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  • Tree shrew  (2)
  • ATP-Binding Cassette Transporters/metabolism  (1)
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  • 1
    Publication Date: 2014-09-16
    Description: The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and (1)H-(15)N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351747/" 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/PMC4351747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Chao -- Liu, Degang -- Li, Liwei -- Wempe, Michael F -- Guin, Sunny -- Khanna, May -- Meier, Jeremy -- Hoffman, Brenton -- Owens, Charles -- Wysoczynski, Christina L -- Nitz, Matthew D -- Knabe, William E -- Ahmed, Mansoor -- Brautigan, David L -- Paschal, Bryce M -- Schwartz, Martin A -- Jones, David N M -- Ross, David -- Meroueh, Samy O -- Theodorescu, Dan -- CA075115/CA/NCI NIH HHS/ -- CA091846/CA/NCI NIH HHS/ -- CA104106/CA/NCI NIH HHS/ -- GM47214/GM/NIGMS NIH HHS/ -- P01 CA104106/CA/NCI NIH HHS/ -- P30 CA044579/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- P50 CA091846/CA/NCI NIH HHS/ -- R01 CA075115/CA/NCI NIH HHS/ -- R01 CA143971/CA/NCI NIH HHS/ -- T32 GM007635/GM/NIGMS NIH HHS/ -- UL1 TR001082/TR/NCATS NIH HHS/ -- UL1TR001082/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):443-7. doi: 10.1038/nature13713. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Colorado, Aurora, Colorado 80045, USA. ; Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045, USA. ; Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Pharmacology, University of Colorado, Aurora, Colorado 80045, USA. ; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Department of Cardiology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Cell Biology, Yale University, New Haven, Connecticut 06511, USA. ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA [2] Department of Chemistry and Chemical Biology, Indiana University - Purdue University, Indianapolis, Indiana 46202, USA. ; 1] Department of Surgery, University of Colorado, Aurora, Colorado 80045, USA [2] Department of Pharmacology, University of Colorado, Aurora, Colorado 80045, USA [3] University of Colorado Comprehensive Cancer Center, Aurora, Colorado 80045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219851" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/metabolism ; Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Computer Simulation ; *Drug Screening Assays, Antitumor ; Female ; GTPase-Activating Proteins/metabolism ; Humans ; Mice ; Models, Molecular ; *Molecular Targeted Therapy ; Neoplasms/drug therapy/enzymology/metabolism/pathology ; Protein Binding/drug effects ; Signal Transduction/drug effects ; Small Molecule Libraries/*chemistry/*pharmacology ; Substrate Specificity ; Xenograft Model Antitumor Assays ; ral GTP-Binding Proteins/*antagonists & inhibitors/chemistry/metabolism ; ras Proteins/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
    Electronic Resource
    Electronic Resource
    Springer
    Cell & tissue research 285 (1996), S. 1-9 
    ISSN: 1432-0878
    Keywords: Key words: Retina ; Photoreceptor cells ; Megamitochondria ; Morphogenesis ; Reconstruction ; 3-D ; Tree shrew ; Tupaia belangeri (Scandentia)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. The morphogenesis of the megamitochondria in the retinal cones of prenatal, young postnatal and adult tree shrews (Tupaia belangeri) was studied by transmission electron microscopy and three-dimensional reconstruction techniques. The initial assembly of the supranuclear cone mitochondria and their subsequent migration towards the developing inner segment conform to the morphogenetic pattern known from other mammals. Within the first postnatal week, however, a marked increase in both the number of the cristae and the matrix density occurs in the inner segment mitochondria of Tupaia. These mitochondria then grow, initially exhibiting a basal-to-apical size-gradient. In the 17-day-old Tupaia, this gradient is superseded by a radial size-gradient that, in addition to the single apical megamitochondrion, is characteristically found in the adult Tupaia. The number of megamitochondria remains almost constant from day 12 of postnatal ontogenesis to the adult stage. Each megamitochondrion consists of an apically located body from which several long processes project towards the base of the inner segment. In the older stages, the number of small mitochondria that most probably have budded off from the megamitochondrial processes clearly increases. We consider that megamitochondria in the cone inner segments of Tupaia arise by the growth of a single mitochondrion and not by the fusion of smaller mitochondria.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Cell & tissue research 292 (1998), S. 67-76 
    ISSN: 1432-0878
    Keywords: Key words Retina ; Photoreceptor cells ; Outer segment ; Disk formation ; Tree shrew ; Tupaiabelangeri (Scandentia)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Existing hypotheses on the mode of disk formation in the photoreceptor cells of mammals appear to be incompatible: (1) plasma membranes of adjacent evaginations form a disk which, subsequently, is internalized by a disk rim; (2) pinocytotic vesicles are pinched off from the plasma membrane and fuse into a larger vesicle, which flattens and forms a disk. We have studied the development of the cone outer segment and the disk formation in Tupaia belangeri by transmission electron microscopy. During the first two postnatal weeks, the distal part of the single cilium, which is inserted apically on the inner segment, becomes balloon-shaped. Apical to the axoneme, it contains tubular and vesicular material, which, most probably, has been detached from the axonemal microtubules. These tubules and vesicles do not contribute to disks. The balloon-shaped expansion, later retained as the ciliary backbone, establishes the contact with the pigment epithelium. Formation of disks, from the 12-day-old Tupaia onwards, occurs between adjacent evaginations at the outer segment base. The initial disk rims are “hooked” to the ciliary axonemal microtubules. The axonemal microtubules are involved in the initiation and in the alignment of the disks. Disk rim formation and, thus, internalization of disks proceeds from the base to the apex of the outer segment, that is, from the younger to the older disks. In the adult Tupaia, an uneven progression of disk rim formation on both sides of the axoneme is found among consecutive disks. The seemingly incompatible hypotheses on the mode of disk formation reflect a heterochrony of the internalization of membranes and of the disk formation among different mammals and, possibly, between cones and rods.
    Type of Medium: Electronic Resource
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