THE MOLECULAR MECHANISMS OF ONCOGENE ACTION

上皮癌分子遗传学的最新进展 导致识别特定的遗传病变， 关键靶基因的激活或失活。这些基因被称为 癌基因，参与细胞调节的各个方面， 生长，因此在早期致癌过程中发挥重要作用， “启蒙”和“促进”。现在重要的是要了解 这些基因发挥作用的精确机制， 可以衍生药理学试剂以改变或抑制它们的作用。 该项目的目的是表征生物化学和 c-jun癌基因转化哺乳动物的分子机制 细胞为此，我们进行了结构/功能分析， Jun癌基因家族的成员。这项研究揭示了各种 这些蛋白质的结构方面是必要的和足够的 用于转化和转录调节。 我们对c-jun癌基因的研究表明，除了DNA 结合和二聚化结构域，N-末端反式激活结构域是 细胞转化和基因反式激活所必需的。因此 c-jun反式激活能力与其 转化细胞。因此，c-jun似乎是通过调节细胞的生长来转化细胞的。 基因表达。此外，c-jun的详细突变分析 证明cJun在丝氨酸63/73处的磷酸化导致 增加反式激活并最终转化。的 这些位点的磷酸化部分是通过ras/raf依赖的 途径，提供了一个重要的生化联系，这些 致癌基因最近的研究表明，c-jun通过以下方式转化细胞： 改变细胞周期的特定部分， 凋亡 c-jun实现这一点的机制现在正在被 探讨了 我们对6月B进行了类似的分析。 Jun B是 c-jun诱导的反式激活。 使用一系列缺失突变体，我们 已经绘制了这种抑制作用的关键区域，包括 亮氨酸拉链、DNA结合结构域和仅在5'端的反式阻遏结构域 DNA结合域。 未来的研究旨在定义生物学 这些突变体的功能，反式阻遏的分子作用， 结构域和抑制活性所需的协作蛋白质 六月B。

Recent developments in the molecular genetics of epithelial cancers has led to the identification of specific genetic lesions resulting in either activation or inactivation of key target genes. These genes called oncogenes, are involved in various aspects in the regulation of cell growth and as such play major roles in the early carcinogenic processes of "initiation" and "promotion". It is now important to understand the precise mechanism by which these genes function so molecular or pharmacologic agents can be derived to alter or repress their effects. The purpose of this project is to characterize the biochemical and molecular mechanisms by which the c-jun oncogene transform mammalian cells. To this end, we have performed structure/function analysis on members of the jun oncogene family. This study has revealed various structural aspects of these proteins which are necessary and sufficient for transformation and transcriptional regulation. Our studies of the c-jun oncogene revealed that in addition to the DNA binding and dimerization domains, the N-terminal transactivation domain is required for cellular transformation and gene transactivation. Thus, the the ability of c-jun to transactivate correlates with its ability to transform cells. Therefore, c-jun appears to transform cells by regulating gene expression. Further, detailed mutation analysis of c-jun has demonstrated that phosphorlylation of cJun at serines 63/73 results in increased transactivation and ultimately transformation. The phosphorlyation of these sites is inpart through a ras/raf dependent pathway which provides an important biochemical link between these oncogenes. More recent studies suggest that c-jun transforms cells by altering specific portions of the cell cycle and may play a role in apoptosis. The mechanisms by which c-jun accomplishes this are now being explored. We have performed a similar analysis on Jun B. Jun B is an inhibitor of c-jun induced transactivation. Using a series of deletion mutants, we have mapped the regions critical for this inhibitory action to include the leucine zipper, DNA binding domain and a transrepression domain just 5' of the DNA binding domain. Future studies are aimed at defining the biologic functions of these mutants, the molecular action of the transrepression domain and the collaborating proteins required for the inhibitory activity of Jun B.