How cells determine when to divide is critical for understanding virtually every biological process that cell proliferation is manifest. Cells monitor their increase in mass before they initiate cell division. Mechanisms that coordinate cell growth with division determine the timing of initiation of cell division and, thus, they are rate limiting for overall cell proliferation. Yet, these mechanisms remain largely unknown. Inappropriate coordination of cell growth with cell division results in numerous diseases, including malignancies of all types and abnormal tissue growth and repair. This proposal seeks to identify molecular processes by which cells couple their growth with cell division, in the genetically tractable simple eukaryote Saccharomyces cerevisiae (yeast). The proposed research builds on methods we have developed for the identification of gene products that can alter the normal coupling of cell growth with cell division. To minimize the bias of the analysis, these methods rely exclusively on when cells initiate cell division. Genetic alterations, such as gene amplifications and disruptions, which can accelerate initiation of cell division, will be specifically analyzed. This proposal also seeks to determine how different nutrients affect cell cycle progression and clarify the role(s) of GI cyclin proteins in this process. GI cyclin proteins are known regulators of initiation of cell division, but the molecular pathways affected and the exact contributions that each cyclin makes are unclear. To reach these goals, the proposed study relies on well-defined continuous cell cultures, to precisely correlate cell cycle progression with specific metabolic parameters. The overall regulation of cell division is highly conserved between yeast and humans. Thus, findings from the proposed study will directly impact on the way that coupling of cell growth with division is perceived in human cells and how this process contributes to human disease.
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