Proper coordination of cell growth with cell division is critical for viability and well-being in biological systems. The precise program of cell cycle progression is determined by the interplay of multiple regulatory mechanisms governing the accumulation and activity of distinct forms of cyclin dependent protein kinases. The research proposed in this application is one component of a larger project directed at understanding the mechanism by which G1 cyclins regulate cell cycle initiation and the mechanism by which the accumulation of those cyclins is coordinated with the cell cycle. This application specifically addresses 1) the phosphorylation dependent recognition of the G1 cyclin Cln2 by the SCFGrr1, the specificity determinant of the ubiquitinating enzyme responsible for Cln2 destruction, 2) the role of SCFGrr1 in regulation of transcription by nutrients, 3) the regulation of Grr1 and SCFGrr1 by nutrients as a potential link to the cell cycle and cellular morphogenesis; 4) the nature and role of the interaction between Cln2 and proteins identified as physical interactors. We are hopeful that the work proposed here will contribute to our understanding of the role of proteolysis in cell proliferation and physiological regulation of transcription and extend our knowledge of an important class of protein-protein interactions. Ubiquitin-mediated proteolysis has been shown to play a central role in the regulation of cell proliferation and other biological functions. Research in yeast has been pivotal in providing the general framework as well as many of the details of this important process. Understanding these regulatory mechanisms is central to understanding a range of human conditions including cancer, developmental defects and heritable disease.
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