MYC DEPENDENT PATHWAYS IN APOPTOSIS AND LYMPHOMAGENESIS

描述：（改编自研究者摘要） c-myc基因是任何一种基因突变中最常见的位点之一。 癌基因在人类癌症中的作用大约15%的癌症 表现出c-myc基因的扩增，大约25%的乳腺癌患者 癌症也有类似的突变。c-myc染色体易位 发生在100%的伯基特淋巴瘤，以及相关的 小鼠浆细胞瘤。尽管这些染色体异常 多年来一直被认可，直到最近才变得明显 错义突变也可以在致癌基因中发挥重要作用， c-myc的活性，超过60%的伯基特氏病和艾滋病， 相关的淋巴瘤有突变，改变蛋白质结构， 已经转移的c-myc基因面临的一个主要问题， c-myc场（和一般的核癌基因）是细胞基因 靶向于癌蛋白以介导其在细胞周期中的功能 进展或凋亡。更广泛的兴趣是c-myc信号是如何 这条通路与其他致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的作用。 他们将使用一种新的细胞系， 内源性c-Myc蛋白表达，通过敲除 染色体等位基因磷酸化在c-Myc活性中的作用， 新分离的Myc相互作用因子TIP 49的功能将 也被调查。2)分析Myc依赖性的表达， 以前鉴定的以及新的靶基因。新的目标， 将选择与c-Myc的特定生物活性相关的 通过减法或差分显示方法。3)确定 c-Myc N端结构域突变的功能作用 在大多数伯基特淋巴瘤中发现的癌蛋白。细胞 仅用突变型或野生型c-Myc蛋白重建的细胞系 表达式将允许对不同的函数进行明确的分析。 不同的c-Myc突变体在B细胞和巨噬细胞中的相对活性 将分析成纤维细胞。

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.