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Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen (1999)

T. U. Mayer ; T. M. Kapoor ; S. J. Haggarty ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 286(5441): 971-4.

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Publication Date: 1999-11-05

Description: Small molecules that perturb specific protein functions are valuable tools for dissecting complex processes in mammalian cells. A combination of two phenotype-based screens, one based on a specific posttranslational modification, the other visualizing microtubules and chromatin, was used to identify compounds that affect mitosis. One compound, here named monastrol, arrested mammalian cells in mitosis with monopolar spindles. In vitro, monastrol specifically inhibited the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. All previously known small molecules that specifically affect the mitotic machinery target tubulin. Monastrol will therefore be a particularly useful tool for studying mitotic mechanisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mayer, T U -- Kapoor, T M -- Haggarty, S J -- King, R W -- Schreiber, S L -- Mitchison, T J -- CA78048/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1999 Oct 29;286(5441):971-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, and Institute of Chemistry and Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Thomas_Mayer@hms.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10542155" target="_blank"〉PubMed〈/a〉

Keywords: Actins/drug effects ; Animals ; Cattle ; Cell Line ; Cytoskeleton/drug effects ; Golgi Apparatus/drug effects ; Kinesin/*drug effects ; Microtubules/drug effects ; Mitosis/*drug effects ; Molecular Motor Proteins/drug effects ; Phenotype ; Phosphoproteins/metabolism ; Protein Processing, Post-Translational ; Pyrimidines/*pharmacology ; RNA-Binding Proteins/metabolism ; Spindle Apparatus/*drug effects ; Thiones/*pharmacology ; Tumor Cells, Cultured ; Xenopus ; *Xenopus Proteins

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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Mechanoregulation: Cellular seat belts (2010)

Y. Shimamoto ; T. M. Kapoor

Nature Publishing Group (NPG)

In: Nature. 468(7323): 518-9. doi: 10.1038/468518a.

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Publication Date: 2010-11-26

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shimamoto, Yuta -- Kapoor, Tarun M -- England -- Nature. 2010 Nov 25;468(7323):518-9. doi: 10.1038/468518a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107420" target="_blank"〉PubMed〈/a〉

Keywords: Cell Division ; *Chromosome Segregation ; Kinetochores/*metabolism ; Saccharomyces cerevisiae/cytology ; Spindle Apparatus/*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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Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient (2008)

B. G. Fuller ; M. A. Lampson ; E. A. Foley ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 453(7198): 1132-6. doi: 10.1038/nature06923.

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Publication Date: 2008-05-09

Description: Proper partitioning of the contents of a cell between two daughters requires integration of spatial and temporal cues. The anaphase array of microtubules that self-organize at the spindle midzone contributes to positioning the cell-division plane midway between the segregating chromosomes. How this signalling occurs over length scales of micrometres, from the midzone to the cell cortex, is not known. Here we examine the anaphase dynamics of protein phosphorylation by aurora B kinase, a key mitotic regulator, using fluorescence resonance energy transfer (FRET)-based sensors in living HeLa cells and immunofluorescence of native aurora B substrates. Quantitative analysis of phosphorylation dynamics, using chromosome- and centromere-targeted sensors, reveals that changes are due primarily to position along the division axis rather than time. These dynamics result in the formation of a spatial phosphorylation gradient early in anaphase that is centred at the spindle midzone. This gradient depends on aurora B targeting to a subpopulation of microtubules that activate it. Aurora kinase activity organizes the targeted microtubules to generate a structure-based feedback loop. We propose that feedback between aurora B kinase activation and midzone microtubules generates a gradient of post-translational marks that provides spatial information for events in anaphase and cytokinesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724008/" 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/PMC2724008/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fuller, Brian G -- Lampson, Michael A -- Foley, Emily A -- Rosasco-Nitcher, Sara -- Le, Kim V -- Tobelmann, Page -- Brautigan, David L -- Stukenberg, P Todd -- Kapoor, Tarun M -- R01 GM063045/GM/NIGMS NIH HHS/ -- R01 GM063045-08/GM/NIGMS NIH HHS/ -- R01 GM065933/GM/NIGMS NIH HHS/ -- R01 GM065933-06/GM/NIGMS NIH HHS/ -- R01 GM083988/GM/NIGMS NIH HHS/ -- R01 GM083988-01/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Jun 19;453(7198):1132-6. doi: 10.1038/nature06923. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463638" target="_blank"〉PubMed〈/a〉

Keywords: Anaphase/*physiology ; Animals ; Aurora Kinase B ; Aurora Kinases ; *Cell Compartmentation ; Centromere/metabolism ; Chromatin/metabolism ; Enzyme Activation ; Fluorescence Resonance Energy Transfer ; HeLa Cells ; Humans ; Intracellular Space/*metabolism ; Microtubules/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Spindle Apparatus/metabolism ; Xenopus

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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Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein (2012)

A. J. Firestone ; J. S. Weinger ; M. Maldonado ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 484(7392): 125-9. doi: 10.1038/nature10936.

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Publication Date: 2012-03-20

Description: The conversion of chemical energy into mechanical force by AAA+ (ATPases associated with diverse cellular activities) ATPases is integral to cellular processes, including DNA replication, protein unfolding, cargo transport and membrane fusion. The AAA+ ATPase motor cytoplasmic dynein regulates ciliary trafficking, mitotic spindle formation and organelle transport, and dissecting its precise functions has been challenging because of its rapid timescale of action and the lack of cell-permeable, chemical modulators. Here we describe the discovery of ciliobrevins, the first specific small-molecule antagonists of cytoplasmic dynein. Ciliobrevins perturb protein trafficking within the primary cilium, leading to their malformation and Hedgehog signalling blockade. Ciliobrevins also prevent spindle pole focusing, kinetochore-microtubule attachment, melanosome aggregation and peroxisome motility in cultured cells. We further demonstrate the ability of ciliobrevins to block dynein-dependent microtubule gliding and ATPase activity in vitro. Ciliobrevins therefore will be useful reagents for studying cellular processes that require this microtubule motor and may guide the development of additional AAA+ ATPase superfamily inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321072/" 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/PMC3321072/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Firestone, Ari J -- Weinger, Joshua S -- Maldonado, Maria -- Barlan, Kari -- Langston, Lance D -- O'Donnell, Michael -- Gelfand, Vladimir I -- Kapoor, Tarun M -- Chen, James K -- R01 CA136574/CA/NCI NIH HHS/ -- R01 GM038839/GM/NIGMS NIH HHS/ -- R01 GM052111/GM/NIGMS NIH HHS/ -- R01 GM052111-14/GM/NIGMS NIH HHS/ -- R01 GM065933/GM/NIGMS NIH HHS/ -- R01 GM52111/GM/NIGMS NIH HHS/ -- R01 GM65933/GM/NIGMS NIH HHS/ -- R01 GM71772/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 18;484(7392):125-9. doi: 10.1038/nature10936.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425997" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Cattle ; Cilia/drug effects/metabolism/pathology ; Cytoplasm/*enzymology ; Cytoplasmic Dyneins/*antagonists & inhibitors/metabolism ; Enzyme Inhibitors/*chemistry/*pharmacology ; Hedgehog Proteins/metabolism ; Kinetochores/drug effects/metabolism ; Kruppel-Like Transcription Factors/metabolism ; Melanosomes/drug effects/metabolism ; Mice ; Microtubules/drug effects/metabolism ; Molecular Weight ; Movement/drug effects ; NIH 3T3 Cells ; Peroxisomes/drug effects/physiology ; Protein Transport/drug effects ; Quinazolinones/*chemistry/*pharmacology ; Signal Transduction/drug effects ; Spindle Apparatus/drug effects/metabolism/pathology

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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Chromosomes can congress to the metaphase plate before biorientation (2006)

T. M. Kapoor ; M. A. Lampson ; P. Hergert ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 311(5759): 388-91. doi: 10.1126/science.1122142.

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Publication Date: 2006-01-21

Description: The stable propagation of genetic material during cell division depends on the congression of chromosomes to the spindle equator before the cell initiates anaphase. It is generally assumed that congression requires that chromosomes are connected to the opposite poles of the bipolar spindle ("bioriented"). In mammalian cells, we found that chromosomes can congress before becoming bioriented. By combining the use of reversible chemical inhibitors, live-cell light microscopy, and correlative electron microscopy, we found that monooriented chromosomes could glide toward the spindle equator alongside kinetochore fibers attached to other already bioriented chromosomes. This congression mechanism depended on the kinetochore-associated, plus end-directed microtubule motor CENP-E (kinesin-7).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768465/" 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/PMC4768465/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kapoor, Tarun M -- Lampson, Michael A -- Hergert, Polla -- Cameron, Lisa -- Cimini, Daniela -- Salmon, E D -- McEwen, Bruce F -- Khodjakov, Alexey -- GM06627/GM/NIGMS NIH HHS/ -- GM24364/GM/NIGMS NIH HHS/ -- GM59363/GM/NIGMS NIH HHS/ -- GM65933/GM/NIGMS NIH HHS/ -- R01 GM024364/GM/NIGMS NIH HHS/ -- R01 GM059363/GM/NIGMS NIH HHS/ -- R37 GM024364/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2006 Jan 20;311(5759):388-91.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16424343" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Aurora Kinases ; Cell Line ; Chromosomal Proteins, Non-Histone/physiology ; Chromosomes, Mammalian/*physiology/ultrastructure ; HeLa Cells ; Humans ; Indoles/pharmacology ; Kinesin/antagonists & inhibitors ; Kinetochores/*physiology/ultrastructure ; Metaphase ; Microscopy, Confocal ; Microscopy, Electron ; Microscopy, Interference ; Microscopy, Video ; Microtubules/*physiology/ultrastructure ; *Mitosis ; Molecular Motor Proteins/physiology ; Movement ; Potoroidae ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Pyrimidines/pharmacology ; RNA Interference ; RNA, Small Interfering ; Spindle Apparatus/*physiology/ultrastructure ; Sulfonamides/pharmacology ; Thiones/pharmacology

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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