POLARITY ESTABLISHMENT IN YEAST

Cdc42p在细胞向多种信号的极化中起关键作用（例如，T细胞向抗原呈递细胞极化，成纤维细胞向伤口部位极化，或酵母芽形成）。人类CDC42可以在功能上替代酵母中的CDC42，这表明CDC42的关键功能已经高度保守，并且能够应用遗传，生化和细胞生物学方法使酵母成为描述CDC42在细胞极化中的作用机制的一个非常强大的系统。在这个系统中，由周期蛋白依赖性激酶Cdc28p提供的细胞周期信号触发Cdc42p的极化，而Cdc42p的极化又促进肌动蛋白细胞骨架的极化，septin丝环的组装，并将分泌靶向到指定的贴片。本研究的目的是了解Cdc28p如何促进Cdc42p极化，以及Cdc42p如何促进下游事件。癌细胞表现出细胞形状、细胞间粘附和细胞运动的改变（都是由Cdc42p调节的肌动蛋白依赖过程），这可能对恶性转化的许多方面都很重要。哺乳动物细胞中Cdc42p的失调促进了锚定不依赖的生长，并且是ras转化细胞中发生的形态变化（以及锚定不依赖）所必需的。因此，Cdc42p解除调控会影响癌细胞的增殖和转移潜能。了解Cdc42p的正常调控和功能是解决其调控不当如何促进癌症的重要第一步。

Cdc42p plays a key role in the polarization of cells towards a variety of signals (e.g., T cell polarization towards antigen-presenting cells, fibroblast polarization towards wound sites, or yeast bud formation). 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 the polarization of the actin cytoskeleton, the assembly of a ring of septin filaments, and the targeting of secretion towards the designated patch. The goal of the proposed research is to understand how Cdc28p promotes Cdc42p polarization, and how Cdc42p promotes downstream events. 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. Understanding the normal regulation and function of Cdc42p is an important first step towards addressing how their misregulation might promote cancer.