Small-molecule Inhibitors of Wee1 Degradation and Mitotic Entry

点击翻译按钮获取中文摘要

Our long term objectives are to understand the basic machinery and mechanism of mitotic entry and cell proliferation. Understanding cell proliferation is essential in generating cancer therapy since many cancer cells replicate uncontrollably. An essential feature of cell proliferation is the irreversible and controlled nature of its cell cycle transitions. Integral to these transitions are ubiquitin mediated proteolytic pathways that target substrates for proteasomal degradation. Proteolytic pathways contain E1, E2, and E3 enzymes that regulate both the timing and fidelity of degradation events. While we have identified many components of these pathways, we still have an incomplete understanding of how proteins are targeted for degradation. Both the timing and regulation of proteasomal targeting is not understood. This is especially true in the case of the mitotic entry. One of the proteins involved in inhibiting mitosis during the S and G2 phases of the cell cycle, weel, is degraded to initiate mitotic entry. Our goals are to elucidate how this particular protein is turned over to initiate mitosis. We will use a biochemical and cell biological approach to understand weel degradation and mitotic entry. We will develop a high through put assay to measure weel degradation in cells. We will determine if the compounds we attain after screening are specific for weel. Furthermore, we will determine if the same compounds also inhibit mitotic entry. The importance of known components affecting weel degradtion is underscored by the finding that they are overexpressed in certain cancers. Relevance to public health: The elucidation of cell proliferation pathways is required for generating novel cancer therapeutics. An inhibitor of the proteasome degradation pathway is currently being used to treat certain cancers including multiple myeloma.