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      A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

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          Abstract

          Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in a haploid human cell line against 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using an SLC-focused CRISPR/Cas9 library, we identified transporters whose absence induced resistance to the drugs tested. This included dependencies involving the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggests a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provides an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

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          Proteomics. Tissue-based map of the human proteome.

          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. Copyright © 2015, American Association for the Advancement of Science.
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            Is Open Access

            DrugBank 5.0: a major update to the DrugBank database for 2018

            Abstract DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year’s update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education.
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              Improved vectors and genome-wide libraries for CRISPR screening.

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                Author and article information

                Journal
                101231976
                Nat Chem Biol
                Nat Chem Biol
                Nature chemical biology
                1552-4450
                1552-4469
                28 January 2020
                01 April 2020
                09 March 2020
                07 June 2021
                : 16
                : 4
                : 469-478
                Affiliations
                [1 ]CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
                [2 ]Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
                [3 ]Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
                [4 ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
                [5 ]Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
                Author notes
                [* ]Corresponding author: Giulio Superti-Furga, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT25.3, 1090 Vienna, Austria, gsuperti@ 123456cemm.oeaw.ac.at , Telephone: +43 1 40160 70 001
                [#]

                Current Address: ViruSure GmbH, Tech Gate Vienna, Donau-City-Strasse 1A - 1220 Vienna

                Article
                EMS85610
                10.1038/s41589-020-0483-3
                7610918
                32152546
                bcc8d981-8f86-4d02-814d-0e3fea15293c

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Biochemistry
                Biochemistry

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