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  • Articles  (5)
  • Cell Line, Tumor  (5)
  • American Association for the Advancement of Science (AAAS)  (5)
  • Institute of Physics
  • 2015-2019  (5)
  • 1965-1969
  • 2016  (5)
  • 1
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    Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5 (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mavrakis, Konstantinos J -- McDonald, E Robert 3rd -- Schlabach, Michael R -- Billy, Eric -- Hoffman, Gregory R -- deWeck, Antoine -- Ruddy, David A -- Venkatesan, Kavitha -- Yu, Jianjun -- McAllister, Gregg -- Stump, Mark -- deBeaumont, Rosalie -- Ho, Samuel -- Yue, Yingzi -- Liu, Yue -- Yan-Neale, Yan -- Yang, Guizhi -- Lin, Fallon -- Yin, Hong -- Gao, Hui -- Kipp, D Randal -- Zhao, Songping -- McNamara, Joshua T -- Sprague, Elizabeth R -- Zheng, Bing -- Lin, Ying -- Cho, Young Shin -- Gu, Justin -- Crawford, Kenneth -- Ciccone, David -- Vitari, Alberto C -- Lai, Albert -- Capka, Vladimir -- Hurov, Kristen -- Porter, Jeffery A -- Tallarico, John -- Mickanin, Craig -- Lees, Emma -- Pagliarini, Raymond -- Keen, Nicholas -- Schmelzle, Tobias -- Hofmann, Francesco -- Stegmeier, Frank -- Sellers, William R -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1208-13. doi: 10.1126/science.aad5944. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. ; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland. ; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA. ; China Novartis Institutes for Biomedical Research, Shanghai 201203, China. ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912361" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Survival ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism ; Deoxyadenosines/metabolism ; Gene Deletion ; Humans ; Methionine/*metabolism ; Neoplasms/drug therapy/genetics/*metabolism ; Protein-Arginine N-Methyltransferases/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; RNA, Small Interfering/genetics ; Thionucleosides/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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  • 2
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    Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-28
    Description: Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toyama, Erin Quan -- Herzig, Sebastien -- Courchet, Julien -- Lewis, Tommy L Jr -- Loson, Oliver C -- Hellberg, Kristina -- Young, Nathan P -- Chen, Hsiuchen -- Polleux, Franck -- Chan, David C -- Shaw, Reuben J -- K99 NS091526/NS/NINDS NIH HHS/ -- K99NS091526/NS/NINDS NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R01CA172229/CA/NCI NIH HHS/ -- R01DK080425/DK/NIDDK NIH HHS/ -- R01GM062967/GM/NIGMS NIH HHS/ -- R01GM110039/GM/NIGMS NIH HHS/ -- R01NS089456/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 15;351(6270):275-81. doi: 10.1126/science.aab4138.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cell Biology Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. ; Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. ; Molecular and Cell Biology Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. shaw@salk.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26816379" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/chemistry/genetics/*metabolism ; Adenosine Monophosphate/metabolism ; Amino Acid Motifs ; Cell Line, Tumor ; Cytoplasm/enzymology ; Dactinomycin/analogs & derivatives/pharmacology ; *Energy Metabolism ; Enzyme Activation ; GTP Phosphohydrolases/genetics/metabolism ; Humans ; Microtubule-Associated Proteins/genetics/metabolism ; Mitochondria/drug effects/enzymology/*physiology ; *Mitochondrial Dynamics ; Mitochondrial Proteins/genetics/metabolism ; Molecular Sequence Data ; Rotenone/pharmacology ; *Stress, Physiological
    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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    DNA-controlled dynamic colloidal nanoparticle systems for mediating cellular interaction (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Precise control of biosystems requires development of materials that can dynamically change physicochemical properties. Inspired by the ability of proteins to alter their conformation to mediate function, we explored the use of DNA as molecular keys to assemble and transform colloidal nanoparticle systems. The systems consist of a core nanoparticle surrounded by small satellites, the conformation of which can be transformed in response to DNA via a toe-hold displacement mechanism. The conformational changes can alter the optical properties and biological interactions of the assembled nanosystem. Photoluminescent signal is altered by changes in fluorophore-modified particle distance, whereas cellular targeting efficiency is increased 2.5 times by changing the surface display of targeting ligands. These concepts provide strategies for engineering dynamic nanotechnology systems for navigating complex biological environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ohta, Seiichi -- Glancy, Dylan -- Chan, Warren C W -- MOP-130143/Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):841-5. doi: 10.1126/science.aad4925.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biomaterials and Biomedical Engineering, Donnelly Center for Cellular and Biomolecular Research, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada. Center for Disease Biology and Integrative Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. ; Institute of Biomaterials and Biomedical Engineering, Donnelly Center for Cellular and Biomolecular Research, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada. ; Institute of Biomaterials and Biomedical Engineering, Donnelly Center for Cellular and Biomolecular Research, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada. Department of Chemical Engineering, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada. Department of Material Science and Engineering, University of Toronto, 160 College Street, Room 450, University of Toronto, Toronto, ON M5S 3E1, Canada. warren.chan@utoronto.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912892" target="_blank"〉PubMed〈/a〉
    Keywords: *Cell Communication ; Cell Line, Tumor ; DNA, Single-Stranded/*chemistry ; Fluorescence Resonance Energy Transfer ; Gold/*chemistry ; Humans ; Ligands ; Metal Nanoparticles/*chemistry ; Nanotechnology/*methods ; Nucleic Acid Conformation ; Particle Size
    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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    MYC regulates the antitumor immune response through CD47 and PD-L1 (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-12
    Description: The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Casey, Stephanie C -- Tong, Ling -- Li, Yulin -- Do, Rachel -- Walz, Susanne -- Fitzgerald, Kelly N -- Gouw, Arvin M -- Baylot, Virginie -- Gutgemann, Ines -- Eilers, Martin -- Felsher, Dean W -- 1F32CA177139/CA/NCI NIH HHS/ -- 5T32AI07290/AI/NIAID NIH HHS/ -- CA 089305/CA/NCI NIH HHS/ -- CA 170378/CA/NCI NIH HHS/ -- CA 184384/CA/NCI NIH HHS/ -- U01 CA 114747/CA/NCI NIH HHS/ -- U01 CA 188383/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 8;352(6282):227-31. doi: 10.1126/science.aac9935. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. ; Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany. ; Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. Theodor Boveri Institute, Biocenter, University of Wurzburg, Am Hubland, 97074 Wurzburg, Germany. ; Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. dfelsher@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26966191" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD274/*genetics ; Antigens, CD47/*genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*immunology ; Down-Regulation ; *Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Immune Tolerance/*genetics ; Jurkat Cells ; Lymphoma/genetics/immunology ; Mice ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/immunology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc/genetics/*metabolism ; RNA, Small Interfering/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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  • 5
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    MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kryukov, Gregory V -- Wilson, Frederick H -- Ruth, Jason R -- Paulk, Joshiawa -- Tsherniak, Aviad -- Marlow, Sara E -- Vazquez, Francisca -- Weir, Barbara A -- Fitzgerald, Mark E -- Tanaka, Minoru -- Bielski, Craig M -- Scott, Justin M -- Dennis, Courtney -- Cowley, Glenn S -- Boehm, Jesse S -- Root, David E -- Golub, Todd R -- Clish, Clary B -- Bradner, James E -- Hahn, William C -- Garraway, Levi A -- KL2 TR001100/TR/NCATS NIH HHS/ -- U01 CA176058/CA/NCI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. levi_garraway@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912360" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Deoxyadenosines/metabolism/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Deletion ; Humans ; Isoquinolines/pharmacology ; Neoplasms/*drug therapy/enzymology ; Protein-Arginine N-Methyltransferases/antagonists & ; inhibitors/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; Pyrimidines/pharmacology ; Thionucleosides/metabolism/pharmacology ; Transcription Factors
    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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