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  • 1
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    CLP1 links tRNA metabolism to progressive motor-neuron loss (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-03-12
    Description: CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1(K/K)) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1(K/K) mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674495/" 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/PMC3674495/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanada, Toshikatsu -- Weitzer, Stefan -- Mair, Barbara -- Bernreuther, Christian -- Wainger, Brian J -- Ichida, Justin -- Hanada, Reiko -- Orthofer, Michael -- Cronin, Shane J -- Komnenovic, Vukoslav -- Minis, Adi -- Sato, Fuminori -- Mimata, Hiromitsu -- Yoshimura, Akihiko -- Tamir, Ido -- Rainer, Johannes -- Kofler, Reinhard -- Yaron, Avraham -- Eggan, Kevin C -- Woolf, Clifford J -- Glatzel, Markus -- Herbst, Ruth -- Martinez, Javier -- Penninger, Josef M -- K99NS077435-01A1/NS/NINDS NIH HHS/ -- NS038253/NS/NINDS NIH HHS/ -- P 19223/Austrian Science Fund FWF/Austria -- P 21667/Austrian Science Fund FWF/Austria -- R00 NS077435/NS/NINDS NIH HHS/ -- R01 NS038253/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Mar 28;495(7442):474-80. doi: 10.1038/nature11923. Epub 2013 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23474986" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis ; Animals ; Animals, Newborn ; Axons/metabolism/pathology ; Cell Death ; Diaphragm/innervation ; Embryo Loss ; Embryo, Mammalian/metabolism/pathology ; Exons/genetics ; Female ; Fibroblasts ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/*metabolism/*pathology ; Muscular Atrophy, Spinal ; Neuromuscular Diseases/metabolism/pathology ; Oxidative Stress ; RNA Processing, Post-Transcriptional ; RNA, Transfer, Tyr/genetics/*metabolism ; Respiration ; Spinal Nerves/cytology ; Transcription Factors/deficiency/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Tyrosine/genetics/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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  • 2
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    Reprogramming in vivo produces teratomas and iPS cells with totipotency features (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-09-13
    Description: Reprogramming of adult cells to generate induced pluripotent stem cells (iPS cells) has opened new therapeutic opportunities; however, little is known about the possibility of in vivo reprogramming within tissues. Here we show that transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs, implying that full reprogramming can occur in vivo. Analyses of the stomach, intestine, pancreas and kidney reveal groups of dedifferentiated cells that express the pluripotency marker NANOG, indicative of in situ reprogramming. By bone marrow transplantation, we demonstrate that haematopoietic cells can also be reprogrammed in vivo. Notably, reprogrammable mice present circulating iPS cells in the blood and, at the transcriptome level, these in vivo generated iPS cells are closer to embryonic stem cells (ES cells) than standard in vitro generated iPS cells. Moreover, in vivo iPS cells efficiently contribute to the trophectoderm lineage, suggesting that they achieve a more plastic or primitive state than ES cells. Finally, intraperitoneal injection of in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic markers. We conclude that reprogramming in vivo is feasible and confers totipotency features absent in standard iPS or ES cells. These discoveries could be relevant for future applications of reprogramming in regenerative medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abad, Maria -- Mosteiro, Lluc -- Pantoja, Cristina -- Canamero, Marta -- Rayon, Teresa -- Ors, Inmaculada -- Grana, Osvaldo -- Megias, Diego -- Dominguez, Orlando -- Martinez, Dolores -- Manzanares, Miguel -- Ortega, Sagrario -- Serrano, Manuel -- England -- Nature. 2013 Oct 17;502(7471):340-5. doi: 10.1038/nature12586. Epub 2013 Sep 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24025773" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Cells/cytology/metabolism ; Cell Dedifferentiation ; Cell Separation ; Cells, Cultured ; *Cellular Reprogramming/genetics ; Ectoderm/cytology ; Embryoid Bodies/cytology/metabolism ; Embryonic Stem Cells/cytology/metabolism ; Female ; Fibroblasts/cytology ; Gene Expression Profiling ; Induced Pluripotent Stem Cells/*cytology/metabolism ; Intestines/cytology ; Kidney/cytology ; Kruppel-Like Transcription Factors/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Octamer Transcription Factor-3/genetics/metabolism ; Organ Specificity ; Pancreas/cytology ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; SOXB1 Transcription Factors/genetics/metabolism ; Stomach/cytology ; Teratoma/genetics/*metabolism/pathology ; Totipotent Stem Cells/*cytology/metabolism ; Transcriptome/genetics ; Trophoblasts/cytology
    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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    T-helper-1-cell cytokines drive cancer into senescence (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-02-05
    Description: Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-gamma (IFN-gamma) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-gamma and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-gamma and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-gamma- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-gamma and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Braumuller, Heidi -- Wieder, Thomas -- Brenner, Ellen -- Assmann, Sonja -- Hahn, Matthias -- Alkhaled, Mohammed -- Schilbach, Karin -- Essmann, Frank -- Kneilling, Manfred -- Griessinger, Christoph -- Ranta, Felicia -- Ullrich, Susanne -- Mocikat, Ralph -- Braungart, Kilian -- Mehra, Tarun -- Fehrenbacher, Birgit -- Berdel, Julia -- Niessner, Heike -- Meier, Friedegund -- van den Broek, Maries -- Haring, Hans-Ulrich -- Handgretinger, Rupert -- Quintanilla-Martinez, Leticia -- Fend, Falko -- Pesic, Marina -- Bauer, Jurgen -- Zender, Lars -- Schaller, Martin -- Schulze-Osthoff, Klaus -- Rocken, Martin -- England -- Nature. 2013 Feb 21;494(7437):361-5. doi: 10.1038/nature11824. Epub 2013 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, Eberhard Karls University, Liebermeister Strasse 25, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23376950" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Polyomavirus Transforming/genetics/metabolism ; Cell Aging/*immunology ; Cell Cycle ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics/metabolism ; Cytokines/*immunology ; Disease Models, Animal ; Disease Progression ; Female ; Humans ; Interferon-gamma/immunology ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Neoplasms/*immunology/*pathology ; Oncogenes/genetics ; Phosphoserine/metabolism ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Retinoblastoma Protein/chemistry/metabolism ; STAT1 Transcription Factor/metabolism ; Th1 Cells/*immunology ; Time Factors ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/immunology ; Tumor Suppressor Protein p53/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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