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  • 1
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    Identification of siRNA delivery enhancers by a chemical library screen (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-19
    Description: Most delivery systems for small interfering RNA therapeutics depend on endocytosis and release from endo-lysosomal compartments. One approach to improve delivery is to identify small molecules enhancing these steps. It is unclear to what extent such enhancers can be universally applied to different delivery systems and cell types. Here, we performed a compound library screen on two well-established siRNA delivery systems, lipid nanoparticles and cholesterol conjugated-siRNAs. We identified fifty-one enhancers improving gene silencing 2–5 fold. Strikingly, most enhancers displayed specificity for one delivery system only. By a combination of quantitative fluorescence and electron microscopy we found that the enhancers substantially differed in their mechanism of action, increasing either endocytic uptake or release of siRNAs from endosomes. Furthermore, they acted either on the delivery system itself or the cell, by modulating the endocytic system via distinct mechanisms. Interestingly, several compounds displayed activity on different cell types. As proof of principle, we showed that one compound enhanced siRNA delivery in primary endothelial cells in vitro and in the endocardium in the mouse heart. This study suggests that a pharmacological approach can improve the delivery of siRNAs in a system-specific fashion, by exploiting distinct mechanisms and acting upon multiple cell types.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Systems survey of endocytosis by multiparametric image analysis (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-03-02
    Description: Endocytosis is a complex process fulfilling many cellular and developmental functions. Understanding how it is regulated and integrated with other cellular processes requires a comprehensive analysis of its molecular constituents and general design principles. Here, we developed a new strategy to phenotypically profile the human genome with respect to transferrin (TF) and epidermal growth factor (EGF) endocytosis by combining RNA interference, automated high-resolution confocal microscopy, quantitative multiparametric image analysis and high-performance computing. We identified several novel components of endocytic trafficking, including genes implicated in human diseases. We found that signalling pathways such as Wnt, integrin/cell adhesion, transforming growth factor (TGF)-beta and Notch regulate the endocytic system, and identified new genes involved in cargo sorting to a subset of signalling endosomes. A systems analysis by Bayesian networks further showed that the number, size, concentration of cargo and intracellular position of endosomes are not determined randomly but are subject to specific regulation, thus uncovering novel properties of the endocytic system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collinet, Claudio -- Stoter, Martin -- Bradshaw, Charles R -- Samusik, Nikolay -- Rink, Jochen C -- Kenski, Denise -- Habermann, Bianca -- Buchholz, Frank -- Henschel, Robert -- Mueller, Matthias S -- Nagel, Wolfgang E -- Fava, Eugenio -- Kalaidzidis, Yannis -- Zerial, Marino -- England -- Nature. 2010 Mar 11;464(7286):243-9. doi: 10.1038/nature08779. Epub 2010 Feb 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Molecular Cell Biology and Genetics, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20190736" target="_blank"〉PubMed〈/a〉
    Keywords: Computing Methodologies ; Endocytosis/*physiology ; Endosomes/metabolism ; Epidermal Growth Factor/metabolism ; Gene Expression Profiling/*methods ; Genome-Wide Association Study ; Humans ; *Image Processing, Computer-Assisted ; Metabolic Networks and Pathways/physiology ; Microscopy, Confocal ; Phenotype ; Protein Transport/physiology ; RNA Interference ; Signal Transduction/physiology ; Transferrin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Reconstitution of Rab- and SNARE-dependent membrane fusion by synthetic endosomes (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-05-22
    Description: Rab GTPases and SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are evolutionarily conserved essential components of the eukaryotic intracellular transport system. Although pairing of cognate SNAREs is sufficient to fuse membranes in vitro, a complete reconstitution of the Rab-SNARE machinery has never been achieved. Here we report the reconstitution of the early endosomal canine Rab5 GTPase, its key regulators and effectors together with SNAREs into proteoliposomes using a set of 17 recombinant human proteins. These vesicles behave like minimal 'synthetic' endosomes, fusing with purified early endosomes or with each other in vitro. Membrane fusion measured by content-mixing and morphological assays requires the cooperativity between Rab5 effectors and cognate SNAREs which, together, form a more efficient 'core machinery' than SNAREs alone. In reconstituting a fusion mechanism dependent on both a Rab GTPase and SNAREs, our work shows that the two machineries act coordinately to increase the specificity and efficiency of the membrane tethering and fusion process.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ohya, Takeshi -- Miaczynska, Marta -- Coskun, Unal -- Lommer, Barbara -- Runge, Anja -- Drechsel, David -- Kalaidzidis, Yannis -- Zerial, Marino -- England -- Nature. 2009 Jun 25;459(7250):1091-7. doi: 10.1038/nature08107. Epub 2009 May 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01309, Dresden, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458617" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cricetinae ; Cytosol/metabolism ; Dogs ; Endosomes/metabolism/*physiology ; Humans ; Membrane Fusion/*physiology ; Microscopy, Electron ; Proteolipids/metabolism/ultrastructure ; Recombinant Proteins/metabolism ; SNARE Proteins/*metabolism ; Vesicular Transport Proteins/metabolism ; rab GTP-Binding Proteins/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Rab5 is necessary for the biogenesis of the endolysosomal system in vivo (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-05-25
    Description: An outstanding question is how cells control the number and size of membrane organelles. The small GTPase Rab5 has been proposed to be a master regulator of endosome biogenesis. Here, to test this hypothesis, we developed a mathematical model of endosome dependency on Rab5 and validated it by titrating down all three Rab5 isoforms in adult mouse liver using state-of-the-art RNA interference technology. Unexpectedly, the endocytic system was resilient to depletion of Rab5 and collapsed only when Rab5 decreased to a critical level. Loss of Rab5 below this threshold caused a marked reduction in the number of early endosomes, late endosomes and lysosomes, associated with a block of low-density lipoprotein endocytosis. Loss of endosomes caused failure to deliver apical proteins to the bile canaliculi, suggesting a requirement for polarized cargo sorting. Our results demonstrate for the first time, to our knowledge, the role of Rab5 as an endosome organizer in vivo and reveal the resilience mechanisms of the endocytic system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zeigerer, Anja -- Gilleron, Jerome -- Bogorad, Roman L -- Marsico, Giovanni -- Nonaka, Hidenori -- Seifert, Sarah -- Epstein-Barash, Hila -- Kuchimanchi, Satya -- Peng, Chang Geng -- Ruda, Vera M -- Del Conte-Zerial, Perla -- Hengstler, Jan G -- Kalaidzidis, Yannis -- Koteliansky, Victor -- Zerial, Marino -- England -- Nature. 2012 May 23;485(7399):465-70. doi: 10.1038/nature11133.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622570" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Polarity ; Cells, Cultured ; Endocytosis ; Endosomes/*metabolism ; Gene Knockdown Techniques ; Hepatocytes/cytology/metabolism ; Isoenzymes/biosynthesis/deficiency/genetics/metabolism ; Lipoproteins, LDL/metabolism ; Liver/cytology/enzymology/metabolism ; Lysosomes/*metabolism ; Mice ; Multivesicular Bodies/metabolism ; Organ Specificity ; Protein Biosynthesis ; RNA Interference ; RNA, Messenger/analysis/genetics ; Time Factors ; Vesicular Transport Proteins/metabolism ; rab5 GTP-Binding Proteins/biosynthesis/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 5
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    The mosaic genome of warm-blooded vertebrates (1985)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1985-05-24
    Description: Most of the nuclear genome of warm-blooded vertebrates is a mosaic of very long (much greater than 200 kilobases) DNA segments, the isochores; these isochores are fairly homogeneous in base composition and belong to a small number of major classes distinguished by differences in guanine-cytosine (GC) content. The families of DNA molecules derived from such classes can be separated and used to study the genome distribution of any sequence which can be probed. This approach has revealed (i) that the distribution of genes, integrated viral sequences, and interspersed repeats is highly nonuniform in the genome, and (ii) that the base composition and ratio of CpG to GpC in both coding and noncoding sequences, as well as codon usage, mainly depend on the GC content of the isochores harboring the sequences. The compositional compartmentalization of the genome of warm-blooded vertebrates is discussed with respect to its evolutionary origin, its causes, and its effects on chromosome structure and function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bernardi, G -- Olofsson, B -- Filipski, J -- Zerial, M -- Salinas, J -- Cuny, G -- Meunier-Rotival, M -- Rodier, F -- New York, N.Y. -- Science. 1985 May 24;228(4702):953-8.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/4001930" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Composition ; Base Sequence ; Biological Evolution ; Centrifugation, Density Gradient ; Chickens/*genetics ; Chromosome Banding ; Codon ; Cytosine/analysis ; DNA/analysis/*genetics ; DNA Replication ; DNA, Viral/genetics ; Gene Amplification ; *Genes ; Genes, Viral ; Guanine/analysis ; Humans ; Mammals/*genetics ; Mice/genetics ; Mutation ; Rabbits/genetics ; Recombination, Genetic ; Repetitive Sequences, Nucleic Acid ; Xenopus/*genetics
    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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  • 6
    Electronic Resource
    Electronic Resource
    The complexity of the Rab and Rho GTP-binding protein subfamilies revealed by a PCR cloning approach
    Amsterdam : Elsevier
    Gene 112 (1992), S. 261-264 
    Details
    ISSN: 0378-1119
    Keywords: Low-molecular-weight GTP-binding proteins ; degenerate oligodeoxyribonucleotides ; mouse ; polymerase chain reaction
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0378-1119(92)90387-5
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    Paper (German National Licenses)
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  • 7
    Electronic Resource
    Electronic Resource
    Rab GTPases in vesicular transport
    Amsterdam : Elsevier
    Current Opinion in Cell Biology 5 (1993), S. 613-620 
    Details
    ISSN: 0955-0674
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0955-0674(93)90130-I
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  • 8
    Electronic Resource
    Electronic Resource
    The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway - Cell 70, 715-728
    Amsterdam : Elsevier
    Trends in Cell Biology 2 (1992), S. 361 
    Details
    ISSN: 0962-8924
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0962-8924(92)90043-M
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  • 9
    Electronic Resource
    Electronic Resource
    Isolation of a mouse cDNA encoding Rab23, a small novel GTPase expressed predominantly in the brain
    Amsterdam : Elsevier
    Gene 138 (1994), S. 207-211 
    Details
    ISSN: 0378-1119
    Keywords: GTP-binding proteins ; Northern blot analysis ; PCR cloning techniques ; Ras-related proteins ; cDNA cloning ; rapid amplification of cDNA ends
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0378-1119(94)90809-5
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  • 10
    Electronic Resource
    Electronic Resource
    Expression, cloning and cDNA sequence of a fibroblast serum-regulated gene encoding a putative actin-associated protein (p27)
    Amsterdam : Elsevier
    Experimental Cell Research 181 (1989), S. 518-530 
    Details
    ISSN: 0014-4827
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1016/0014-4827(89)90108-0
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