Polarity Establishment in Yeast

描述（由申请人提供）：Cdc42p在细胞朝向多种信号（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CDC42可以在功能上取代其酵母对应物，这表明Cdc42p的关键功能是高度保守的，并且应用遗传、生物化学和细胞生物学方法的能力使酵母成为描绘Cdc42p在细胞极化中的作用机制的非常强大的系统。在该系统中，由细胞周期蛋白依赖性激酶提供的细胞周期信号触发Cdc42p的极化，这反过来又促进肌动蛋白细胞骨架的极化，Septin细丝环的组装，以及分泌物朝向指定补丁的靶向。这项研究的目的是了解Cdc42p极化是如何调节的，以及这个过程是如何被限制的，以至于细胞只形成一个极化“前沿”。癌细胞显示细胞形状、细胞间粘附和细胞运动性的改变（所有肌动蛋白依赖性过程由Cdc42p调节），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的失调促进锚定非依赖性生长，并且对于Ras转化细胞中发生的形态学变化（以及锚定非依赖性）是必需的。因此，Cdc42p失调影响癌细胞的增殖以及转移潜力。了解Cdc42p的正常调节和功能是解决其失调如何促进癌症的重要第一步。 公共卫生相关性：该研究涉及真核细胞中细胞极性的基本机制。细胞极性使细胞迁移，转移性恶性肿瘤的一个关键方面。因此，了解极性是如何建立和调节的，可能会揭示癌症治疗可能攻击的薄弱环节。

DESCRIPTION (provided by applicant): 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 a cyclin-dependent kinase 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 Cdc42p polarization is regulated, and how the process is restricted so that cells only form one polarization "front". 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. PUBLIC HEALTH RELEVANCE: The research concerns the basic mechanisms responsible for cell polarity in eukaryotic cells. Cell polarity enables cell migration, a key aspect of metastatic malignancy. Therefore, understanding how polarity is established and regulated may reveal weak links that can be attacked by cancer therapies.