ACTIVATION OF BCL 2 IN HEMATOLOGIC MALIGNANCIES

BCL 2 在血液系统恶性肿瘤中的激活

• 批准号: 2871775
• 负责人: LINDA M BOXER
• 金额: $ 21.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2871775
• 关键词: B lymphocyte; BCL2 gene /protein; DNA footprinting; apoptosis; cAMP response element binding protein; chromosome translocation; gene expression; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; human tissue; immunoglobulin genes; laboratory mouse; leukocyte activation /transformation; lymphoma; neoplasm /cancer genetics; neoplastic transformation; oncogenes; protooncogene; transcription factor; tumor suppressor proteins

DESCRIPTION: Specific chromosomal translocations are associated with a number of hematologic malignancies. Several of these have been demonstrated to result in the activation of an oncogene. How an oncogene becomes activated by a translocation that does not affect its coding sequence is not known and is a central question in cancer research. This proposal will attempt to answer that question for the BCL-2 oncogene. In lymphomas with the t(14;18) translocation, the BCL-2 gene is translocated to the immunoglobulin locus. Because the immunoglobulin gene is active in B cells, a reasonable hypothesis is that the translocation somehow activates BCL-2, this is one step along the way to development of the malignant phenotype. The applicant proposes to study the mechanism of activation at a molecular level in human lymphoma tissue. The activation of the translocated BCL-2 gene will be compared to the transcriptional regulation of the normal BCL-2 gene during B-cell development and during B-cell activation. The goal is to reach a better understanding of the mechanisms of malignant transformation. The specific aims are: A) determination of the role of CREB in the regulation of BCL-2 in normal B cells; B) determination of the role of other transcription factors in modifying the activity of CREB on the BCL-2 promoter in normal B cells; C) determination of the role of CREB, WT1, pi1, p53, the URE factor, Myb and the immunoglobulin enhancers in the deregulation of the translocated BCL-2 gene in t(14;18) lymphomas; D) creation of a model system of the t(14;18) translocation to test the hypotheses for the deregulation of BCL-2. The successful completion of this proposal will represent the first instance where the molecular mechanisms involved in the transcriptional activation of an oncogene by translocation are known. The transcription factors that are required for the activation of expression of BCL-2 will be identified, and the region of the immunoglobulin locus that are responsible for this will be characterized.

描述：特定的染色体易位与 血液系统恶性肿瘤的数量。 其中几个已被证明 导致致癌基因的激活。 癌基因如何变成 被不影响其编码顺序的易位激活不是 已知，是癌症研究中的一个核心问题。 该提议将 尝试为BCL-2癌基因回答这个问题。 在带有淋巴瘤中 t（14; 18）易位，bcl-2基因被转移到 免疫球蛋白基因座。 因为免疫球蛋白基因在B细胞中活跃，所以 一个合理的假设是易位以某种方式激活了Bcl-2， 这是沿着恶性表型发展的一步。 申请人建议研究分子的激活机制 人体淋巴瘤组织的水平。 易位的Bcl-2的激活 基因将与正常Bcl-2的转录调节进行比较 B细胞发育期间和B细胞激活期间的基因。 目标是 更好地了解恶性转化的机制。 具体目的是：a）确定克里布在 正常B细胞​​中Bcl-2的调节； b）确定其他角色 修改CREB活性在Bcl-2上的转录因子 正常B细胞​​中的启动子； c）确定CREB，WT1，PI1的作用 p53，URE因子，MYB和免疫球蛋白增强剂 T（14; 18）淋巴瘤中易位的Bcl-2基因的放松管制； d） 创建t（14; 18）易位的模型系统以测试 假设对Bcl-2的管制。 成功完成 提案将代表分子机制的第一个实例 通过易位参与致癌基因的转录激活 已知。 激活所需的转录因子 将确定Bcl-2的表达，并确定 为此负责的免疫球蛋白基因座将被表征。