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  • Mice, Inbred C57BL  (470)
  • Nature Publishing Group (NPG)  (470)
  • American Geophysical Union
  • Blackwell Publishing Ltd
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  • 11
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    Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-15
    Description: Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T(reg)) cells capable of suppressing over-exuberant immune responses. The T(reg) cell subset is comprised of cells that commit to the T(reg) lineage by upregulating the transcription factor Foxp3 either in the thymus (tT(reg)) or in the periphery (iT(reg)). Considering a central role for Foxp3 in T(reg) cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T(reg) cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T(reg) cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T(reg) cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-beta-NFAT response element, is superfluous for tT(reg) cell differentiation, but has a prominent role in iT(reg) cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T(reg) cells. Foxp3 binds to CNS2 in a Cbf-beta-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this 'cellular memory module' facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T(reg) lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T(reg) cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884187/" 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/PMC2884187/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Ye -- Josefowicz, Steven -- Chaudhry, Ashutosh -- Peng, Xiao P -- Forbush, Katherine -- Rudensky, Alexander Y -- R37 AI034206/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 11;463(7282):808-12. doi: 10.1038/nature08750. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Immunology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072126" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Lineage/*genetics ; Chromatin Assembly and Disassembly ; Conserved Sequence/*genetics ; CpG Islands/genetics ; DNA Methylation ; Female ; Forkhead Transcription Factors/*genetics/metabolism ; Gene Expression Regulation ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-rel/metabolism ; Regulatory Sequences, Nucleic Acid/*genetics ; Response Elements/genetics ; T-Lymphocytes, Regulatory/*cytology/immunology/*metabolism ; Thymus Gland/cytology/immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 12
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    Encoding of conditioned fear in central amygdala inhibitory circuits (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-11-12
    Description: The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ciocchi, Stephane -- Herry, Cyril -- Grenier, Francois -- Wolff, Steffen B E -- Letzkus, Johannes J -- Vlachos, Ioannis -- Ehrlich, Ingrid -- Sprengel, Rolf -- Deisseroth, Karl -- Stadler, Michael B -- Muller, Christian -- Luthi, Andreas -- England -- Nature. 2010 Nov 11;468(7321):277-82. doi: 10.1038/nature09559.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068837" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Amygdala/anatomy & histology/cytology/*physiology ; Animals ; Conditioning, Classical/*physiology ; Fear/*physiology ; Freezing Reaction, Cataleptic ; Male ; Mice ; Mice, Inbred C57BL ; Neural Inhibition/*physiology ; Neural Pathways/cytology/*physiology ; Neuronal Plasticity/physiology ; Neurons/physiology ; gamma-Aminobutyric Acid/metabolism
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  • 13
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    mTORC1 controls fasting-induced ketogenesis and its modulation by ageing (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-24
    Description: The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARalpha (peroxisome proliferator activated receptor alpha), the master transcriptional activator of ketogenic genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARalpha, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARalpha activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARalpha function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sengupta, Shomit -- Peterson, Timothy R -- Laplante, Mathieu -- Oh, Stephanie -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-04/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 23;468(7327):1100-4. doi: 10.1038/nature09584.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179166" target="_blank"〉PubMed〈/a〉
    Keywords: *Aging ; Animals ; Cell Line ; Fasting/*metabolism ; *Gene Expression Regulation ; Humans ; Ketone Bodies/*biosynthesis/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Multiprotein Complexes ; Nuclear Receptor Co-Repressor 1/metabolism ; PPAR alpha/antagonists & inhibitors/metabolism ; Proteins/genetics/*metabolism ; TOR Serine-Threonine Kinases
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  • 14
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    Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-11-05
    Description: Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage-the peri-infarct zone-is critical for rehabilitation, as it shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important for the development of new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA(A) receptors and is caused by an impairment in GABA (gamma-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for alpha5-subunit-containing extrasynaptic GABA(A) receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of alpha5- or delta-subunit-containing GABA(A) receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A) receptor function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058798/" 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/PMC3058798/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clarkson, Andrew N -- Huang, Ben S -- Macisaac, Sarah E -- Mody, Istvan -- Carmichael, S Thomas -- NS30549/NS/NINDS NIH HHS/ -- R01 NS030549/NS/NINDS NIH HHS/ -- R01 NS030549-18/NS/NINDS NIH HHS/ -- England -- Nature. 2010 Nov 11;468(7321):305-9. doi: 10.1038/nature09511. Epub 2010 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21048709" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzodiazepines/pharmacology ; Cerebral Infarction/metabolism/pathology/physiopathology ; Disease Models, Animal ; Drug Inverse Agonism ; GABA Antagonists/pharmacology ; GABA Plasma Membrane Transport Proteins/metabolism ; Imidazoles/pharmacology ; Male ; Membrane Potentials/drug effects ; Mice ; Mice, Inbred C57BL ; Motor Cortex/metabolism/pathology/*physiology/*physiopathology ; Neuronal Plasticity/physiology ; Receptors, GABA/deficiency/genetics/metabolism ; Recovery of Function/*physiology ; Stroke/drug therapy/*metabolism/pathology ; Synapses/metabolism ; Time Factors ; gamma-Aminobutyric Acid/*metabolism
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  • 15
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    The prion protein as a receptor for amyloid-beta (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-08-13
    Description: Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Lauren et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057871/" 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/PMC3057871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kessels, Helmut W -- Nguyen, Louis N -- Nabavi, Sadegh -- Malinow, Roberto -- R01 AG032132/AG/NIA NIH HHS/ -- R01 AG032132-14/AG/NIA NIH HHS/ -- R01 AG032132-15/AG/NIA NIH HHS/ -- R01 AG032132-17/AG/NIA NIH HHS/ -- R01 AG032132-18/AG/NIA NIH HHS/ -- R01 MH049159/MH/NIMH NIH HHS/ -- R01 MH049159-09/MH/NIMH NIH HHS/ -- R01 MH049159-21/MH/NIMH NIH HHS/ -- R01 MH049159-22/MH/NIMH NIH HHS/ -- England -- Nature. 2010 Aug 12;466(7308):E3-4; discussion E4-5. doi: 10.1038/nature09217.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neural Circuits and Behavior, 9500 Gilman Drive 0634, University of California at San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20703260" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/chemistry/genetics/*metabolism ; Animals ; Learning/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; PrPC Proteins/deficiency/genetics/*metabolism ; Reproducibility of Results ; Serotonin/metabolism ; Synapses/*metabolism/*pathology ; Synaptic Transmission
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  • 16
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    T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-15
    Description: Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins. It is induced in activated T cells and is reported to process a variety of substrates including the anti-inflammatory cytokine transforming growth factor (TGF)-beta1 (refs 2-4), but the non-redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGF-beta1. Furin-deficient T regulatory (Treg) cells were less protective in a T-cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin-deficient effector cells were inherently over-active and were resistant to suppressive activity of wild-type Treg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-beta1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758057/" 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/PMC2758057/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pesu, Marko -- Watford, Wendy T -- Wei, Lai -- Xu, Lili -- Fuss, Ivan -- Strober, Warren -- Andersson, John -- Shevach, Ethan M -- Quezado, Martha -- Bouladoux, Nicolas -- Roebroek, Anton -- Belkaid, Yasmine -- Creemers, John -- O'Shea, John J -- Z99 EY999999/Intramural NIH HHS/ -- England -- Nature. 2008 Sep 11;455(7210):246-50. doi: 10.1038/nature07210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Immunology and Inflammation Branch, National Institute for Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. pesum@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18701887" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/immunology ; Antigens, CD4/immunology/metabolism ; Autoimmunity/immunology ; Colitis/immunology ; Furin/deficiency/genetics/*metabolism ; Gene Expression Profiling ; Immune Tolerance/*immunology ; Immunologic Memory/immunology ; Integrin alpha Chains/immunology ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/cytology/*enzymology/*immunology ; Thymus Gland/cytology/immunology ; Transforming Growth Factor beta1/biosynthesis/genetics/immunology
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  • 17
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    Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-18
    Description: The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA. Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Emu-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs. We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE), which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Emu-Myc/+ mice. When accurate translational control is re-established in Emu-Myc/+ mice, genome instability is suppressed. Our findings demonstrate how perturbations in translational control provide a highly specific outcome for gene expression, genome stability and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880952/" 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/PMC2880952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barna, Maria -- Pusic, Aya -- Zollo, Ornella -- Costa, Maria -- Kondrashov, Nadya -- Rego, Eduardo -- Rao, Pulivarthi H -- Ruggero, Davide -- R01 HL085572/HL/NHLBI NIH HHS/ -- R01 HL085572-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):971-5. doi: 10.1038/nature07449. Epub 2008 Nov 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry & Biophysics, University of California San Francisco, Rock Hall Room 384C, 1550 Fourth Street, San Francisco, California 94158-2517, USA. maria.barna@ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19011615" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; B-Lymphocytes/cytology/metabolism/pathology ; Cell Division ; Cell Size ; Cells, Cultured ; Cytokinesis ; Gene Expression Regulation, Neoplastic ; Genes, myc/*genetics ; Genomic Instability ; Heterozygote ; Lymphoma/genetics/pathology ; Mice ; Mice, Inbred C57BL ; Mitosis ; Oncogene Protein p55(v-myc)/*genetics/*metabolism ; Precancerous Conditions/metabolism/pathology ; *Protein Biosynthesis ; Protein-Serine-Threonine Kinases/metabolism ; Ribosomal Proteins/*deficiency/*genetics
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  • 18
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    GILT is a critical host factor for Listeria monocytogenes infection (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-09-26
    Description: Listeria monocytogenes is a gram-positive, intracellular, food-borne pathogen that can cause severe illness in humans and animals. On infection, it is actively phagocytosed by macrophages; it then escapes from the phagosome, replicates in the cytosol, and subsequently spreads from cell to cell by a non-lytic mechanism driven by actin polymerization. Penetration of the phagosomal membrane is initiated by the secreted haemolysin listeriolysin O (LLO), which is essential for vacuolar escape in vitro and for virulence in animal models of infection. Reduction is required to activate the lytic activity of LLO in vitro, and we show here that reduction by the enzyme gamma-interferon-inducible lysosomal thiol reductase (GILT, also called Ifi30) is responsible for the activation of LLO in vivo. GILT is a soluble thiol reductase expressed constitutively within the lysosomes of antigen-presenting cells, and it accumulates in macrophage phagosomes as they mature into phagolysosomes. The enzyme is delivered by a mannose-6-phosphate receptor-dependent mechanism to the endocytic pathway, where amino- and carboxy-terminal pro-peptides are cleaved to generate a 30-kDa mature enzyme. The active site of GILT contains two cysteine residues in a CXXC motif that catalyses the reduction of disulphide bonds. Mice lacking GILT are deficient in generating major histocompatibility complex class-II-restricted CD4(+) T-cell responses to protein antigens that contain disulphide bonds. Here we show that these mice are resistant to L. monocytogenes infection. Replication of the organism in GILT-negative macrophages, or macrophages expressing an enzymatically inactive GILT mutant, is impaired because of delayed escape from the phagosome. GILT activates LLO within the phagosome by the thiol reductase mechanism shared by members of the thioredoxin family. In addition, purified GILT activates recombinant LLO, facilitating membrane permeabilization and red blood cell lysis. The data show that GILT is a critical host factor that facilitates L. monocytogenes infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775488/" 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/PMC2775488/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singh, Reshma -- Jamieson, Amanda -- Cresswell, Peter -- AI023081/AI/NIAID NIH HHS/ -- R37 AI023081/AI/NIAID NIH HHS/ -- R37 AI023081-24/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Oct 30;455(7217):1244-7. doi: 10.1038/nature07344. Epub 2008 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06250-8011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18815593" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Toxins/metabolism ; Cell-Free System ; Heat-Shock Proteins/metabolism ; Hemolysin Proteins/metabolism ; Hemolysis ; Listeria monocytogenes/growth & development/*physiology ; Listeriosis/*metabolism/*microbiology ; Macrophages/cytology/metabolism/microbiology ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction ; Oxidoreductases/chemistry/deficiency/genetics/*metabolism ; Phagocytosis ; Phagosomes/microbiology ; Thioredoxins/metabolism ; Virulence Factors/metabolism
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  • 19
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    REST maintains self-renewal and pluripotency of embryonic stem cells (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-26
    Description: The neuronal repressor REST (RE1-silencing transcription factor; also called NRSF) is expressed at high levels in mouse embryonic stem (ES) cells, but its role in these cells is unclear. Here we show that REST maintains self-renewal and pluripotency in mouse ES cells through suppression of the microRNA miR-21. We found that, as with known self-renewal markers, the level of REST expression is much higher in self-renewing mouse ES cells than in differentiating mouse ES (embryoid body, EB) cells. Heterozygous deletion of Rest (Rest+/-) and its short-interfering-RNA-mediated knockdown in mouse ES cells cause a loss of self-renewal-even when these cells are grown under self-renewal conditions-and lead to the expression of markers specific for multiple lineages. Conversely, exogenously added REST maintains self-renewal in mouse EB cells. Furthermore, Rest+/- mouse ES cells cultured under self-renewal conditions express substantially reduced levels of several self-renewal regulators, including Oct4 (also called Pou5f1), Nanog, Sox2 and c-Myc, and exogenously added REST in mouse EB cells maintains the self-renewal phenotypes and expression of these self-renewal regulators. We also show that in mouse ES cells, REST is bound to the gene chromatin of a set of miRNAs that potentially target self-renewal genes. Whereas mouse ES cells and mouse EB cells containing exogenously added REST express lower levels of these miRNAs, EB cells, Rest+/- ES cells and ES cells treated with short interfering RNA targeting Rest express higher levels of these miRNAs. At least one of these REST-regulated miRNAs, miR-21, specifically suppresses the self-renewal of mouse ES cells, corresponding to the decreased expression of Oct4, Nanog, Sox2 and c-Myc. Thus, REST is a newly discovered element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mouse ES cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830094/" 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/PMC2830094/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singh, Sanjay K -- Kagalwala, Mohamedi N -- Parker-Thornburg, Jan -- Adams, Henry -- Majumder, Sadhan -- CA81255/CA/NCI NIH HHS/ -- CA97124/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA081255/CA/NCI NIH HHS/ -- R01 CA081255-10/CA/NCI NIH HHS/ -- R01 CA097124/CA/NCI NIH HHS/ -- R01 CA097124-07/CA/NCI NIH HHS/ -- England -- Nature. 2008 May 8;453(7192):223-7. doi: 10.1038/nature06863. Epub 2008 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18362916" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers ; Cell Differentiation ; Cell Line ; Cell Lineage ; Cell Proliferation ; Chromatin/genetics/metabolism ; Embryonic Stem Cells/*cytology/*metabolism ; Mice ; Mice, Inbred C57BL ; Pluripotent Stem Cells/*cytology/*metabolism ; Repressor Proteins/genetics/*metabolism ; Transcription Factors/deficiency/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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    STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-30
    Description: The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-kappaB and IRF3 transcription pathways to induce expression of type I interferon (IFN-alpha and IFN-beta ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-beta, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPbeta), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit STING's ability to stimulate expression of IFN-beta. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804933/" 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/PMC2804933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ishikawa, Hiroki -- Barber, Glen N -- R01 AI079336/AI/NIAID NIH HHS/ -- R01 AI079336-01/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):674-8. doi: 10.1038/nature07317. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724357" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Endoplasmic Reticulum/*metabolism ; Fibroblasts ; Humans ; Immunity, Innate/*immunology ; Interferons/biosynthesis/immunology ; Membrane Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Signal Transduction
    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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