Cancer cells must acquire multiple mutations to evade the many restraints that prevent uncontrolled proliferation. Normal cells are vigilant in maintaining genome integrity (i.e. preventing mutations), but one hallmark of cancer cells is a defect in such self-surveillance and hence genome instability. Checkpoint controls that govern entry into mitosis are essential for maintaining genome integrity during cell proliferation. The Wee1 family kinases that inhibit cdc25 are among the targets for these checkpoints in mammalian cells and in yeast, but the basis for their regulation remains unclear. In budding yeast, the wee1 relative Swe1p is employed by the morphogenesis checkpoint, responding to perturbations of the actin cytoskeleton. We have identified a novel pathway controlling Swe1p degradation, and one aim of this proposal is to understand how Swe1p is targeted for degradation during the normal cell cycle, and how this process is halted by the checkpoint. The upstream pathways whereby cells can monitor the organization of the actin cytoskeleton will also be investigated. Although the morphogenesis checkpoint has not yet been identified in cells other than yeast, appropriate responses of mammalian cells to geometrical and mechanical features of their microenvironment are thought to involve sensing of similar types of cytoskeletal information. The metastatic potential of cancer cells increases upon derangement of these pathways, and the proposed studies will therefore provide new insight into cancer progression, and may yield potential targets for therapeutic intervention.
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