REGULATION OF THE MITOSIS INHIBITING KINASE--WEEL

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The correct timing of mitosis is a critical element of the eukaryotic cell cycle. If mitosis initiates prematurely then damage to the genetic material transmitted to daughter cells can occur. Such genetic damage in multicellular organisms is a contributory factor in the initiation of cancer. This project aims to define the regulation of a key mitotic inhibitory kinase, Wee1. The regulation of Wee1 will be studied in Schizzosaccharomyces pombe, which represents an excellent model eukaryotic system for such studies. That is, the regulatory elements of fundamental processes in yeast are well conserved in man. The kinase activity(ies) responsible for inactivating Wee1 at mitosis is (are) to be identified. Cdc2 has been postulated to represent such a kinase however, preliminary data suggest that in S.pombe, Cdc2 is not a major contributor to this activity. Other potential candidates such as Plo1 or Cds1 will be tested as Wee1 inhibitory kinases. If these are excluded, the kinase activity(ies) associated with the N-terminus of Wee1 will be purified biochemically, by virtue of their affinity for GST-Wee1(N-terminus) fusion proteins. Once isolated, the kinase(s) can be rapidly tested for their roles in Wee1 and cell cycle control using yeast genetics and biochemical techniques. These studies will provide a more complete understanding of the regulation of mitosis and therefore oncogenesis.