REGULATION OF RAS FUNCTION

Ras原癌基因的突变已被认为与 超过20%的人类癌症的发生。阐明了 调节正常ras活性的生化途径 蛋白以及激活的ras蛋白刺激的途径 对于我们理解正常的细胞生长以及 Ras诱导肿瘤中生化途径的调节缺陷。而当 正常的ras蛋白调节大多数细胞的生长和分裂。 类型，ras蛋白也可以诱导某些细胞的终末分化。 类型。RAS蛋白在非分裂细胞中高表达 大脑。有证据表明，RAS对于维持 神经细胞的表型。然而，ras蛋白可能有额外的 在神经细胞生物学中的生物学作用(S)。理解 对大脑中ras功能的调节是定义更多 确切地说，ras蛋白在神经元中的生物学作用。这样做的一个目的是 建议是审查最近确定的 脊椎动物ras特异的核苷酸交换因子调节ras功能。 我们将利用体外生化和分子遗传学技术来 实现这一目标。另一个目标是描述特定于大脑的NEF (CDC25)。我们将检测CDC25的致癌潜力并研究 CDC25-NEF是如何利用生化技术以及 NIH-3T3细胞致瘤性测定。另一个目标是识别新的近场效应。 它调节ras和ras相关蛋白。我们将使用生化手段 为了提纯已知的NEF；我们还将使用分子遗传筛选来 发现新奇的NEF。新的近场效应的识别和研究 了解它们如何调节RAS或与RAS相关的功能 蛋白质对于理解ras的复杂性至关重要。 通路信号。此外，因为RAS牵涉到很大一部分 在人类肿瘤中，它是化疗药物的潜在靶点。它 对于理解ras在神经元(和其他非 增殖组织)在抗ras化疗药物可以 开发成功。

Mutations in the ras proto-oncogenes have been implicated in the development of greater than 20% of all human cancers. The elucidation of the biochemical pathways which regulate the activity of the normal ras proteins as well as the pathways which the activated ras proteins stimulate is critical to our understanding of normal cell growth as well as of the defective regulation of biochemical pathway in ras-induced tumors. While the normal ras proteins regulate growth and cell division for most cell types, ras protein can also induce terminal differentiation of certain cell types. Ras proteins are highly expressed in the non-dividing cells of the brain. There is evidence suggesting ras is critical for the maintenance of the neuronal phenotype. However, ras proteins could have additional biological role(s) in the biology of the neuronal cell. The understanding of the regulation of ras function in the brain is key to defining more precisely the biological role of ras protein in neurons. One aim of this proposal is to examine the mechanism by which the recently-identified vertebrate ras-specific nucleotide-exchange factors regulate ras function. We will employ in vitro biochemical and molecular genetic techniques to address this aim. Another aim is to characterize the brain-specific NEF (cdc25). We will examine the oncogenic potential of cdc25 and investigate how cdc25-NEF is regulated, using biochemical techniques as well as the NIH-3T3 cell oncogenicity assay. Another aim is to identify novel NEFs which regulate ras and ras-related proteins. We will use biochemical means to purify known NEFs; we will also employ molecular genetic screens to discover novel NEFs. The identification of novel NEFs and the understanding of how they regulate the function of ras or ras-related proteins is all-important to an understanding of the complexity of ras pathway signaling. Further, because ras is implicated in a large percent of human tumors, it is a potential target for chemotherapeutic agents. it is critical to understand the function of ras in neurons (and other non- proliferating tissues) before anti-ras chemotherapeutic agents can be successfully developed.