KS1, A NOVEL SUPPRESSOR OF NEOPLASTIC TRANSFORMATION

KS1，一种新型肿瘤转化抑制剂

• 批准号: 6197832
• 负责人: RAUL A. URRUTIA
• 金额: $ 18.2万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197832
• 关键词: DNA binding protein; antineoplastics; apoptosis; cell growth regulation; cell proliferation; growth inhibitors; neoplastic transformation; pancreas neoplasms; protein structure function; tissue /cell culture; transcription factor; tumor suppressor proteins

Zinc finger proteins are key regulators of normal morphogenesisi and can also act as either oncogenes or tumor suppressors. The investigators laboratory has been focused on studying the role of these proteins in the regulation of pancreatic gene expression, cell growth, and the modulation of neoplastic transformation. Pancreatic cancer currently ranks fifth as a cause of death by cancer in the USA and has one fo the poorest prognoses among the human neoplasias. Although the etiology and pathophysiology of pancreatic ductal cancer is poorly understood, increasing evidence indicates that alterations in transcription factors (e.g. DPC4/Smad4) are often associated with this disease. Furthermore, transcription factors such as p53 are beginning to be tested as genetic therapeutic tools to treat this disease. The proposal is focused on the biochemical and functional characterization of KS1, a novel zinc finger transcription factor isolated from the pancreas that represses transcription and suppresses neoplastic transformation. Both of these functional properties of KS1 are interrelated since the deletion of a distinct transcriptional repressor domain, R2 abolishes the ability of this protein to suppress neoplastic transformation. Currently, however, the mechanisms that KS1 uses to perform these functions are poorly understood. Moreover, the role of KS1 in the regulation of pancreatic epithelial cell growth is also undefined. In this proposal, the investigator will test the central hypothesis that KS1 is a sequence-specific transcriptional repressor protein that inhibits cell growth and neoplastic transformation by regulating apoptosis and/or cell proliferation. The investigator will use state-of-the-art biochemical and molecular techniques combined with well established assays and cell models for studying neoplastic transformation and pancreatic epithelial cell growth. The proposed aims are to: 1) determine the role of KS1 in the regulation of cell proliferation and apoptosis, 2) determine the DNA binding activity of KS1, and 3) characterize the mechanisms underlying the function of the R2 domain of KS1 as a transcriptional repressor and suppressor of transformation. The investigator expects that successful completion of this proposal will provide novel information on molecular mechanisms used by zinc finger proteins to regulate cell growth and neoplastic transformation. This knowledge will serve as the foundation for future studies aimed at using these proteins as therapeutic tools for controlling abnormal cell growth.

锌指蛋白是正常形态发生的关键调节因子 也可以作为癌基因或肿瘤抑制基因。调查人员 实验室一直致力于研究这些蛋白质在 胰腺基因表达、细胞生长的调节以及 肿瘤转化。胰腺癌目前位居第五位 美国因癌症死亡的人数最多，并且是全球预后最差的国家之一 人类肿瘤。尽管胰腺炎的病因学和病理生理学 人们对导管癌知之甚少，越来越多的证据表明 转录因子（例如 DPC4/Smad4）的改变通常与 患有这种疾病。此外，p53等转录因子也开始出现 作为治疗这种疾病的基因治疗工具进行测试。提案 专注于 KS1 的生化和功能表征，KS1 是一种新型 从胰腺中分离出的锌指转录因子可抑制 转录并抑制肿瘤转化。这两个 KS1 的功能特性是相互关联的，因为删除了一个不同的 转录抑制结构域，R2 消除了该蛋白的能力 抑制肿瘤转化。然而，目前 KS1 的机制 人们对执行这些功能的用途知之甚少。此外，作用 KS1 在胰腺上皮细胞生长调节中的作用也未明确。 在这个提案中，研究者将检验中心假设 KS1 是 抑制细胞生长的序列特异性转录阻遏蛋白 通过调节细胞凋亡和/或细胞发生肿瘤转化 增殖。研究人员将使用最先进的生化和 分子技术与成熟的测定和细胞模型相结合 研究肿瘤转化和胰腺上皮细胞生长。这 提出的目标是：1）确定KS1在细胞调节中的作用 增殖和凋亡，2) 测定 KS1 的 DNA 结合活性，以及 3) 表征KS1 R2结构域功能的潜在机制 作为转录抑制子和转化抑制子。这 研究者期望该提案的成功完成将提供 有关锌指蛋白分子机制的新信息 调节细胞生长和肿瘤转化。这些知识将服务于 作为未来研究的基础，旨在使用这些蛋白质作为 控制异常细胞生长的治疗工具。