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: 6850691
• 负责人: AMY S. YEE
• 金额: $ 26.35万
• 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/6850691
• 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：（由申请人提供）乳腺癌是女性的主要杀手 其中肿瘤诱导的病因学知之甚少。Wnt途径 已成为一个主要的致癌途径，具有复杂的相互作用的癌基因 和肿瘤抑制基因。一个关键特征是f3-连环蛋白的稳定性， 作为LEF和TCF家族的转录辅激活因子发挥作用， 转录因子致癌表型最终通过以下方式建立： 关键生长调节基因启动子的调节。比如说， 细胞周期蛋白D1通过Wnt-betacatenin途径激活。Cyclin D1 mRNA 在许多乳腺癌中增加，其在乳腺细胞增殖中的作用是 很好地建立了。虽然该通路的组分和激活具有 一直是一个深入研究的领域， 在正常组织中的通路还不清楚。这些抑制机制 是鉴定新的肿瘤抑制基因的极好候选者。 该建议的工作假设是HBP 1是一种抑制剂， Wnt-β-catenin信号通过癌基因的转录抑制 和其他基因靶点。我们以前已经确定HBP 1是一种转录因子， 阻遏物和细胞周期抑制剂。与LEF和TCF一样，HBP 1是一个HMG盒 转录因子然而，HBP 1仍然是为数不多的阻遏物之一， 在这个重要的转录因子家族中。最近的研究表明， HBP 1是细胞周期蛋白D1启动子的转录阻遏物， 由Wnt-B-catenin信号激活。实验是专门设计的， 检测HBP 1和转录抑制在乳腺肿瘤发生中的作用。 HBP 1作为抑癌基因在乳腺癌中的作用 将直接测试。HBP 1位于人类染色体7 q31区域 在乳腺癌和其他癌症中经常缺失。癌症中的缺失是一种 肿瘤抑制基因的标志。长期目标是一种机制， 可能支配正常的乳腺细胞增殖， 肿瘤发生这对于理解肿瘤抑制以及如何抑制肿瘤是至关重要的。 错误调节可导致肿瘤发生。与其他工作一起， 研究可提供新的诊断和/或治疗策略的见解 治疗乳腺癌