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Kwiatkowski, Nicholas

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Kwiatkowski

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Nicholas

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Kwiatkowski, Nicholas

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Author's Publications: search.filters.isAuthorOfPublication.12e642f6-f40b-44fa-8f4d-81b44787f9ec

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    Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease
    (Proceedings of the National Academy of Sciences, 2010) Bradner, James E; Mak, Raymond; Tanguturi, Shyam; Mazitschek, Ralph; Haggarty, Stephen; Ross, Kenneth; Chang, Cindy Y.; Bosco, Jocelyn; West, Nathan; Morse, Elizabeth; Lin, Katherine; Shen, John Paul; Kwiatkowski, Nicholas; Gheldof, Nele; Dekker, Job; DeAngelo, Daniel; Carr, Steven A.; Schreiber, Stuart; Golub, Todd; Ebert, Benjamin
    The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.
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    Release of Mps1 from Kinetochores Is Crucial for Timely Anaphase Onset
    (The Rockefeller University Press, 2010) Jelluma, Nannette; Dansen, Tobias B.; Sliedrecht, Tale; Kwiatkowski, Nicholas; Kops, Geert J.P.L.
    Mps1 kinase activity is required for proper chromosome segregation during mitosis through its involvements in microtubule–chromosome attachment error correction and the mitotic checkpoint. Mps1 dynamically exchanges on unattached kinetochores but is largely removed from kinetochores in metaphase. Here we show that Mps1 promotes its own turnover at kinetochores and that removal of Mps1 upon chromosome biorientation is a prerequisite for mitotic checkpoint silencing. Inhibition of Mps1 activity increases its half-time of recovery at unattached kinetochores and causes accumulation of Mps1 protein at these sites. Strikingly, preventing dissociation of active Mps1 from kinetochores delays anaphase onset despite normal chromosome attachment and alignment, and high interkinetochore tension. This delay is marked by continued recruitment of Mad1 and Mad2 to bioriented chromosomes and is attenuated by Mad2 depletion, indicating chronic engagement of the mitotic checkpoint in metaphase. We propose that release of Mps1 from kinetochores is essential for mitotic checkpoint silencing and a fast metaphase-to-anaphase transition.