Mechanisms of Transcriptional Repressor HBP1 in Cancer

转录抑制因子 HBP1 在癌症中的作用机制

• 批准号: 7003676
• 负责人: AMY S. YEE
• 金额: $ 25.73万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7003676
• 关键词: biological signal transduction; breast neoplasms; cadherins; clinical research; cyclins; gene induction /repression; gene mutation; human subject; neoplasm /cancer genetics; protein structure function; transcription factor; tumor suppressor proteins

DESCRIPTION: (provided by applicant) Breast cancer is a major killer of women in whom the etiology of tumor induction is poorly understood. The Wnt pathway has emerged as a major oncogenic pathway with a complex interplay of oncogenes and tumor suppressor genes. A key feature is the stability of f3-catenin, which functions as a transcriptional co-activator with the LEF and TCF family of transcription factors. The oncogenic phenotypes are ultimately established by the regulation of promoters for key growth regulatory genes. For example, Cyclin D1 is activated by, the Wnt-betacatenin pathway. Cyclin D1 mRNA is increased in many breast cancers, and its role in breast cell proliferation is well established. While the components and the activation of the pathway have been an area of intense study, the molecular mechanisms that inactivate the Wnt pathway in normal tissues are not well understood. These suppressive mechanisms are excellent candidates for the identification of new tumor suppressor genes. The working hypothesis of this proposal is that HBP1 is a suppressor of Wnt-beta-catenin signaling through the transcriptional repression of oncogenes and other gene targets. We had previously identified HBP1 as a transcriptional repressor and cell cycle inhibitor. Like LEF and TCF, HBP1 is an HMG box transcription factor. However, HBP1 remains one of few examples of repressors within this important transcription factor family. Recent work indicates that HBP1 is a transcriptional repressor of the Cyclin Dl promoter, which is activated by Wnt-B-catenin signaling. Experiments are specifically designed to test the role of HBP1 and transcriptional repression in breast tumorigenesis. The possible role of HBP1 as a tumor suppressor gene in human breast cancer will be tested directly. HBP1 is located in human Chromosome 7q31--a region that is frequently deleted in breast and other cancers. Deletion in cancer is a hallmark of tumor suppressor genes. The long-term goals are the mechanisms that may govern normal breast cell proliferation and that may become aberrant in tumorigenesis. This is critical to understanding tumor suppression and to how mis-regulation may lead to oncogenesis. Together with other work, the proposed studies may provide insights into new diagnostic and/or therapeutic strategies for breast cancer.

描述：(申请人提供)乳腺癌是女性的主要杀手 其诱发肿瘤的病因学知之甚少。WNT路径 已经成为一种主要的致癌途径，具有复杂的致癌基因相互作用 和肿瘤抑制基因。一个关键特征是f3-catenin的稳定性，它 与LEF和TCF家族作为转录共激活因子发挥作用 转录因子。致癌表型最终是由 关键生长调控基因启动子的调控。例如, 细胞周期蛋白D1被Wnt-Betacatenin途径激活。细胞周期蛋白D1mRNA是 在许多乳腺癌中增加，它在乳腺细胞增殖中的作用是 久负盛名。而该途径的成分和激活 WNT失活的分子机制一直是人们密切研究的领域 正常组织中的信号转导途径还不是很清楚。这些抑制机制 是鉴定新的肿瘤抑制基因的极佳候选者。 这一建议的工作假设是HBP1是一种抑制 癌基因转录抑制中的WNT-β-连环蛋白信号转导 和其他基因靶点。我们之前发现HBP1是一种转录 抑制物和细胞周期抑制物。与LEF和TCF一样，HBP1也是一个HMG盒子 转录因子。然而，HBP1仍然是为数不多的抑制因子之一 在这个重要的转录因子家族中。最近的研究表明， HBP1是Cyclin DL启动子的转录抑制因子，它是 被WNT-B-连环蛋白信号激活。实验是专门为 检测HBP1和转录抑制在乳腺肿瘤发生中的作用。 HBP1作为抑癌基因在乳腺癌中的可能作用 将直接接受测试。HBP1位于人类染色体7q31-a区 在乳腺癌和其他癌症中，该基因经常被缺失。癌症中的缺失是一种 肿瘤抑制基因的标志。长期目标是这样一种机制 可能控制正常的乳腺细胞增殖，这可能会在 肿瘤发生学。这对于理解肿瘤抑制以及如何 错误的调控可能导致肿瘤的发生。连同其他工作，建议的 研究可能为新的诊断和/或治疗策略提供见解 治疗乳腺癌。