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  • 1
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    Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-01-11
    Description: Mutations in DKC1 cause dyskeratosis congenita (DC), a disease characterized by premature aging and increased tumor susceptibility. The DKC1 protein binds to the box H + ACA small nucleolar RNAs and the RNA component of telomerase. Here we show that hypomorphic Dkc1 mutant (Dkc1m) mice recapitulate in the first and second generations (G1 and G2) the clinical features of DC. Dkc1m cells from G1 and G2 mice were impaired in ribosomal RNA pseudouridylation before the onset of disease. Reductions of telomere length in Dkc1m mice became evident only in later generations. These results suggest that deregulated ribosome function is important in the initiation of DC, whereas telomere shortening may modify and/or exacerbate DC.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ruggero, Davide -- Grisendi, Silvia -- Piazza, Francesco -- Rego, Eduardo -- Mari, Francesca -- Rao, Pulivarthi H -- Cordon-Cardo, Carlos -- Pandolfi, Pier Paolo -- New York, N.Y. -- Science. 2003 Jan 10;299(5604):259-62.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12522253" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia ; Animals ; Apoptosis ; Bone Marrow Cells ; Cell Cycle Proteins/*genetics/*physiology ; Colony-Forming Units Assay ; Disease Models, Animal ; Dyskeratosis Congenita/complications/*genetics/*metabolism ; Female ; Genetic Predisposition to Disease ; Hematopoietic Stem Cells/physiology ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mutation ; Neoplasms/*etiology ; Nuclear Proteins/*genetics/*physiology ; Pseudouridine/*metabolism ; RNA, Ribosomal/*metabolism ; Ribosomes/physiology ; Telomerase/metabolism ; Telomere/metabolism/ultrastructure
    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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  • 2
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    The translational landscape of mTOR signalling steers cancer initiation and metastasis (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-01
    Description: The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663483/" 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/PMC3663483/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hsieh, Andrew C -- Liu, Yi -- Edlind, Merritt P -- Ingolia, Nicholas T -- Janes, Matthew R -- Sher, Annie -- Shi, Evan Y -- Stumpf, Craig R -- Christensen, Carly -- Bonham, Michael J -- Wang, Shunyou -- Ren, Pingda -- Martin, Michael -- Jessen, Katti -- Feldman, Morris E -- Weissman, Jonathan S -- Shokat, Kevan M -- Rommel, Christian -- Ruggero, Davide -- R01 CA140456/CA/NCI NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 22;485(7396):55-61. doi: 10.1038/nature10912.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367541" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Benzoxazoles/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factors/metabolism ; Gene Expression Regulation, Neoplastic/drug effects/genetics ; Genome/genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Invasiveness/genetics ; *Neoplasm Metastasis/drug therapy/genetics ; Phosphoproteins/metabolism ; Prostatic Neoplasms/drug therapy/genetics/*pathology ; *Protein Biosynthesis ; Pyrimidines/pharmacology ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/metabolism ; *Signal Transduction ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*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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    Exaggerated translation causes synaptic and behavioural aberrations associated with autism (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-25
    Description: Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548017/" 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/PMC3548017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santini, Emanuela -- Huynh, Thu N -- MacAskill, Andrew F -- Carter, Adam G -- Pierre, Philippe -- Ruggero, Davide -- Kaphzan, Hanoch -- Klann, Eric -- CA154916/CA/NCI NIH HHS/ -- NS034007/NS/NINDS NIH HHS/ -- NS047384/NS/NINDS NIH HHS/ -- NS078718/NS/NINDS NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- R01 NS034007/NS/NINDS NIH HHS/ -- R01 NS047384/NS/NINDS NIH HHS/ -- R21 NS078718/NS/NINDS NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Jan 17;493(7432):411-5. doi: 10.1038/nature11782. Epub 2012 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neural Science, New York University, New York, New York 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23263185" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/drug therapy/*genetics/pathology/*physiopathology ; Behavior, Animal/drug effects ; Dendrites/metabolism/pathology ; Eukaryotic Initiation Factor-4E/genetics/*metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; Female ; Hippocampus/metabolism ; Hydrazones ; Infusions, Intraventricular ; Male ; Mice ; Mice, Transgenic ; Neostriatum/metabolism ; Neuronal Plasticity ; Nitro Compounds/administration & dosage/pharmacology/therapeutic use ; Prefrontal Cortex/metabolism ; *Protein Biosynthesis/drug effects/genetics ; RNA Caps/metabolism ; Synapses/*metabolism/*pathology ; Thiazoles/administration & dosage/pharmacology/therapeutic use
    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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    Autism-related deficits via dysregulated eIF4E-dependent translational control (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-11-23
    Description: Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133997/" 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/PMC4133997/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gkogkas, Christos G -- Khoutorsky, Arkady -- Ran, Israeli -- Rampakakis, Emmanouil -- Nevarko, Tatiana -- Weatherill, Daniel B -- Vasuta, Cristina -- Yee, Stephanie -- Truitt, Morgan -- Dallaire, Paul -- Major, Francois -- Lasko, Paul -- Ruggero, Davide -- Nader, Karim -- Lacaille, Jean-Claude -- Sonenberg, Nahum -- MOP-10848/Canadian Institutes of Health Research/Canada -- MOP-114994/Canadian Institutes of Health Research/Canada -- MOP-44050/Canadian Institutes of Health Research/Canada -- MOP-93679/Canadian Institutes of Health Research/Canada -- R01 CA140456/CA/NCI NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- R01 GM088813/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jan 17;493(7432):371-7. doi: 10.1038/nature11628. Epub 2012 Nov 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23172145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/*genetics/*physiopathology ; Cell Adhesion Molecules, Neuronal/genetics/metabolism ; Eukaryotic Initiation Factor-4E/antagonists & inhibitors/*metabolism ; Eukaryotic Initiation Factors/deficiency/genetics/metabolism ; Male ; Mice ; Mice, Knockout ; Phenotype ; *Protein Biosynthesis ; Synapses/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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    Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-05-13
    Description: The DKC1 gene encodes a pseudouridine synthase that modifies ribosomal RNA (rRNA). DKC1 is mutated in people with X-linked dyskeratosis congenita (X-DC), a disease characterized by bone marrow failure, skin abnormalities, and increased susceptibility to cancer. How alterations in ribosome modification might lead to cancer and other features of the disease remains unknown. Using an unbiased proteomics strategy, we discovered a specific defect in IRES (internal ribosome entry site)-dependent translation in Dkc1(m) mice and in cells from X-DC patients. This defect results in impaired translation of messenger RNAs containing IRES elements, including those encoding the tumor suppressor p27(Kip1) and the antiapoptotic factors Bcl-xL and XIAP (X-linked Inhibitor of Apoptosis Protein). Moreover, Dkc1(m) ribosomes were unable to direct translation from IRES elements present in viral messenger RNAs. These findings reveal a potential mechanism by which defective ribosome activity leads to disease and cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoon, Andrew -- Peng, Guang -- Brandenburger, Yves -- Zollo, Ornella -- Xu, Wei -- Rego, Eduardo -- Ruggero, Davide -- New York, N.Y. -- Science. 2006 May 12;312(5775):902-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16690864" target="_blank"〉PubMed〈/a〉
    Keywords: *5' Untranslated Regions ; Animals ; Cell Cycle Proteins/chemistry/*genetics/physiology ; Cell Line ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p27/biosynthesis/genetics ; Dyskeratosis Congenita/*genetics ; Humans ; Insect Viruses/genetics ; Lymphocytes/metabolism ; Male ; Mice ; Nuclear Proteins/chemistry/*genetics/physiology ; Oligonucleotide Array Sequence Analysis ; Point Mutation ; Polyribosomes/metabolism ; *Protein Biosynthesis ; Proteomics ; Pseudouridine/metabolism ; RNA Viruses/genetics ; RNA, Messenger/*genetics/metabolism ; RNA, Ribosomal/metabolism ; Transfection ; X-Linked Inhibitor of Apoptosis Protein/biosynthesis/genetics ; bcl-X Protein/biosynthesis/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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