Ras protein signaling and the control of cell growth

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DESCRIPTION (provided by applicant): When conditions are not optimal for continued growth, cells stop dividing and enter into a specialized resting state, known as G0 in mammals and stationary phase in bacteria and yeasts. Cells in these quiescent states exhibit an increased resistance to environmental stress and can remain viable, although not dividing, for very long periods of time. Moreover, the transitions between these periods of quiescence and the mitotic cycle have been shown to be key points of proliferative control. Therefore, an understanding of the biology of the resting cell is an essential requirement for a complete description of the mechanisms governing eukaryotic cell proliferation. This proposal is focused on the mechanisms regulating the entry into stationary phase in the budding yeast, Saccharomyces cerevisiae. In particular, the proposed experiments focus on a collection of mutants that are defective for stationary phase entry. Several of the genes identified by these rye mutants have been found to encode important regulators of RNA polymerase (pol) II activity. Moreover, studies of the rye mutants have suggested that RNA pol II activity is controlled by the Ras protein signaling pathway. This signal transduction pathway is a key regulator of cell growth in most, if not all, eukaryotes. Interestingly, these Ras effects appear to be mediated by the proteins encoded by the above RYE genes. Therefore, the Rye proteins could be an essential link between Ras signaling and RNA pol II that allows for the proper coordination of growth and gene expression. The above work has suggested a novel mode of transcriptional control whereby signaling pathways regulate gene expression by directly targeting proteins within the RNA pol II holoenzyme. This proposal will test this hypothesis by examining whether particular Rye proteins are indeed targeted by the Ras signaling pathway. In addition, the proposed experiments will examine the roles of the Rye proteins in stationary phase entry and how these roles are affected by Ras signaling activity. Finally, the remaining rye mutants will be characterized as well as the gene expression changes that occur upon the entry into stationary phase. In all, the completion of the proposed experiments should provide insights into the role of Ras signaling activity during stationary phase entry and the manner in which growth control is coordinated with the regulation of gene expression.