Browsing by Subject "Mitotic Spindle Apparatus"
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Item The Mitotic Spindle Mediates Inheritance of the Golgi Ribbon Structures(2010-05-14) Wei, Jen-Hsuan; Seemann, JoachimThe mammalian Golgi ribbon disassembles during mitosis and reforms in both daughter cells after division. Mitotic Golgi membranes concentrate around the spindle poles, suggesting that the spindle may control Golgi partitioning. To test this, cells were induced to divide asymmetrically with the entire spindle segregated into only one daughter cell. A ribbon reforms in the nucleated karyoplasts, whereas the Golgi stacks in the cytoplasts are scattered. However, the scattered Golgi stacks are polarized and transport cargo. Microinjection of Golgi extract together with tubulin or incorporation of spindle materials rescues Golgi ribbon formation. Therefore, the factors required for postmitotic Golgi ribbon assembly are transferred by the spindle, but the constituents of functional stacks are partitioned independently, suggesting that Golgi inheritance is regulated by two distinct mechanisms.Item Synthesis and Molecular Pharmacology of the Diazonamides(2006-12-19) Burgett, Anthony William George; Harran, PatrickDiazonamide A is structurally novel, marine-derived natural product potently capable of inhibiting the growth of the cultured human cancer cell lines in vitro. Following the eassignment of diazonamide structure in 2001, we began a program to understand the compound's cellular mode of action. I determined that the diazonamides are potent antimitotic agents that induce the formation of mono-aster mitotic spindles. The synthesis of numerous analogs established structure activity relationships which guided the preparation of biotinylated, fluorescent, and radiolabeled forms of the natural product. These analogs were used in a variety of experiments to demonstrate diazonamide A effects mitotic spindle assembly in novel manner distinct from conventional tubulin interacting agents. This finding suggests diazonamide A will prove a valuable probe of new cell biology and a unique chemotherapeutic drug lead. The second major focus of my work involved the total synthesis of diazonamide A. The central feature of our approach employed a hypervalent iodine species to oxidatively install the central diazonamide diarylaminal. This net two electron oxidative internal crosslink between tyrosine and tryptophan accesses the diazonamide core from a simple peptide-derived substrate. Building on the discovery, fully synthetic diazonamide A was prepared in a total of 19 operations from 5 segments of comparable complexity. This successful synthesis allows for a truly scalable and practical synthesis of diazonamide structures for further pre-clinical evaluation as new anti-cancer drugs.