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: 6691755
• 负责人: AMY S. YEE
• 金额: $ 28.45万
• 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/6691755
• 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）乳腺癌是女性的一大杀手 对其中肿瘤诱导的病因知之甚少。 Wnt通路 已成为具有复杂的致癌基因相互作用的主要致癌途径 和抑癌基因。 f3-连环蛋白的一个关键特征是稳定性， 与 LEF 和 TCF 家族一起作为转录共激活因子 转录因子。致癌表型最终由以下因素确定： 关键生长调节基因启动子的调节。例如， Cyclin D1 由 Wnt-betacatenin 途径激活。细胞周期蛋白 D1 mRNA 是 在许多乳腺癌中增加，其在乳腺细胞增殖中的作用是 建立良好。虽然该途径的成分和激活具有 失活 Wnt 的分子机制一直是一个深入研究的领域 正常组织中的途径尚不清楚。这些抑制机制 是鉴定新肿瘤抑制基因的优秀候选基因。 该提案的工作假设是 HBP1 是 通过癌基因转录抑制的 Wnt-β-连环蛋白信号传导 和其他基因靶标。我们之前已将 HBP1 鉴定为转录因子 阻遏物和细胞周期抑制剂。与 LEF 和 TCF 一样，HBP1 是一个 HMG 盒 转录因子。然而，HBP1 仍然是阻遏蛋白的少数例子之一 在这个重要的转录因子家族中。最近的工作表明 HBP1 是 Cyclin D1 启动子的转录抑制因子， 由 Wnt-B-catenin 信号传导激活。实验专门设计用于 测试 HBP1 和转录抑制在乳腺肿瘤发生中的作用。 HBP1作为抑癌基因在人类乳腺癌中的可能作用 将直接进行测试。 HBP1位于人类染色体7q31区域 它在乳腺癌和其他癌症中经常被删除。癌症中的缺失是 肿瘤抑制基因的标志。长期目标是机制 可能控制正常的乳腺细胞增殖，并且可能在以下情况下变得异常 肿瘤发生。这对于理解肿瘤抑制以及如何抑制肿瘤至关重要 错误的调节可能导致肿瘤发生。与其他工作一起，拟议的 研究可能为新的诊断和/或治疗策略提供见解 用于乳腺癌。