MYC DEPENDENT PATHWAYS IN APOPTOSIS AND LYMPHOMAGENESIS

描述：(改编自调查人员的摘要) C-myc基因是所有 人类癌症中的癌基因。在所有癌症中约有15% 展示了c-myc基因的扩增和大约25%的乳房 癌症也有类似的突变。C-myc的染色体易位 100%发生在Burkitt淋巴瘤以及相关的 小鼠浆细胞瘤。尽管这些粗大的染色体异常 它已经被认识了很多年，直到最近才变得明显起来 错义突变也可以在致癌过程中发挥重要作用 C-myc的活性，以及超过60%的伯基特病和艾滋病- 相关淋巴瘤具有改变蛋白结构的突变 已经易位的c-myc基因。面临的一个主要问题是 C-myc域(以及一般的核癌基因)是哪些细胞基因 是以癌蛋白为靶点来调节其在细胞周期中的功能 进展或细胞凋亡。更令人感兴趣的是c-myc信号如何 通路与其他癌基因发出的信号交织在一起。 本项目的具体目标是：1)剖析 C-Myc蛋白在导致细胞生长或凋亡的信号通路中。 他们将使用新的细胞系，这些细胞系完全缺乏 基因敲除后内源性c-Myc蛋白的表达 染色体等位基因。磷酸化在c-Myc活性和蛋白表达中的作用 一种新分离的Myc相互作用因子TIP49的功能将 也被调查。2)分析Myc依赖的表达 以前发现的以及新的靶基因。新的目标是 与c-Myc的特定生物活性相关的基因将被选中 通过减法或差分显示方法。3)确定 C-Myc N-末端结构域突变的功能作用 在大多数Burkitt淋巴瘤中发现的癌蛋白。细胞 仅用突变或wt c-Myc蛋白重组的品系 表达式将允许对不同功能进行明确的分析。 不同c-Myc突变体在B细胞和B细胞中的相对活性 将对成纤维细胞进行分析。

DESCRIPTION: (adapted from the investigator's abstract) The c-myc gene is among the most frequent sites of mutation for any oncogene in human cancer. Approximately 15 percent of all cancers exhibit amplification of the c-myc gene and about 25 percent of breast cancers have similar mutations. Chromosomal translocations at c-myc occur in 100 percent of Burkitt's lymphomas, as well as in the related mouse plasmacytomas. Although these gross chromosomal abnormalities have been recognized for many years, it has only recently become apparent that missense mutations can also play a major role in the oncogenic activity of c-myc, and more that 60 percent of Burkitt's and AIDS- associated lymphomas have mutations that alter the protein structure of the already translocated c-myc gene. A major question confronting the c-myc field (and nuclear oncogenes in general) is which cellular genes are targeted ty the oncoprotein to mediate its function in cell cycle progression or apoptosis. Of broader interest is how the c-myc signaling pathway is interwoven with the signals emanating from other oncogenes. The specific goals of this project are to: 1) Dissect the role of the c-Myc protein in signaling pathways leading to cell growth or apoptosis. They will use novel cell lines that are completely deficient in endogenous c-Myc protein expression through the knockout of both chromosomal alleles. The role of phosphorylation in c-Myc activity and the function of a newly isolated Myc-interacting factor, TIP49, will also be investigated. 2) Analyze the Myc-dependent expression of previously identified as well as novel target genes. Novel targets that are linked to specific biological activities of c-Myc will be selected for by subtractive or differential display approaches. 3) Determine the functional role of mutations in the N-terminal domain of the c-Myc oncoprotein that are found in the majority of Burkitt's lymphomas. Cell lines that are reconstituted with only mutant or wt c-Myc protein expression will allow the unambiguous analysis of different functions. The relative activity of different c-Myc mutants in both B cells and fibroblasts will be analyzed.