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  • 1
    Publication Date: 2012-08-17
    Description: Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712624/" 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/PMC3712624/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Florian L -- Colla, Simona -- Aquilanti, Elisa -- Manzo, Veronica E -- Genovese, Giannicola -- Lee, Jaclyn -- Eisenson, Daniel -- Narurkar, Rujuta -- Deng, Pingna -- Nezi, Luigi -- Lee, Michelle A -- Hu, Baoli -- Hu, Jian -- Sahin, Ergun -- Ong, Derrick -- Fletcher-Sananikone, Eliot -- Ho, Dennis -- Kwong, Lawrence -- Brennan, Cameron -- Wang, Y Alan -- Chin, Lynda -- DePinho, Ronald A -- 3 P01 CA095616-08S1/CA/NCI NIH HHS/ -- 57006984/Howard Hughes Medical Institute/ -- P01 CA095616/CA/NCI NIH HHS/ -- P01CA95616/CA/NCI NIH HHS/ -- T32-CA009361/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 16;488(7411):337-42. doi: 10.1038/nature11331.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895339" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Biomarkers, Tumor/deficiency/genetics ; Brain Neoplasms/*drug therapy/*genetics/pathology ; Cell Line, Tumor ; Cell Proliferation ; Chromosomes, Human, Pair 1/genetics ; DNA-Binding Proteins/deficiency/genetics ; Enzyme Inhibitors ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genes, Essential/*genetics ; Genes, Tumor Suppressor ; Glioblastoma/*drug therapy/*genetics/pathology ; Homozygote ; Humans ; Hydroxamic Acids/pharmacology/therapeutic use ; Mice ; Molecular Targeted Therapy/*methods ; Neoplasm Transplantation ; Phosphonoacetic Acid/analogs & derivatives/pharmacology/therapeutic use ; Phosphopyruvate Hydratase/antagonists & inhibitors/deficiency/genetics/metabolism ; RNA, Small Interfering/genetics ; Sequence Deletion/*genetics ; Tumor Suppressor Proteins/deficiency/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2010-11-30
    Description: An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2(+) neural progenitors, Dcx(+) newborn neurons, and Olig2(+) oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057569/" 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/PMC3057569/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jaskelioff, Mariela -- Muller, Florian L -- Paik, Ji-Hye -- Thomas, Emily -- Jiang, Shan -- Adams, Andrew C -- Sahin, Ergun -- Kost-Alimova, Maria -- Protopopov, Alexei -- Cadinanos, Juan -- Horner, James W -- Maratos-Flier, Eleftheria -- Depinho, Ronald A -- R01 CA084628/CA/NCI NIH HHS/ -- R01 CA084628-19/CA/NCI NIH HHS/ -- R01CA84628/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- U01CA141508/CA/NCI NIH HHS/ -- England -- Nature. 2011 Jan 6;469(7328):102-6. doi: 10.1038/nature09603. Epub 2010 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science and Departments of Medical Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21113150" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/drug effects/*metabolism/*pathology ; Animals ; Avoidance Learning/drug effects ; Brain/anatomy & histology/cytology/drug effects/pathology ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; DNA Damage/drug effects ; Enzyme Activation/drug effects ; Enzyme Reactivators/pharmacology ; Mice ; Mice, Inbred C57BL ; Models, Animal ; Myelin Sheath/metabolism ; Neural Stem Cells/cytology/drug effects/enzymology/pathology ; Organ Size/drug effects ; Phenotype ; Receptors, Estrogen/genetics/metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Regenerative Medicine ; Smell/drug effects/physiology ; Tamoxifen/analogs & derivatives/pharmacology ; Telomerase/*deficiency/genetics/*metabolism ; Telomere/drug effects/metabolism/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-10-25
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346172/" 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/PMC4346172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwarzlander, Markus -- Wagner, Stephan -- Ermakova, Yulia G -- Belousov, Vsevolod V -- Radi, Rafael -- Beckman, Joseph S -- Buettner, Garry R -- Demaurex, Nicolas -- Duchen, Michael R -- Forman, Henry J -- Fricker, Mark D -- Gems, David -- Halestrap, Andrew P -- Halliwell, Barry -- Jakob, Ursula -- Johnston, Iain G -- Jones, Nick S -- Logan, David C -- Morgan, Bruce -- Muller, Florian L -- Nicholls, David G -- Remington, S James -- Schumacker, Paul T -- Winterbourn, Christine C -- Sweetlove, Lee J -- Meyer, Andreas J -- Dick, Tobias P -- Murphy, Michael P -- 098565/Wellcome Trust/United Kingdom -- MC_U105663142/Medical Research Council/United Kingdom -- P30 CA086862/CA/NCI NIH HHS/ -- P30 ES005605/ES/NIEHS NIH HHS/ -- R01 AG027349/AG/NIA NIH HHS/ -- R01 CA169046/CA/NCI NIH HHS/ -- R01 GM073929/GM/NIGMS NIH HHS/ -- R21 AG046799/AG/NIA NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):E12-4. doi: 10.1038/nature13858.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Crop Science and Resource Conservation (INRES), University of Bonn, Friedrich-Ebert-Allee 144, 53113 Bonn, Germany. ; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia. ; Departamento de Bioquimica, and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la Republica, Avda. General Flores 2125, 11800 Montevideo, Uruguay. ; Linus Pauling Institute, Environmental Health Sciences Center, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331, USA. ; The University of Iowa, Department of Radiation Oncology and Interdisciplinary Graduate Program in Human Toxicology, and ESR Facility, College of Medicine, Med Labs B180K, Iowa City, Iowa 52242-1181, USA. ; Department of Cell Physiology and Metabolism, University of Geneva, 1, rue Michel-Servet, Geneva 4 CH-1211, Switzerland. ; Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, University College London, Gower Street, London WC1E 6BT, UK. ; 1] Life and Environmental Sciences Unit, University of California, Merced, 5200 North Lake Road, Merced, California 95344, USA [2] Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089-0191, USA. ; Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK. ; Institute of Healthy Ageing, and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK. ; School of Biochemistry and Bristol CardioVascular, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK. ; Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore. ; Molecular, Cellular and Developmental Biology Department, University of Michigan, Ann Arbor, Michigan 48109-1048, USA. ; Department of Mathematics, South Kensington Campus, Imperial College London, London SW7 2AZ, UK. ; Universite d'Angers &INRA &Agrocampus Ouest, UMR 1345 Institut de Recherche en Horticulture et Semences, Angers, F-49045, France. ; Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. ; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California 94945, USA. ; Department of Physics, Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403-1229, USA. ; Department of Pediatrics, Division of Neonatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, 60611, USA. ; Centre for Free Radical Research, Department of Pathology, University of Otago, ChristchurchPO Box 4345, Christchurch, New Zealand. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25341790" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/*metabolism ; *Longevity ; Male ; Mitochondria/*metabolism ; Superoxides/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-02-11
    Description: Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1alpha and PGC-1beta, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1alpha expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1alpha and PGC-1beta promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741661/" 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/PMC3741661/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sahin, Ergun -- Colla, Simona -- Liesa, Marc -- Moslehi, Javid -- Muller, Florian L -- Guo, Mira -- Cooper, Marcus -- Kotton, Darrell -- Fabian, Attila J -- Walkey, Carl -- Maser, Richard S -- Tonon, Giovanni -- Foerster, Friedrich -- Xiong, Robert -- Wang, Y Alan -- Shukla, Sachet A -- Jaskelioff, Mariela -- Martin, Eric S -- Heffernan, Timothy P -- Protopopov, Alexei -- Ivanova, Elena -- Mahoney, John E -- Kost-Alimova, Maria -- Perry, Samuel R -- Bronson, Roderick -- Liao, Ronglih -- Mulligan, Richard -- Shirihai, Orian S -- Chin, Lynda -- DePinho, Ronald A -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30DK079638/DK/NIDDK NIH HHS/ -- R01 CA084628/CA/NCI NIH HHS/ -- R01 DK035914/DK/NIDDK NIH HHS/ -- R01 DK056690/DK/NIDDK NIH HHS/ -- R01 DK063356/DK/NIDDK NIH HHS/ -- R01 DK089185/DK/NIDDK NIH HHS/ -- U24 DK-59635/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Feb 17;470(7334):359-65. doi: 10.1038/nature09787. Epub 2011 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307849" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/biosynthesis ; Aging/metabolism/pathology ; Animals ; Cardiomyopathies/chemically induced/metabolism/pathology/physiopathology ; Cell Proliferation ; DNA, Mitochondrial/analysis ; Doxorubicin/toxicity ; Gluconeogenesis ; Hematopoietic Stem Cells/metabolism/pathology ; Liver/cytology/metabolism ; Mice ; Mitochondria/*metabolism/*pathology ; Myocardium/cytology/metabolism ; RNA/genetics ; Reactive Oxygen Species/metabolism ; Telomerase/deficiency/genetics ; Telomere/enzymology/genetics/*metabolism/*pathology ; Transcription Factors/antagonists & inhibitors/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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