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  • Protein Binding  (3)
  • *Neurogenesis  (2)
  • American Association for the Advancement of Science (AAAS)  (5)
  • Wiley
  • 2010-2014  (5)
  • 1980-1984
  • 1910-1914
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  • American Association for the Advancement of Science (AAAS)  (5)
  • Wiley
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Year
  • 1
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    Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-07-06
    Description: The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez Molina, Daniel -- Jafari, Rozbeh -- Ignatushchenko, Marina -- Seki, Takahiro -- Larsson, E Andreas -- Dan, Chen -- Sreekumar, Lekshmy -- Cao, Yihai -- Nordlund, Par -- New York, N.Y. -- Science. 2013 Jul 5;341(6141):84-7. doi: 10.1126/science.1233606.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23828940" target="_blank"〉PubMed〈/a〉
    Keywords: Antimetabolites, Antineoplastic/metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Monitoring/*methods ; Folic Acid Antagonists/metabolism ; *Hot Temperature ; Humans ; Kidney/metabolism ; Ligands ; Liver/metabolism ; *Molecular Targeted Therapy ; Pharmaceutical Preparations/*metabolism ; Protein Binding ; Protein Stability ; Proteins/*metabolism ; Quinazolines/metabolism ; Thiophenes/metabolism ; Tissue Distribution
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Tracking cancer drugs in living cells by thermal profiling of the proteome (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-10-04
    Description: The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Savitski, Mikhail M -- Reinhard, Friedrich B M -- Franken, Holger -- Werner, Thilo -- Savitski, Maria Falth -- Eberhard, Dirk -- Martinez Molina, Daniel -- Jafari, Rozbeh -- Dovega, Rebecca Bakszt -- Klaeger, Susan -- Kuster, Bernhard -- Nordlund, Par -- Bantscheff, Marcus -- Drewes, Gerard -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):1255784. doi: 10.1126/science.1255784. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. mikhail.m.savitski@gsk.com marcus.x.bantscheff@gsk.com gerard.c.drewes@gsk.com. ; Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. ; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. ; Department of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil Erlenmeyer Forum 5, Freising, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. ; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Centre for Biomedical Structural Biology, Nanyang Technological University, Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278616" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Antineoplastic Agents/*pharmacology ; Hot Temperature ; Humans ; K562 Cells ; Ligands ; Protein Binding ; Protein Denaturation ; Protein Stability ; Proteome/*drug effects ; Proteomics/*methods
    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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  • 3
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    Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-04-10
    Description: Transcription factors (TFs) direct gene expression by binding to DNA regulatory regions. To explore the evolution of gene regulation, we used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to determine experimentally the genome-wide occupancy of two TFs, CCAAT/enhancer-binding protein alpha and hepatocyte nuclear factor 4 alpha, in the livers of five vertebrates. Although each TF displays highly conserved DNA binding preferences, most binding is species-specific, and aligned binding events present in all five species are rare. Regions near genes with expression levels that are dependent on a TF are often bound by the TF in multiple species yet show no enhanced DNA sequence constraint. Binding divergence between species can be largely explained by sequence changes to the bound motifs. Among the binding events lost in one lineage, only half are recovered by another binding event within 10 kilobases. Our results reveal large interspecies differences in transcriptional regulation and provide insight into regulatory evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008766/" 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/PMC3008766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Dominic -- Wilson, Michael D -- Ballester, Benoit -- Schwalie, Petra C -- Brown, Gordon D -- Marshall, Aileen -- Kutter, Claudia -- Watt, Stephen -- Martinez-Jimenez, Celia P -- Mackay, Sarah -- Talianidis, Iannis -- Flicek, Paul -- Odom, Duncan T -- 062023/Wellcome Trust/United Kingdom -- 079643/Wellcome Trust/United Kingdom -- 15603/Cancer Research UK/United Kingdom -- 202218/European Research Council/International -- A15603/Cancer Research UK/United Kingdom -- WT062023/Wellcome Trust/United Kingdom -- WT079643/Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2010 May 21;328(5981):1036-40. doi: 10.1126/science.1186176. Epub 2010 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20378774" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Animals ; Base Sequence ; Binding Sites ; Biological Evolution ; CCAAT-Enhancer-Binding Protein-alpha/*metabolism ; Chickens/genetics ; Chromatin Immunoprecipitation ; DNA/genetics/metabolism ; Dogs ; *Evolution, Molecular ; *Gene Expression Regulation ; *Genome ; Genome, Human ; Hepatocyte Nuclear Factor 4/*metabolism ; Humans ; Liver/*metabolism ; Mice ; Opossums/genetics ; Protein Binding ; Regulatory Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Species Specificity ; Vertebrates/*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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  • 4
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    Fate-restricted neural progenitors in the mammalian cerebral cortex (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-08-11
    Description: During development of the mammalian cerebral cortex, radial glial cells (RGCs) generate layer-specific subtypes of excitatory neurons in a defined temporal sequence, in which lower-layer neurons are formed before upper-layer neurons. It has been proposed that neuronal subtype fate is determined by birthdate through progressive restriction of the neurogenic potential of a common RGC progenitor. Here, we demonstrate that the murine cerebral cortex contains RGC sublineages with distinct fate potentials. Using in vivo genetic fate mapping and in vitro clonal analysis, we identified an RGC lineage that is intrinsically specified to generate only upper-layer neurons, independently of niche and birthdate. Because upper cortical layers were expanded during primate evolution, amplification of this RGC pool may have facilitated human brain evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287277/" 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/PMC4287277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Franco, Santos J -- Gil-Sanz, Cristina -- Martinez-Garay, Isabel -- Espinosa, Ana -- Harkins-Perry, Sarah R -- Ramos, Cynthia -- Muller, Ulrich -- MH078833/MH/NIMH NIH HHS/ -- NS046456/NS/NINDS NIH HHS/ -- NS060355/NS/NINDS NIH HHS/ -- R01 NS046456/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2012 Aug 10;337(6095):746-9. doi: 10.1126/science.1223616.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dorris Neuroscience Center and Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22879516" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Cell Proliferation ; Cells, Cultured ; Cerebral Cortex/*cytology/embryology ; Homeodomain Proteins/genetics ; Mice ; Neural Stem Cells/*cytology/physiology ; *Neurogenesis ; Neuroglia/*cytology ; Neurons/*cytology/physiology ; Recombination, Genetic
    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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  • 5
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    Hippocampal neurogenesis regulates forgetting during adulthood and infancy (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-05-09
    Description: Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Akers, Katherine G -- Martinez-Canabal, Alonso -- Restivo, Leonardo -- Yiu, Adelaide P -- De Cristofaro, Antonietta -- Hsiang, Hwa-Lin Liz -- Wheeler, Anne L -- Guskjolen, Axel -- Niibori, Yosuke -- Shoji, Hirotaka -- Ohira, Koji -- Richards, Blake A -- Miyakawa, Tsuyoshi -- Josselyn, Sheena A -- Frankland, Paul W -- MOP74650/Canadian Institutes of Health Research/Canada -- MOP86762/Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2014 May 9;344(6184):598-602. doi: 10.1126/science.1248903.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24812394" target="_blank"〉PubMed〈/a〉
    Keywords: Amnesia/*pathology/*physiopathology ; Animals ; Dentate Gyrus/cytology ; Female ; Guinea Pigs ; Hippocampus/*cytology ; Male ; *Memory ; Mice ; Mice, Inbred C57BL ; *Neurogenesis ; Neurons/cytology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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