Dividing cells must co-ordinate their rate of division with their rate of cell growth and protein synthesis. In many microbes, and in yeast in particular, this co-ordination is achieved by a size control mechanism: when the cell grows to a certain """"""""critical size"""""""", it triggers commitment to the cell cycle. Thus division depends on growth. Our central interest is in understanding how """"""""critical size"""""""" is measured or determined by the cell; in other words, mechanistically, what is it about growth to a certain size that allows cells to commit to the cell cycle? In S. cerevisiae, it has long been recognized that the G1 cyclin Cln3 plays a role in this co-ordination. At critical cell size, a Cln3-Cdc28 kinase activates the transcription factors SBF and MBF, which in turn induce the transcription of over 200 genes important for cell cycle progress into S-phase. More recently, we have found preliminary evidence for two additional mechanisms of size control, one involving translation, and one involving accumulation of storage carbohydrates. Here, we will study these three mechanisms of size control. First, we will study the mechanism by which Cln3 activates the SBF transcription factor, and why this activation is size-dependent. An exciting recent result suggests that the amount of Cln3 is being titrated against the number of SBF binding sites in the genome, and this constitutes the size measurement device. Second, we will study size-dependent changes in the quality and quantity of translation. These changes may be influenced by the size control genes WHI3 and WHI4, and by the mysterious """"""""translation factor"""""""" Tif51. Third, for cells growing under poor nutrient conditions, another kind of size control appears, and this size control measures the levels of internal storage carbohydrates (glycogen and trehalose). We will characterize and explore this mechanism. These three pathways have interconnections and crosstalk. All three of these pathways may have analogous if not homologous pathways in mammalian cells. ? ? ?
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