Molecular mechanisms controlling entry into mitosis

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DESCRIPTION (provided by applicant): Single-celled organisms show a remarkable ability to maintain the same size over widely varying external conditions. Multicellular organisms also show a remarkable ability to control cell size, as they are able to generate many different cell types of different sizes. Despite the fundamental importance of cell size control, we know little about the molecular mechanisms that control cell size and cell growth. Maintenance of a specific cell size requires coordination of cell growth and cell division. In fission yeast, the Wee1 kinase and the Cdc25 phosphatase are required for coordination of cell growth and cell division at G2/M. Wee1 phosphorylates and inhibits cyclin-dependent kinases, thereby delaying entry into mitosis until a critical size has been reached. Cdc25 removes the inhibitory phosphate added by Wee1, thereby promoting entry into mitosis. An understanding of the signaling mechanisms that control the activity of Wee1 and Cdc25 should provide important clues to how cells sense and maintain a specific cell size. Surprisingly, however, these mechanisms are largely unknown. The budding yeast homologs of Wee1 and Cdc25 are called Swel and Mih1. Our recent work has shown that Swel and Mih1 are required for coordination of cell growth and cell division at G2/M, indicating that the basic functions of fission yeast Wee1 and Cdc25 have been conserved in budding yeast. The goal of the experiments described in this proposal will be to use the powerful experimental approaches available in budding yeast to understand coordination of cell growth and cell division at G2/M. We will first characterize the molecular mechanisms that regulate Swe1 and Mih1 during a normal cell cycle and during a Swe1 dependent checkpoint delay. We will then identify proteins responsible for regulation of Swe1 and Mih1 and determine how they are controlled. Our long-term goal is to discover the upstream physiological signals that regulate Swe1 and Mih1 to coordinate cell growth and cell division at G2/M. An understanding of the mechanisms that coordinate cell growth and cell division may be relevant to cancer, since they represent potential targets for drugs aimed at blocking the growth of tumor cells.