MYC Dependent Pathways in Apoptosis and Lymphomagenesis

细胞凋亡和淋巴瘤发生中的 MYC 依赖性途径

• 批准号: 7008498
• 负责人: MICHAEL David COLE
• 金额: $ 35.13万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008498
• 关键词: RNA interference; apoptosis; arthropod genetics; cell growth regulation; cell proliferation; fibroblasts; functional /structural genomics; gene expression; genetic screening; laboratory mouse; laboratory rabbit; lymphoma; microarray technology; molecular oncology; monoclonal antibody; neoplastic transformation; protein structure function; site directed mutagenesis; transcription factor

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.

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部位之一。大约15％的癌症表现出C-MYC基因的扩增，约25％的乳腺癌具有相似的突变。 C-MYC处的染色体易位发生在伯基特淋巴瘤的100％以及相关的小鼠浆细胞瘤中。除了这些严重的重排外，错义突变还可以在C-MYC的致癌活性中起主要作用，而伯基特和艾滋病相关的淋巴瘤中有60％以上具有突变，可以改变已经易位的C-MYC基因的蛋白质结构。 C-MYC领域（通常是核致癌基因）面临的主要问题是哪种细胞基因是由癌蛋白靶向的，以介导其在致癌转化，细胞周期进展或凋亡中的功能。更广泛的关注是如何根据各种信号通路来调节C-MYC基因本身。该项目的具体目标是： 1）剖析单个靶基因在介导MYC转录因子的增殖活性中的功能作用。研究将涉及功能性筛选，以发现直接促进MYC途径的特定基因。 2）使用专用的MYC靶基因微阵列在每种生物学活性中有缺陷的特定突变体，解剖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基因表达的调节途径，特别强调了解C-MYC基因自动抑制的独特特征。