Cdc42p plays a key role in the polarization of cells towards a variety of signals. Human CDC42 can functionally substitute for its yeast counterpart, suggesting that key functions of Cdc42p have been highly conserved, and the ability to apply genetic, biochemical, and cell biological approaches makes yeast a very powerful system for delineating the mechanism of Cdc42p action in cell polarization. In this system, a cell-cycle signal provided by the cyclin-dependent kinase Cdc28p triggers the polarization of Cdc42p, which in turn promotes downstream events including the assembly of a ring of septin filaments. The goal of the proposed research is to understand how Cdc28p promotes Cdc42p polarization, and how Cdc42p promotes septin organization. Cancer cells display alterations of cell shape, cell-cell adhesion, and cell motility (all actin-dependent processes regulated by Cdc42p), which are likely to be important for numerous aspects of malignant transformation. Deregulation of Cdc42p in mammalian cells promotes anchorage-independent growth, and is necessary for the morphological changes (as well as anchorage independence) that occur in Ras-transformed cells. Thus, Cdc42p deregulation affects the proliferation as well as the metastatic potential of cancer cells. In recent years, many studies have also uncovered links between mammalian septins and cancer. Because so little is known about septin organization and function in mammalian cells, the basis for these links is poorly understood. A better understanding of how septins are organized in yeast may provide inroads into septin behavior in mammals, and provide clues as to how their misregulation leads to cancer. ? ?
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