Study the Role of Chfr in Tumorigenesis

研究 Chfr 在肿瘤发生中的作用

• 批准号: 7140776
• 负责人: Junjie Chen
• 金额: $ 0.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140776
• 关键词: human; neoplasm /cancer; role

DESCRIPTION (provided by applicant): Chromosomal instability is a common feature of human cancers. Chromosomal instability allows the accumulation of multiple genetic alterations that ultimately leads to the development of cancer. Increasing evidence in the last decade suggest that mitotic checkpoint controls are essential for the maintenance of chromosomal stability. Chfr (checkpoint with FHA and ring finger domains) is a newly identified checkpoint protein involved in mitotic transitions. Studies of human primary tumors and tumor cell lines suggest that Chfr downregulation is associated with human cancer development. However, it remains to be determined whether Chfr downregulation directly contributes to tumorigenesis. We recently generated Chfr knockout mice. Using these mice, we have demonstrated that Chfr-deficient mice have an increased incidence of spontaneous and carcinogen-induced tumors, suggesting that loss or downregulation of Chfr expression contributes to tumorigenesis. Here, we propose to study mechanistically how Chfr controls mitotic progression and suppress tumor formation. Chfr contains a RING domain and has E3 ubiquitin ligase activity in vitro. We have shown that one of the physiological substrates of Chfr is a key mitotic kinase Aurora-A. In Specific Aim 1, we will determine the structure of Chfr/Aurora A complex and study at molecular level how Chfr interacts with and regulates Aurora A. In Specific Aim 2, we will explore whether Aurora A overexpression and/or p53 mutation are critical for tumor development in the absence of Chfr. These studies will reveal the mechanisms by which Chfr deficiency promotes tumorigenesis. We and others have shown that Chfr is frequently downregulated in colorectal cancers, suggesting that Chfr deficiency may contribute to colorectal cancer development in humans. This possibility will be explored in Specific Aim 3. In conclusion, studies outlined here will elucidate the precise molecular role of Chfr in the control of mitotic transition, and provide insights into the function of this newly defined early mitotic checkpoint in the maintenance of genomic stability and cancer prevention.

描述（由申请人提供）：染色体不稳定是人类癌症的一个共同特征。染色体不稳定性导致多种基因改变的积累，最终导致癌症的发生。过去十年越来越多的证据表明有丝分裂检查点控制对于维持染色体稳定性至关重要。 Chfr（具有 FHA 和无名指结构域的检查点）是一种新发现的参与有丝分裂转变的检查点蛋白。对人类原发性肿瘤和肿瘤细胞系的研究表明 Chfr 下调与人类癌症的发展有关。然而，Chfr 下调是否直接导致肿瘤发生仍有待确定。我们最近生成了 Chfr 基因敲除小鼠。使用这些小鼠，我们证明 Chfr 缺陷小鼠自发性肿瘤和致癌物诱发肿瘤的发生率增加，这表明 Chfr 表达的缺失或下调有助于肿瘤发生。在这里，我们建议从机制上研究 Chfr 如何控制有丝分裂进展和抑制肿瘤形成。 Chfr 含有 RING 结构域，并在体外具有 E3 泛素连接酶活性。我们已经证明 Chfr 的生理底物之一是关键的有丝分裂激酶 Aurora-A。在具体目标 1 中，我们将确定 Chfr/Aurora A 复合物的结构，并在分子水平研究 Chfr 如何与 Aurora A 相互作用并调节 Aurora A。在具体目标 2 中，我们将探讨在 Chfr 缺失的情况下 Aurora A 过度表达和/或 p53 突变是否对肿瘤发展至关重要。这些研究将揭示 Chfr 缺乏促进肿瘤发生的机制。我们和其他人已经证明 Chfr 在结直肠癌中经常下调，这表明 Chfr 缺乏可能导致人类结直肠癌的发展。这种可能性将在具体目标 3 中进行探讨。总之，这里概述的研究将阐明 Chfr 在控制有丝分裂转变中的精确分子作用，并深入了解这个新定义的早期有丝分裂检查点在维持基因组稳定性和癌症预防中的功能。