This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Eukaryotic cells show extraordinary diversity in size and morphology. Since each cell type is characterized by a unique size and shape, the control of cell growth is integral to cellular form, function, and identity. It is likely that cell growth is controlled by highly intricate mechanisms, since single-celled organisms can maintain the same size and shape over widely varying growth conditions, and multicellular organisms are composed of cells of widely differing size and shape. Genetic experiments in both budding yeast and fission yeast have demonstrated that cyclin-dependent kinases play a critical role in controlling cell growth; however, the molecular mechanisms by which they do so are poorly understood.The focus of our research is to understand how cyclin-dependent kinases coordinate cell growth and cell division during mitosis in budding yeast. Inactivation of mitotic cyclin-dependent kinase complexes results in continuous cell growth during a G2/M arrest, causing the formation of highly elongated cells. The elongated cells grow significantly larger than wild type cells, indicating a severe failure in the mechanisms that control cell size and cell growth. We have found that an intricate signaling network functions during G2/M to control cell growth. Biochemical and genetic data argue that this signaling network is regulated by mitotic CDK activity and plays an important role in regulating the budding yeast homolog of the Wee1 kinase, which has been shown to play a central role in coordinating cell growth and mitosis in fission yeast. Our most recent work suggests that Swe1 associates directly with mitotic Cdk complexes and proteins involved in cell growth, providing the first clues to the long mysterious molecular mechanisms that coordinate cell growth with the cell cycle. A focus of our future work will be to use biochemical and genetic approaches to understand the molecular signaling mechanisms that coordinate cell growth and cell division.Another major focus of our work is to understand the mechanisms that control passage through the G1 phase of the cell cycle. G1 is a crucial period where cells assess external conditions and cell size, and then make a decision regarding whether to commit to a new round of cell division. Cells in G1 initiate a new round of cell division only when they have reached a critical size and have received the appropriate external signals in the form of growth factors or nutrients. Although a number of key regulators of G1 events have been identified, we still do not understand the molecular mechanisms that integrate cell size and external signals with entry into the cell cycle. We have discovered a highly conserved protein that is required for entry into G1 in budding yeast. In addition, a number of the proteins that function in the mitotic signaling network described above also appear to be involved in controlling passage through G1. We are currently characterizing G1 control using the same biochemical and genetic approaches that we are using to characterize mitotic signaling networks.
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