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  • 1
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    Mediator kinase inhibition further activates super-enhancer-associated genes in AML (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-09-30
    Description: Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641525/" 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/PMC4641525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pelish, Henry E -- Liau, Brian B -- Nitulescu, Ioana I -- Tangpeerachaikul, Anupong -- Poss, Zachary C -- Da Silva, Diogo H -- Caruso, Brittany T -- Arefolov, Alexander -- Fadeyi, Olugbeminiyi -- Christie, Amanda L -- Du, Karrie -- Banka, Deepti -- Schneider, Elisabeth V -- Jestel, Anja -- Zou, Ge -- Si, Chong -- Ebmeier, Christopher C -- Bronson, Roderick T -- Krivtsov, Andrei V -- Myers, Andrew G -- Kohl, Nancy E -- Kung, Andrew L -- Armstrong, Scott A -- Lemieux, Madeleine E -- Taatjes, Dylan J -- Shair, Matthew D -- CA66996/CA/NCI NIH HHS/ -- F31 CA180419/CA/NCI NIH HHS/ -- P01 CA066996/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- R01 CA170741/CA/NCI NIH HHS/ -- T32 GM08759/GM/NIGMS NIH HHS/ -- UL1 TR001082/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Oct 8;526(7572):273-6. doi: 10.1038/nature14904. Epub 2015 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, Colorado 80303, USA. ; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02215, USA. ; Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Martinsried, Germany. ; Max-Planck-Institut fur Biochemie, Am Kloperspitz 18, D-82152 Martinsried, Germany. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; Bioinfo, Plantagenet, Ontario K0B 1L0, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416749" target="_blank"〉PubMed〈/a〉
    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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    Stable inhibitory activity of regulatory T cells requires the transcription factor Helios (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-17
    Description: The maintenance of immune homeostasis requires regulatory T cells (T(regs)). Given their intrinsic self-reactivity, T(regs) must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3(+) CD4 and Qa-1-restricted CD8 T(regs) results in defective regulatory activity and autoimmunity in mice. Helios-deficient T(regs) develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 T(regs) also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. The definition of Helios as a key transcription factor that stabilizes T(regs) in the face of inflammatory responses provides a genetic explanation for a core property of T(regs).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627635/" 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/PMC4627635/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Hye-Jung -- Barnitz, R Anthony -- Kreslavsky, Taras -- Brown, Flavian D -- Moffett, Howell -- Lemieux, Madeleine E -- Kaygusuz, Yasemin -- Meissner, Torsten -- Holderried, Tobias A W -- Chan, Susan -- Kastner, Philippe -- Haining, W Nicholas -- Cantor, Harvey -- R01 AI037562/AI/NIAID NIH HHS/ -- R01AI37562/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):334-9. doi: 10.1126/science.aad0616.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. ; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. ; Bioinfo, Plantagenet, Canada. ; Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Universite de Strasbourg, 67404 Illkirch, France. Faculte de Medecine, Universite de Strasbourg, Strasbourg, France. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. ; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA. harvey_cantor@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472910" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/genetics/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; DNA-Binding Proteins/*biosynthesis/genetics ; Forkhead Transcription Factors/immunology ; Gene Expression ; Kidney/immunology ; Liver/immunology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pancreas/immunology ; STAT5 Transcription Factor/metabolism ; T-Lymphocytes, Regulatory/*immunology ; Transcription Factors/*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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  • 3
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    Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis (2009)
    National Academy of Sciences
    Details
    Publication Date: 2009-03-02
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Glucocorticoids, KLF15, muscle physiology, and DMD [Medical Sciences] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-12-09
    Description: Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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