- N01 AI50025/AI/NIAID NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- R56 AI048638/AI/NIAID NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- U54 AI057157/AI/NIAID NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):313-7. doi: 10.1126/science.1246829. Epub 2013 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24310610" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Antigen Presentation ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line ; Cricetinae ; Dendritic Cells/enzymology/*immunology ; Enzyme Activation ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microtubule-Associated Proteins/genetics ; Protein-Serine-Threonine Kinases/*biosynthesis/genetics ; Yellow Fever Vaccine/*immunology
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    The ancient drug salicylate directly activates AMP-activated protein kinase (2012)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2012-04-21
    Description: Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399766/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hawley, Simon A -- Fullerton, Morgan D -- Ross, Fiona A -- Schertzer, Jonathan D -- Chevtzoff, Cyrille -- Walker, Katherine J -- Peggie, Mark W -- Zibrova, Darya -- Green, Kevin A -- Mustard, Kirsty J -- Kemp, Bruce E -- Sakamoto, Kei -- Steinberg, Gregory R -- Hardie, D Grahame -- 080982/Wellcome Trust/United Kingdom -- 097726/Wellcome Trust/United Kingdom -- MC_U127088492/Medical Research Council/United Kingdom -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2012 May 18;336(6083):918-22. doi: 10.1126/science.1215327. Epub 2012 Apr 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22517326" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/genetics/*metabolism ; Amino Acid Substitution ; Animals ; Aspirin/pharmacology ; Binding Sites ; Carbohydrate Metabolism/drug effects ; Cell Line ; Enzyme Activation ; Enzyme Activators/pharmacology ; HEK293 Cells ; Humans ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Mice ; Mice, Knockout ; Mutation ; Oxygen Consumption/drug effects ; Phosphorylation ; Pyrones/pharmacology ; Rats ; Salicylates/blood/*metabolism/*pharmacology ; Thiophenes/pharmacology
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    Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-03-31
    Description: Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324089/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324089/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lamming, Dudley W -- Ye, Lan -- Katajisto, Pekka -- Goncalves, Marcus D -- Saitoh, Maki -- Stevens, Deanna M -- Davis, James G -- Salmon, Adam B -- Richardson, Arlan -- Ahima, Rexford S -- Guertin, David A -- Sabatini, David M -- Baur, Joseph A -- 1F32AG032833-01A1/AG/NIA NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- F32 AG032833/AG/NIA NIH HHS/ -- P30DK19525/DK/NIDDK NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Mar 30;335(6076):1638-43. doi: 10.1126/science.1215135.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22461615" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/metabolism ; Animals ; Carrier Proteins/genetics/metabolism ; Female ; Gluconeogenesis ; Glucose/metabolism ; Glucose Clamp Technique ; Homeostasis ; Insulin/administration & dosage/blood ; *Insulin Resistance ; Liver/metabolism ; *Longevity ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes ; Muscle, Skeletal/metabolism ; Phosphorylation ; Proteins/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/genetics/metabolism
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 87
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    Secreted kinase phosphorylates extracellular proteins that regulate biomineralization (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-05-15
    Description: Protein phosphorylation is a fundamental mechanism regulating nearly every aspect of cellular life. Several secreted proteins are phosphorylated, but the kinases responsible are unknown. We identified a family of atypical protein kinases that localize within the Golgi apparatus and are secreted. Fam20C appears to be the Golgi casein kinase that phosphorylates secretory pathway proteins within S-x-E motifs. Fam20C phosphorylates the caseins and several secreted proteins implicated in biomineralization, including the small integrin-binding ligand, N-linked glycoproteins (SIBLINGs). Consequently, mutations in Fam20C cause an osteosclerotic bone dysplasia in humans known as Raine syndrome. Fam20C is thus a protein kinase dedicated to the phosphorylation of extracellular proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754843/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754843/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tagliabracci, Vincent S -- Engel, James L -- Wen, Jianzhong -- Wiley, Sandra E -- Worby, Carolyn A -- Kinch, Lisa N -- Xiao, Junyu -- Grishin, Nick V -- Dixon, Jack E -- DK018024-37/DK/NIDDK NIH HHS/ -- DK018849-36/DK/NIDDK NIH HHS/ -- GM094575/GM/NIGMS NIH HHS/ -- R01 DK018849/DK/NIDDK NIH HHS/ -- R37 DK018024/DK/NIDDK NIH HHS/ -- T32 CA009523/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Jun 1;336(6085):1150-3. doi: 10.1126/science.1217817. Epub 2012 May 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0721, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22582013" target="_blank"〉PubMed〈/a〉
    Keywords: Abnormalities, Multiple/genetics/metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Calcification, Physiologic ; Casein Kinase I ; Casein Kinases/metabolism ; Caseins/*metabolism ; Cattle ; Cell Line, Tumor ; Cleft Palate/genetics/metabolism ; Exophthalmos/genetics/metabolism ; Extracellular Matrix Proteins/chemistry/genetics/*metabolism/secretion ; Glycoproteins/metabolism ; Golgi Apparatus/*enzymology ; HEK293 Cells ; HeLa Cells ; Humans ; Microcephaly/genetics/metabolism ; Milk/enzymology ; Molecular Sequence Data ; Mutation ; Osteopontin ; Osteosclerosis/genetics/metabolism ; Phosphorylation ; Protein Sorting Signals ; Recombinant Fusion Proteins/chemistry/metabolism/secretion ; *Secretory Pathway ; Substrate Specificity
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 88
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    Kinetic responses of beta-catenin specify the sites of Wnt control (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-11-10
    Description: Despite more than 30 years of work on the Wnt signaling pathway, the basic mechanism of how the extracellular Wnt signal increases the intracellular concentration of beta-catenin is still contentious. Circumventing much of the detailed biochemistry, we used basic principles of chemical kinetics coupled with quantitative measurements to define the reactions on beta-catenin directly affected by the Wnt signal. We conclude that the core signal transduction mechanism is relatively simple, with only two regulated phosphorylation steps. Their partial inhibition gives rise to the full dynamics of the response and subsequently maintains a steady state in which the concentration of beta-catenin is increased.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hernandez, Ana R -- Klein, Allon M -- Kirschner, Marc W -- New York, N.Y. -- Science. 2012 Dec 7;338(6112):1337-40. doi: 10.1126/science.1228734. Epub 2012 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23138978" target="_blank"〉PubMed〈/a〉
    Keywords: Casein Kinase I/chemistry/metabolism ; Cell Line, Tumor ; Cysteine Proteinase Inhibitors/pharmacology ; Glycogen Synthase Kinase 3/metabolism ; HEK293 Cells ; Humans ; Kinetics ; Leupeptins/pharmacology ; Phosphorylation ; *Signal Transduction ; Wnt Proteins/*metabolism ; Wnt3A Protein/metabolism ; beta Catenin/*metabolism
    Print ISSN: 0036-8075
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  • 89
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    Erasure of a spinal memory trace of pain by a brief, high-dose opioid administration (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-01-17
    Description: Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. mu-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca(2+)-dependent signaling and normalization of the phosphorylation state of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Drdla-Schutting, Ruth -- Benrath, Justus -- Wunderbaldinger, Gabriele -- Sandkuhler, Jurgen -- New York, N.Y. -- Science. 2012 Jan 13;335(6065):235-8. doi: 10.1126/science.1211726.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246779" target="_blank"〉PubMed〈/a〉
    Keywords: Analgesics, Opioid/*administration & dosage ; Animals ; Calcium Signaling ; Evoked Potentials ; Hyperalgesia/chemically induced/drug therapy ; Long-Term Potentiation/*drug effects ; Male ; Naloxone/administration & dosage ; Nerve Fibers, Unmyelinated/*drug effects/physiology ; Nociceptive Pain/*drug therapy/physiopathology ; Phosphorylation ; Piperidines/*administration & dosage ; Protein Kinase C/antagonists & inhibitors/metabolism ; Protein Phosphatase 1/antagonists & inhibitors/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/metabolism ; Receptors, Opioid, mu/agonists/metabolism ; Sciatic Nerve/*drug effects/physiology ; Somatostatin/administration & dosage/analogs & derivatives ; Spinal Cord/physiology ; Synapses/*drug effects/physiology
    Print ISSN: 0036-8075
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  • 90
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    Sedlin controls the ER export of procollagen by regulating the Sar1 cycle (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-09-29
    Description: Newly synthesized proteins exit the endoplasmic reticulum (ER) via coat protein complex II (COPII) vesicles. Procollagen (PC), however, forms prefibrils that are too large to fit into typical COPII vesicles; PC thus needs large transport carriers, which we term megacarriers. TANGO1 assists PC packing, but its role in promoting the growth of megacarriers is not known. We found that TANGO1 recruited Sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT), and that Sedlin was required for the ER export of PC. Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils. This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471527/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471527/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venditti, Rossella -- Scanu, Tiziana -- Santoro, Michele -- Di Tullio, Giuseppe -- Spaar, Alexander -- Gaibisso, Renato -- Beznoussenko, Galina V -- Mironov, Alexander A -- Mironov, Alexander Jr -- Zelante, Leopoldo -- Piemontese, Maria Rosaria -- Notarangelo, Angelo -- Malhotra, Vivek -- Vertel, Barbara M -- Wilson, Cathal -- De Matteis, Maria Antonietta -- AR053696/AR/NIAMS NIH HHS/ -- GGP06166/Telethon/Italy -- GGP07075/Telethon/Italy -- GSP08002/Telethon/Italy -- GTF08001/Telethon/Italy -- New York, N.Y. -- Science. 2012 Sep 28;337(6102):1668-72.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Telethon Institute of Genetics and Medicine, Naples, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23019651" target="_blank"〉PubMed〈/a〉
    Keywords: Aryl Hydrocarbon Receptor Nuclear Translocator/*metabolism ; COP-Coated Vesicles/metabolism ; Cell Line ; Chondrogenesis/genetics ; Endoplasmic Reticulum/*metabolism ; Golgi Apparatus/metabolism ; Humans ; Membrane Transport Proteins/genetics/*metabolism ; Monomeric GTP-Binding Proteins/*metabolism ; Mutation ; Osteochondrodysplasias/genetics/metabolism ; Procollagen/*metabolism ; Protein Transport ; Transcription Factors/genetics/*metabolism
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    Chemistry. Algae under pressure and in hot water (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-11-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Savage, Phillip E -- New York, N.Y. -- Science. 2012 Nov 23;338(6110):1039-40. doi: 10.1126/science.1224310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Chemical Engineering Department, University of Michigan, Ann Arbor, MI 48109, USA. psavage@umich.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23180853" target="_blank"〉PubMed〈/a〉
    Keywords: *Biofuels ; Cell Culture Techniques ; Chemical Engineering ; Chlorophyta/*chemistry/growth & development ; *Hot Temperature ; *Hydrostatic Pressure ; *Water
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  • 92
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    GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-04-28
    Description: In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser(86), which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60(S86A) that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1(-/-) mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Shu-Yong -- Li, Terytty Yang -- Liu, Qing -- Zhang, Cixiong -- Li, Xiaotong -- Chen, Yan -- Zhang, Shi-Meng -- Lian, Guili -- Liu, Qi -- Ruan, Ka -- Wang, Zhen -- Zhang, Chen-Song -- Chien, Kun-Yi -- Wu, Jiawei -- Li, Qinxi -- Han, Jiahuai -- Lin, Sheng-Cai -- New York, N.Y. -- Science. 2012 Apr 27;336(6080):477-81. doi: 10.1126/science.1217032.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22539723" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Autophagy ; Cell Line ; Cell Line, Tumor ; Culture Media ; Culture Media, Serum-Free ; Glucose/metabolism ; Glycogen Synthase Kinase 3/genetics/*metabolism ; HEK293 Cells ; Histone Acetyltransferases/genetics/*metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Mice ; Phosphorylation ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Rats ; *Signal Transduction ; Trans-Activators/genetics/metabolism
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    Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE (2012)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2012-01-17
    Description: The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFalpha-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the endoplasmic reticulum. The failure of TACE to exit the endoplasmic reticulum in the absence of iRhom2 prevents the furin-mediated maturation and trafficking of TACE to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272371/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272371/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adrain, Colin -- Zettl, Markus -- Christova, Yonka -- Taylor, Neil -- Freeman, Matthew -- MC_U105178780/Medical Research Council/United Kingdom -- U.1051.01.009(78780)/Medical Research Council/United Kingdom -- U105178780/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2012 Jan 13;335(6065):225-8. doi: 10.1126/science.1214400.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246777" target="_blank"〉PubMed〈/a〉
    Keywords: ADAM Proteins/*metabolism ; Animals ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Cell Membrane/metabolism ; Endoplasmic Reticulum/metabolism ; Enzyme Activation ; Furin/metabolism ; Humans ; Lipopolysaccharides/immunology ; Macrophages/metabolism ; Mice ; Mice, Knockout ; Protein Binding ; Protein Transport ; *Signal Transduction ; Tumor Necrosis Factor-alpha/*metabolism
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  • 94
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    A DOC2 protein identified by mutational profiling is essential for apicomplexan parasite exocytosis (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-01-17
    Description: Exocytosis is essential to the lytic cycle of apicomplexan parasites and required for the pathogenesis of toxoplasmosis and malaria. DOC2 proteins recruit the membrane fusion machinery required for exocytosis in a Ca(2+)-dependent fashion. Here, the phenotype of a Toxoplasma gondii conditional mutant impaired in host cell invasion and egress was pinpointed to a defect in secretion of the micronemes, an apicomplexan-specific organelle that contains adhesion proteins. Whole-genome sequencing identified the etiological point mutation in TgDOC2.1. A conditional allele of the orthologous gene engineered into Plasmodium falciparum was also defective in microneme secretion. However, the major effect was on invasion, suggesting that microneme secretion is dispensable for Plasmodium egress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354045/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354045/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farrell, Andrew -- Thirugnanam, Sivasakthivel -- Lorestani, Alexander -- Dvorin, Jeffrey D -- Eidell, Keith P -- Ferguson, David J P -- Anderson-White, Brooke R -- Duraisingh, Manoj T -- Marth, Gabor T -- Gubbels, Marc-Jan -- AI057919/AI/NIAID NIH HHS/ -- AI081220/AI/NIAID NIH HHS/ -- AI087874/AI/NIAID NIH HHS/ -- AI088314/AI/NIAID NIH HHS/ -- HG004719/HG/NHGRI NIH HHS/ -- K08 AI087874/AI/NIAID NIH HHS/ -- K08 AI087874-02/AI/NIAID NIH HHS/ -- R01 AI057919/AI/NIAID NIH HHS/ -- R01 HG004719/HG/NHGRI NIH HHS/ -- R21 AI081220/AI/NIAID NIH HHS/ -- R21 AI088314/AI/NIAID NIH HHS/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2012 Jan 13;335(6065):218-21. doi: 10.1126/science.1210829.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246776" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Calcium/*metabolism ; Calcium-Binding Proteins/chemistry/genetics/*metabolism ; Cell Line ; *Exocytosis ; Genes, Protozoan ; Genetic Complementation Test ; Genome, Protozoan ; Humans ; Models, Molecular ; Molecular Sequence Data ; Movement ; Mutagenesis ; Organelles/*metabolism ; Plasmodium falciparum/genetics/growth & development/physiology ; Point Mutation ; Protein Structure, Tertiary ; Protozoan Proteins/chemistry/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism ; Toxoplasma/genetics/growth & development/*physiology/ultrastructure
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    An overlapping protein-coding region in influenza A virus segment 3 modulates the host response (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-06-30
    Description: Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame ("X-ORF"), accessed via ribosomal frameshifting. The frameshift product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T lymphocyte-signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552242/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jagger, B W -- Wise, H M -- Kash, J C -- Walters, K-A -- Wills, N M -- Xiao, Y-L -- Dunfee, R L -- Schwartzman, L M -- Ozinsky, A -- Bell, G L -- Dalton, R M -- Lo, A -- Efstathiou, S -- Atkins, J F -- Firth, A E -- Taubenberger, J K -- Digard, P -- 073126/Wellcome Trust/United Kingdom -- 088789/Wellcome Trust/United Kingdom -- G0700815/Medical Research Council/United Kingdom -- G0700815(82260)/Medical Research Council/United Kingdom -- G9800943/Medical Research Council/United Kingdom -- MR/J002232/1/Medical Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2012 Jul 13;337(6091):199-204. doi: 10.1126/science.1222213. Epub 2012 Jun 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22745253" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Cell Line ; Codon ; Conserved Sequence ; Female ; *Frameshifting, Ribosomal ; Gene Expression Regulation ; Genome, Viral ; HEK293 Cells ; Humans ; Influenza A Virus, H1N1 Subtype/*genetics/growth & development/pathogenicity ; Influenza A virus/*genetics/metabolism ; Lung/pathology/virology ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Mutation ; *Open Reading Frames ; Orthomyxoviridae Infections/genetics/immunology/pathology/*virology ; Protein Interaction Domains and Motifs ; Proteome ; RNA Replicase/chemistry/*genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Viral/genetics/metabolism ; Reassortant Viruses/genetics ; Repressor Proteins/chemistry/*genetics/*metabolism ; Viral Nonstructural Proteins/chemistry/*genetics/*metabolism ; Viral Proteins/biosynthesis/chemistry/*genetics/*metabolism ; Virus Replication
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-05-26
    Description: Metabolic reprogramming has been proposed to be a hallmark of cancer, yet a systematic characterization of the metabolic pathways active in transformed cells is currently lacking. Using mass spectrometry, we measured the consumption and release (CORE) profiles of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated these data with a preexisting atlas of gene expression. This analysis identified glycine consumption and expression of the mitochondrial glycine biosynthetic pathway as strongly correlated with rates of proliferation across cancer cells. Antagonizing glycine uptake and its mitochondrial biosynthesis preferentially impaired rapidly proliferating cells. Moreover, higher expression of this pathway was associated with greater mortality in breast cancer patients. Increased reliance on glycine may represent a metabolic vulnerability for selectively targeting rapid cancer cell proliferation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526189/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526189/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jain, Mohit -- Nilsson, Roland -- Sharma, Sonia -- Madhusudhan, Nikhil -- Kitami, Toshimori -- Souza, Amanda L -- Kafri, Ran -- Kirschner, Marc W -- Clish, Clary B -- Mootha, Vamsi K -- K08 HL107451/HL/NHLBI NIH HHS/ -- K08HL107451/HL/NHLBI NIH HHS/ -- R01 DK081457/DK/NIDDK NIH HHS/ -- R01 GM026875/GM/NIGMS NIH HHS/ -- R01DK081457/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2012 May 25;336(6084):1040-4. doi: 10.1126/science.1218595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22628656" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/genetics/metabolism/pathology ; Cell Cycle ; Cell Line ; Cell Line, Tumor ; *Cell Proliferation ; Cell Transformation, Neoplastic ; Chromatography, Liquid ; Culture Media ; Gene Expression ; Gene Expression Profiling ; Glycine/biosynthesis/*metabolism ; Humans ; Metabolic Networks and Pathways/genetics ; Metabolome ; Mitochondria/enzymology/metabolism ; Neoplasms/genetics/*metabolism/*pathology ; Purines/biosynthesis ; Tandem Mass Spectrometry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Chitin-induced dimerization activates a plant immune receptor (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-06-02
    Description: Pattern recognition receptors confer plant resistance to pathogen infection by recognizing the conserved pathogen-associated molecular patterns. The cell surface receptor chitin elicitor receptor kinase 1 of Arabidopsis (AtCERK1) directly binds chitin through its lysine motif (LysM)-containing ectodomain (AtCERK1-ECD) to activate immune responses. The crystal structure that we solved of an AtCERK1-ECD complexed with a chitin pentamer reveals that their interaction is primarily mediated by a LysM and three chitin residues. By acting as a bivalent ligand, a chitin octamer induces AtCERK1-ECD dimerization that is inhibited by shorter chitin oligomers. A mutation attenuating chitin-induced AtCERK1-ECD dimerization or formation of nonproductive AtCERK1 dimer by overexpression of AtCERK1-ECD compromises AtCERK1-mediated signaling in plant cells. Together, our data support the notion that chitin-induced AtCERK1 dimerization is critical for its activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Tingting -- Liu, Zixu -- Song, Chuanjun -- Hu, Yunfei -- Han, Zhifu -- She, Ji -- Fan, Fangfang -- Wang, Jiawei -- Jin, Changwen -- Chang, Junbiao -- Zhou, Jian-Min -- Chai, Jijie -- New York, N.Y. -- Science. 2012 Jun 1;336(6085):1160-4. doi: 10.1126/science.1218867.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22654057" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/chemistry/metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Arabidopsis/immunology/*metabolism ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Chitin/chemistry/*metabolism ; Crystallography, X-Ray ; Hydrogen Bonding ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Phosphorylation ; Plants, Genetically Modified ; Protein Multimerization ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry/genetics/*metabolism ; Receptors, Pattern Recognition/*chemistry/genetics/*metabolism ; Signal Transduction
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 98
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    Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-11-01
    Description: Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507442/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507442/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Richard C -- Wei, Yongjie -- An, Zhenyi -- Zou, Zhongju -- Xiao, Guanghua -- Bhagat, Govind -- White, Michael -- Reichelt, Julia -- Levine, Beth -- K08 CA164047/CA/NCI NIH HHS/ -- P30 CA142543/CA/NCI NIH HHS/ -- R01 CA071443/CA/NCI NIH HHS/ -- R01 CA084254/CA/NCI NIH HHS/ -- R01 CA109618/CA/NCI NIH HHS/ -- R01 CA129451/CA/NCI NIH HHS/ -- R01 CA84254-S1/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Nov 16;338(6109):956-9. doi: 10.1126/science.1225967. Epub 2012 Oct 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23112296" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/genetics/*metabolism ; *Autophagy ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; Fibroblasts/metabolism/pathology ; HeLa Cells ; Humans ; Membrane Proteins/genetics/*metabolism ; Mice ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; RNA, Small Interfering/genetics ; Rats ; Transduction, Genetic ; Vimentin/genetics ; Xenograft Model Antitumor Assays
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 99
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    Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-03-10
    Description: We have identified tens of thousands of short extrachromosomal circular DNAs (microDNA) in mouse tissues as well as mouse and human cell lines. These microDNAs are 200 to 400 base pairs long, are derived from unique nonrepetitive sequence, and are enriched in the 5'-untranslated regions of genes, exons, and CpG islands. Chromosomal loci that are enriched sources of microDNA in the adult brain are somatically mosaic for microdeletions that appear to arise from the excision of microDNAs. Germline microdeletions identified by the "Thousand Genomes" project may also arise from the excision of microDNAs in the germline lineage. We have thus identified a previously unknown DNA entity in mammalian cells and provide evidence that their generation leaves behind deletions in different genomic loci.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703515/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703515/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shibata, Yoshiyuki -- Kumar, Pankaj -- Layer, Ryan -- Willcox, Smaranda -- Gagan, Jeffrey R -- Griffith, Jack D -- Dutta, Anindya -- ES013773/ES/NIEHS NIH HHS/ -- GM31819/GM/NIGMS NIH HHS/ -- GM84465/GM/NIGMS NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R01 CA060499/CA/NCI NIH HHS/ -- R01 CA060499-18/CA/NCI NIH HHS/ -- R01 CA60499/CA/NCI NIH HHS/ -- R01 ES013773/ES/NIEHS NIH HHS/ -- R01 GM031819/GM/NIGMS NIH HHS/ -- R01 GM084465/GM/NIGMS NIH HHS/ -- R01 GM084465-04/GM/NIGMS NIH HHS/ -- T32 GM008136/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2012 Apr 6;336(6077):82-6. doi: 10.1126/science.1213307. Epub 2012 Mar 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22403181" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions ; Animals ; Base Pairing ; Base Sequence ; Brain/*embryology ; Brain Chemistry ; Cell Line ; Cell Line, Tumor ; *Chromosome Deletion ; Chromosomes, Human/*genetics ; Chromosomes, Mammalian/*genetics ; CpG Islands ; DNA Replication ; *DNA, Circular/analysis/chemistry/isolation & purification/metabolism ; Exons ; Germ Cells/chemistry ; Heart/embryology ; Humans ; Liver/chemistry/embryology ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron ; Molecular Sequence Data ; Polymerase Chain Reaction ; Repetitive Sequences, Nucleic Acid
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Genomics. ENCODE project writes eulogy for junk DNA (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-09-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, Elizabeth -- New York, N.Y. -- Science. 2012 Sep 7;337(6099):1159, 1161. doi: 10.1126/science.337.6099.1159.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955811" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Conserved Sequence ; *DNA, Intergenic/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Gene Expression Regulation ; Gene Regulatory Networks ; Genetic Predisposition to Disease ; Genome ; *Genome, Human ; *Genomics ; Humans ; Mammals/genetics ; RNA, Untranslated/genetics/metabolism ; Sequence Analysis, DNA ; Transcription Factors/genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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