The cell cycle seems to be controlled by a molecular machine that generates and regulates its own oscillations. This machine has an important point of action in G1 phase called """"""""commitment"""""""" or """"""""the restriction point"""""""" in mammalian cells, and called Start in yeast. The machine adjusts the abundance and protein kinase activity of a set of cyclin-Cdc28 complexes. The ultimate goal of this project is to find out what the molecular machine is, how it works, and what it does at Start. One specific goal is to characterize the components of the machine, such as the G1 cyclins, by a mixture of genetic and biochemical analysis. A second goal is to identify and characterize the phosphorylated substrates of the cyclin-Cdc28 complexes using a genetic screen developed by S. Fields for unknown proteins that physically interact with a known protein. A third goal is to examine the relationship between growth rate and the cyclin-Cdc28 kinase activity using immunological reagents against the Cln proteins. A fourth goal is to find out how the machine is reset after Start has occurred by seeing whether direct inhibition of the kinase activity is involved, and by looking for mutants that cannot reset. It appears that the cell cycle control mechanisms used by yeast are fundamentally similar to those used by mammalian cells. Many major medical problems such as cancer, aging, wound healing are cell cycle control problems, and may be better managed when we have a better idea of the fundamental mechanisms involved.
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