Appropriate control of cell proliferation is fundamental to all biological systems from unicellular organisms to man. Understanding cell cycle regulatory mechanisms is central to understanding human development and disease. Coordination of cell cycle events involves a complex interplay of regulatory mechanisms ranging from regulated gene expression to regulated protein degradation. Those mechanisms are integrated to achieve a system of control that is both precise and malleable. As a consequence cells can be rapidly and reliably duplicated and at the same time be responsive to a broad range of internal and environmental influences that lead to alterations in cell cycle organization or rates of cell cycle progression. Regulated gene expression is critical for the proper organization of cell cycle events. A large number of genes required for important cell cycle functions are periodically transcribed during the cell cycle. Among them are cyclins, the essential activators of the cyclin dependent protein kinase (CDK) that comprises the primary cell cycle engine. In addition to being periodically expressed, cyclins, in association with CDKs, are important regulators of the cell cycle dependent transcriptional machinery. This proposal addresses the mechanisms governing cell cycle dependent transcription of a large family of genes that are specifically expressed during G1 phase of the cell cycle. Using genetic, molecular biological and biochemical approaches, we propose to i) elucidate the mechanism of G1-specific transcriptional activation by the G1 cyclin Cln3, ii) identify and characterize proteins required for the activity and regulation of the G1-specific transcription factors, SBF and MBF, iii) elucidate the mechanism by which glucose, the preferred carbon source of most cells, modulates cell cycle-regulated expression of G1 cyclins. We are hopeful that these studies will contribute to our overall understanding of this fundamental cell cycle control mechanism and the manner by which it is regulated by environmental signals.
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