CHROMOSOME TRANSLOCATED ONCOGENES AND NEOPLASIA

染色体易位癌基因和肿瘤

• 批准号: 3173774
• 负责人: KENNETH B MARCU
• 金额: $ 27.46万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1994-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173774
• 关键词: B lymphocyte; DNA binding protein; Retroviridae; cell type; chromosome disorders; chromosome translocation; developmental genetics; gene expression; genetic manipulation; genetic mapping; genetic transcription; laboratory mouse; leukocyte activation /transformation; molecular cloning; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; nucleic acid sequence; oncogenes; posttranscriptional RNA processing; protooncogene; transcription factor

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)

禽逆转录病毒转化的鼠和人细胞类似物 基因（c-myc）与染色体易位直接相关 常见于小鼠浆细胞瘤 (t(12;15)) 和伯基特淋巴瘤 (t(8;14))。 我们建议继续并扩展我们的分子研究 myc 基因激活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 （PCT）将被本地化及其结构和对 myc 的意义 表达确定。 为此，我们最近确定了一本小说 具有易位断点的 PCT 类聚集在 c-myc 的 5' 处，其中 改变 myc 表达的调节。 这些易位的地点 定义对正常情况重要的假定监管要素的位置 c-myc 基因控制。 c-myc启动子的活性和潜力 增强子元件将通过其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） 成纤维细胞和不同的淋巴细胞类型。 染色质结构 转录活性和沉默的 c-myc 等位基因将与 进一步描述重要监管区域的特征。 修饰后的 myc 基因将 稳定整合到表达正常的淋巴肿瘤细胞中 或截短的 myc RNA。 对正常和隐匿 myc 的最终影响 将确定发起人的活动。 转染的活性和 还将这些转染细胞中的内源性 myc 基因与 myc 外显子和内含子特异性探针。 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 将在多种淋巴肿瘤系中评估 c-myc 表达 破坏 c-myc 基因座的轴承易位。 最后是鼠类 含有激活的 myc 或人 ras 癌基因的逆转录病毒载体 将被引入正常增殖的 B 细胞及其对 分析生长因子依赖性。 （十）