Cycle progression is regulated primarily during G1 phase. This is true in majority of cells of organisms from yeast to man. It is during G1 that environmental signals are monitored to make important decisions concerning initiation of a new cell cycle. In metazoans, making the proper decision is of the utmost relevance to the course of embryonic development as well as to maintain appropriate constraints on cell proliferation. Improper regulation of cell cycle progression can result in both aberrant development and neoplastic growth. Consequently, understanding the mechanisms governing cell proliferation and the ways in which that regulation is lost is critical to understanding of human development and disease. The ultimate targets of many regulatory signals have been shown to be the cyclin dependent protein kinases (CDKs), These components of the cell cycle machinery are highly conserved from yeast to man. The primary regulatory event during G1 phase that regulates cell proliferation is governed by G1 cyclin-associated CDKs. In yeast, three G1 cyclins, Cln1-3 , comprise an essential but functionally redundant family of rate-limiting activators of cell cycle initiation. The proposed research is directed at understanding the regulation of G1 cyclin abundance and activity both during the cell cycle and in response to extracellular regulators of cell cycle progression. The proposal is presented in four specific aims. First, we will study the phosphorylation of the G1 cyclin Cln2 and its recently identified role in targeting the Cln2 protein for degradation. This will include characterization of the targeting signals on Cln2 phosphorylation will also be considered. Next, we will investigate the interface between the extracellular signals that regulate cell cycle progression during G1 phase and the cell cycle regulatory machinery. These studies will be directed at both the mating pheromone and nutrient signaling pathways. Finally, in the hope of identifying components of each of these systems as well as potential substrates o the Cln2/Cdc28 CD, we will employ both genetic and biochemical approaches to identify Cln/Cdc28 interacting proteins. It is our hope that these studies will make significant contributions to an integrated understanding of the regulation of cell cycle initiation in eukaryotes. Such information is expected to be relevant to understanding conditions arising from defects in the control of cell proliferation including developmental defects and cancer.
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