A NOVEL F BOX PROTEIN REGULATING MITOSIS

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DESCRIPTION (Verbatim from the applicant's abstract): The accumulation of cyclin B and activation of the cyclin B/Cdc2 kinase drives mitosis. The ubiquitination of cyclin B by a mitotically activated ubiquitin ligase, the Anaphase Promoting Complex (APC), and the subsequent destruction of cyclin B are critical for mitotic exit. A distinct class of ubiquitin ligases, called SCF complexes, control a number of cell cycle transitions, including the G 1-S and G2-M transitions. SCF complexes contain proteins that contain F-box motifs. These F-box proteins are adapter proteins that allow the SCF complexes to bind to ubiquitination targets. The investigator has discovered a new F-box called SBP5 that controls the entry into and exit from mitosis. Much like the mitotic cyclins, SBP5 is required for mitotic entry and must be destroyed for mitotic exit. The ability for SBP5 to block mitotic exit results from its targeting a regulatory subunit of the APC, called Cdc2O. SPB5 is destroyed in mitosis, but by an APC-independent mechanism. SPB5 also localizes to the mitotic spindle. They suspect that an SBP5-associated ubiquitin ligase activity mediates destruction of regulators of the mitotic spindle. Overexpression of SBP5 induces a metaphase arrest, spindle abnormalities, and apoptosis. The aims include (1) Biochemical and mutational studies of SBP5; (2) defining the interaction of SBP5 with the mitotic spindle; (3) in vitro studies of an SBP5-associated ubiquitin ligase activity; and (4) studies of a human homolog of SBP5. By coupling spindle control to a metaphase block and apoptosis, SBP5 may participate in the pathway that microtubule poisons like Taxol and vinca alkaloids use to trigger cell death. Understanding how SBP5 blocks mitosis and induces apoptosis may provide important insight for creating new cancer chemotherapeutic drugs that act similarly or synergistically with vinca alkaloids and Taxol.