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  • 1
    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
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Molecular Structure: THEOCHEM 200 (1989), S. 251-260 
    ISSN: 0166-1280
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Melatonin, a pineal secretory product, has been shown to exert a direct anti-proliferative action on the androgen-sensitive LNCaP prostate cancer cell line through hitherto undefined mechanisms. In this communication, expression of mt1 melatonin receptor protein in human prostate cancer tissues and LNCaP cells was demonstrated by immunohisto(cyto)chemistry and western blotting, hence supporting the use of LNCaP cell line as a model for the study of melatonin signaling in prostate cancer cell growth. Using 〈displayedItem type="mathematics" xml:id="di-fml-1" numbered="no"〉〈mediaResource alt="image" href="urn:x-wiley:07423098:JPI290307:JPI_0007_mu1"/〉 H-thymidine incorporation assay, LNCaP cell proliferation was inhibited by 2-iodomelatonin, a high-affinity melatonin receptor agonist. Furthermore, melatonin inhibited 〈displayedItem type="mathematics" xml:id="di-fml-2" numbered="no"〉〈mediaResource alt="image" href="urn:x-wiley:07423098:JPI290307:JPI_0007_mu2"/〉 H-thymidine incorporation into LNCaP cells and attenuated 5α-dihydrotestosterone (DHT) or 17β-estradiol (E2)-induced stimulation of LNCaP cell proliferation at physiological and pharmacological concentrations. Similar concentration-dependent inhibition of sex steroid-induced stimulation of thymidine incorporation into LNCaP cells by 2-iodomelatonin was also observed. Interestingly, attenuation of sex steroid-stimulated calcium influx into LNCaP cells by pharmacological concentrations of melatonin was recorded, whereas 2-iodomelatonin had no effect on cytosolic calcium changes induced by sex steroids. In addition, proliferative and cytosolic calcium changes were associated with inhibition of total prostate-specific antigen (PSA) production by LNCaP cells at high physiological and pharmacological concentrations of melatonin. Our data suggest that activated mt1 receptor and attenuated sex steroid-induced calcium influx are two important mechanisms mediating the direct anti-proliferative action of melatonin on androgen-responsive human prostate cancer cells.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 2[125I]Iodomelatonin ([125I]Mel) binding sites were characterized on membrane preparations of young chick hearts. [125I]Mel binding was rapid, saturable, stable, reversible, specific and of picomolar affinity and femtomolar density. Guanosine 5′-O-(3-thiotriphosphate) significantly lowered the binding affinity by one- to twofold, supporting G-protein linkage of melatonin receptors. Binding was detected as early as embryonic day-9 (E9), and increased steadily peaking at E13 before it slowly declined to about 15% of the peak level a week posthatch. Specific [125I]Mel binding was significantly increased by in ovo administration of inotropic agents dopamine and isoproterenol. Melatonin or 2-iodo-N-butanoyl-tryptamine inhibited isoproterenol-stimulated cAMP accumulation in primary heart cell cultures and the effect was attenuated after pretreatment with pertussis toxin (PTX). Localization of melatonin receptors using autoradiography showed intense labeling in the coronary arteries in all age groups whereas those in the myoblasts decreased as the heart matured. While the myoblasts and undifferentiated developing coronary arteries expressed melatonin MT1 receptor subtype in E11 hearts as detected by immunostaining with anti-MT1 receptor serum, immunoreactivities were observed mostly on the endothelium/subendothelium and smooth muscle cells of the well developed coronary vessels in posthatch hearts. Collectively, our data suggest the presence of PTX-sensitive, G protein-coupled melatonin receptors, whose expression is up-regulated by dopamine and isoproterenol, in the chick heart. Activation of these receptors, which include MT1 subtype, may modulate β-adrenergic receptor-mediated cAMP signaling in the control of chick heart and coronary artery physiology.
    Type of Medium: Electronic Resource
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