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      CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression

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          Abstract

          CD98 heavy chain (CD98hc) forms heteromeric amino acid (AA) transporters by interacting with different light chains. Cancer cells overexpress CD98hc-transporters in order to meet their increased nutritional and antioxidant demands, since they provide branched-chain AA (BCAA) and aromatic AA (AAA) availability while protecting cells from oxidative stress. Here we show that BCAA and AAA shortage phenocopies the inhibition of mTORC1 signalling, protein synthesis and cell proliferation caused by CD98hc ablation. Furthermore, our data indicate that CD98hc sustains glucose uptake and glycolysis, and, as a consequence, the pentose phosphate pathway (PPP). Thus, loss of CD98hc triggers a dramatic reduction in the nucleotide pool, which leads to replicative stress in these cells, as evidenced by the enhanced DNA Damage Response (DDR), S-phase delay and diminished rate of mitosis, all recovered by nucleoside supplementation. In addition, proper BCAA and AAA availability sustains the expression of the enzyme ribonucleotide reductase. In this regard, BCAA and AAA shortage results in decreased content of deoxynucleotides that triggers replicative stress, also recovered by nucleoside supplementation. On the basis of our findings, we conclude that CD98hc plays a central role in AA and glucose cellular nutrition, redox homeostasis and nucleotide availability, all key for cell proliferation.

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          Bidirectional transport of amino acids regulates mTOR and autophagy.

          Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.
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            A chemical method for fast and sensitive detection of DNA synthesis in vivo.

            We have developed a method to detect DNA synthesis in proliferating cells, based on the incorporation of 5-ethynyl-2'-deoxyuridine (EdU) and its subsequent detection by a fluorescent azide through a Cu(I)-catalyzed [3 + 2] cycloaddition reaction ("click" chemistry). Detection of the EdU label is highly sensitive and can be accomplished in minutes. The small size of the fluorescent azides used for detection results in a high degree of specimen penetration, allowing the staining of whole-mount preparations of large tissue and organ explants. In contrast to BrdU, the method does not require sample fixation or DNA denaturation and permits good structural preservation. We demonstrate the use of the method in cultured cells and in the intestine and brain of whole animals.
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              Glutathione: overview of its protective roles, measurement, and biosynthesis.

              This review is the introduction to a special issue concerning, glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. Here, the functions and GSH and the sources of oxidants and electrophiles, the elimination of oxidants by reduction and electrophiles by conjugation with GSH are briefly described. Methods of assessing GSH status in the cells are also described. GSH synthesis and its regulation are addressed along with therapeutic approaches for manipulating GSH content that have been proposed. The purpose here is to provide a brief overview of some of the important aspects of glutathione metabolism as part of this special issue that will provide a more comprehensive review of the state of knowledge regarding this essential molecule.
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                Author and article information

                Contributors
                sara.cano@irbbarcelona.org
                manuel.palacin@irbbarcelona.org
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                1 October 2019
                1 October 2019
                2019
                : 9
                : 14065
                Affiliations
                [1 ]GRID grid.473715.3, Institute for Research in Biomedicine (IRB Barcelona), , The Barcelona Institute of Science and Technology, ; Barcelona, 08028 Spain
                [2 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Department of Cell Biology, Physiology and Immunology, Faculty of Biology, , Universitat de Barcelona, ; Barcelona, 08028 Spain
                [3 ]ISNI 0000 0001 2284 9230, GRID grid.410367.7, Metabolomics Platform, IISPV, Department of Electronic Engineering (DEEEA), , Universitat Rovira i Virgili, ; Tarragona, 43003 Spain
                [4 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ; Madrid, 28029 Spain
                [5 ]ISNI 0000 0000 9635 9413, GRID grid.410458.c, Secció Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, ; Barcelona, Spain
                [6 ]ISNI 0000 0004 1791 1185, GRID grid.452372.5, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ; Madrid, 28029 Spain
                [7 ]ISNI 0000 0001 2287 2617, GRID grid.9026.d, Institute of Biochemistry and Molecular Biology University of Hamburg, ; Hamburg, 20246 Germany
                [8 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, , University of Oslo, ; Oslo, 0372 Norway
                [9 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Centre for Cancer Cell Reprogramming, Institute for Clinical Medicine, Faculty of Medicine, , University of Oslo, ; Oslo, 0372 Norway
                [10 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, , University of Barcelona, ; Barcelona, 08028 Spain
                Author information
                http://orcid.org/0000-0001-5363-7433
                http://orcid.org/0000-0003-3695-7157
                http://orcid.org/0000-0002-1638-0306
                http://orcid.org/0000-0001-8045-320X
                Article
                50547
                10.1038/s41598-019-50547-9
                6773781
                31575908
                b34f2e1c-be60-46b6-a482-bb7dda48a956
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 April 2019
                : 13 September 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100002809, Generalitat de Catalunya (Government of Catalonia);
                Award ID: SGR2009-1355
                Award ID: SGR2017-961
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100008666, Fundació la Marató de TV3 (TV3 Marathon Foundation);
                Award ID: 20132330
                Award Recipient :
                Funded by: Spanish Ministry of Science and Innovation: SAF2015-64869-R-FEDER
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                dna synthesis,nutrient signalling,cell-cycle exit,dna damage and repair
                Uncategorized
                dna synthesis, nutrient signalling, cell-cycle exit, dna damage and repair

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