CHROMOSOME TRANSLOCATED ONCOGENES AND NEOPLASIA

一种禽类逆转录病毒转化的小鼠和人类细胞类似物 C-myc基因与染色体易位有直接关系 常见于小鼠浆细胞瘤(t(12；15))和Burkitt淋巴瘤 (t(8；14))。我们建议继续和扩大我们对分子的研究。 Myc基因激活对细胞转化的基础和后果。 小鼠浆细胞瘤中myc重排的不同分子靶点 (PCTS)将本地化及其对MyC的结构和意义 确定了表达式。为此，我们最近确定了一部小说 带有c-myc 5‘端易位断裂点的PCT类 改变myc表达的调控。这些易位的位置 确定对正常情况很重要的假定监管要素的位置 C-myc基因对照。C-myc启动子的活性和潜力 增强子元件将根据它们驱动表达的能力进行评估 融合基因(即氯霉素乙酰转移酶或CAT)在 成纤维细胞和不同类型的淋巴细胞。的染色质结构 转录活跃和沉默的c-myc等位基因将与 进一步确定重要监管区域的特征。修改后的myc基因将 稳定地整合到淋巴肿瘤细胞中，表达正常的 或截短的myc RNA。对正常和隐匿性真菌的联合作用(S) 将确定启动子的活性。转染组和转染组的活性 内源性myc基因也将在这些转基因细胞中与 MYC外显子和内含子特异的探针。这些实验将使我们能够 研究调节myc表达的潜在顺式或反式系统。 转录和转录后机制的贡献 对于c-myc的表达将在各种淋巴肿瘤系中进行评估 携带破坏c-myc基因的易位基因。最后，小鼠 含有激活的myc或人ras癌基因的逆转录病毒载体 将被引入到正常增殖的B细胞中，并对 分析了增长因素依赖关系。(十)

The murine and human cellular analogues of an avian retroviral transforming gene (c-myc) have been directly associated with chromosome translocations commonly observed in murine plasmacytomas (t(12;15)) and Burkitt lymphomas (t(8;14)). We propose to continue and extend our studies of the molecular basis and consequences of myc gene activation for cell transformation. Different molecular targets for myc rearrangements in murine plasmacytomas (PCTs) will be localized and their structures and significance for myc expression determined. To this end, we have recently identified a novel class of PCTs with translocation breakpoints clustered 5' of c-myc which alter the regulation of myc expression. The site of these translocations define the locations of putative regulatory elements important for normal c-myc gene control. The activities of c-myc promoter and potential enhancer elements will be assessed by their ability to drive the expression of a fused gene (i.e., chloramphenicol acetyl transferase or CAT) in fibroblasts and different lymphoid cell types. The chromatin structures of transcriptionally active and silent c-myc alleles will be compared to further characterize important regulatory regions. Modified myc genes will be stably integrated into lymphoid tumor cells which express either normal or truncated myc RNAs. The resultant effect(s) on normal and cryptic myc promoter activities will be determined. The activity of transfected and endogenous myc genes will also be compared in these transfected cells with myc exon and intron specific probes. These experiments will allow us to investigate potential cis or trans systems for regulating myc expression. The contributions of transcriptional and post-transcriptional mechanisms for c-myc expression will be assessed in a variety of lymphoid tumor lines bearing translocations which disrupt the c-myc locus. Finally, murine retroviral vectors containing either activated myc or human ras oncogenes will be introduced into normal proliferating B cells and their effects on growth factor dependency analyzed. (X)