MYC Dependent Pathways in Apoptosis and Lymphomagenesis

描述（由申请人提供）：c-myc基因是人类癌症中任何癌基因最常见的突变位点之一。大约15%的癌症表现出c-myc基因的扩增，大约25%的乳腺癌具有类似的突变。100%的伯基特淋巴瘤以及相关的小鼠浆细胞瘤中发生c-myc染色体易位。除了这些总的重排，错义突变也可以在c-myc的致癌活性中起主要作用，并且超过60%的伯基特和AIDS相关淋巴瘤具有改变已经易位的c-myc基因的蛋白质结构的突变。c-myc领域（以及一般的核癌基因）面临的主要问题是癌蛋白靶向哪些细胞基因以介导其在致癌转化、细胞周期进展或凋亡中的功能。更广泛的兴趣是c-myc基因本身是如何响应于不同的信号通路进行调节的。该项目的具体目标是： 1)剖析单个靶基因在介导Myc转录因子增殖活性中的功能作用。研究将涉及功能筛选，以发现直接参与Myc途径的特定基因。 2)使用专用Myc靶基因微阵列，使用在每种生物活性中有缺陷的特定突变体，剖析Myc转录因子的凋亡、增殖和致癌反应。 3)使用果蝇遗传学来深入了解控制c-myc基因表达的调控途径，特别强调理解c-myc基因自抑制的独特功能。

DESCRIPTION (provided by applicant): The c-myc gene is among the most frequent sites of mutation for any oncogene in human cancer. Approximately 15% of all cancers exhibit amplification of the c-myc gene and about 25% of breast cancers have similar mutations. Chromosomal translocations at c-myc occur in 100% of Burkitt's lymphomas, as well as in the related mouse plasmacytomas. In addition to these gross rearrangements, missense mutations can also play a major role in the oncogenic activity of c-myc, and more than 60% of Burkitt's and AIDS associated lymphomas have mutations that alter the protein structure of the already translocated c-myc gene. The major question confronting the c-myc field (and nuclear oncogenes in general) is which cellular genes are targeted by the oncoprotein to mediate its function in oncogenic transformation, cell cycle progression or apoptosis. Of broader interest is how the c-myc gene itself is regulated in response to diverse signaling pathways. The specific goals of this project are to: 1) Dissect the functional role of individual target genes in mediating the proliferative activity of the Myc transcription factor. Research will involve functional screens to discover specific genes that contribute directly to the Myc pathway. 2) Dissect the apoptotic, proliferative and oncogenic response of the Myc transcription factor using specific mutants that are defective in each biological activity using a dedicated Myc target gene microarray. 3) Use Drosophila genetics to gain insight into the regulatory pathways that govern c-myc gene expression, with particular emphasis on understanding the unique features of c-myc gene auto-suppression.