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  • 1
    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
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  • 2
    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
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  • 3
    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
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  • 4
    Publication Date: 2012-10-09
    Description: The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein-folding demand leads to "ER stress," and activates IRE1alpha, an ER transmembrane kinase-endoribonuclease (RNase). IRE1alpha promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1alpha RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, and -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1alpha endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1alpha regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742121/" 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/PMC3742121/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Upton, John-Paul -- Wang, Likun -- Han, Dan -- Wang, Eric S -- Huskey, Noelle E -- Lim, Lionel -- Truitt, Morgan -- McManus, Michael T -- Ruggero, Davide -- Goga, Andrei -- Papa, Feroz R -- Oakes, Scott A -- DK063720/DK/NIDDK NIH HHS/ -- DP2 OD001925/OD/NIH HHS/ -- DP2OD001925/OD/NIH HHS/ -- GM080783/GM/NIGMS NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- R01 CA136577/CA/NCI NIH HHS/ -- R01 CA136717/CA/NCI NIH HHS/ -- R01 CA140456/CA/NCI NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- R01 DK080955/DK/NIDDK NIH HHS/ -- R01 GM080783/GM/NIGMS NIH HHS/ -- R01CA136577/CA/NCI NIH HHS/ -- R01CA136717/CA/NCI NIH HHS/ -- R01CA140456/CA/NCI NIH HHS/ -- R01CA154916/CA/NCI NIH HHS/ -- R01DK080955/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Nov 9;338(6108):818-22. doi: 10.1126/science.1226191. Epub 2012 Oct 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23042294" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Apoptosis ; Brefeldin A/pharmacology ; Caspase 2/*genetics/*metabolism ; Cell-Free System ; Cells, Cultured ; Cysteine Endopeptidases/*genetics/*metabolism ; Down-Regulation ; Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum Stress ; Endoribonucleases/chemistry/genetics/*metabolism ; Enzyme Activation ; HEK293 Cells ; Humans ; Mice ; Mice, Knockout ; MicroRNAs/*metabolism ; Mutant Proteins ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases/chemistry/genetics/*metabolism ; RNA Stability ; RNA, Messenger/genetics/metabolism ; Up-Regulation
    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
    Publication Date: 2018-05-03
    Description: Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2–α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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