Study the Role of Chfr in Tumorigenesis

研究 Chfr 在肿瘤发生中的作用

• 批准号: 8232694
• 负责人: Junjie Chen
• 金额: $ 27.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232694
• 关键词: Aneuploidy; Cells; Chromosomal Instability; Chromosomal Stability; Chromosome Structures; Chromosomes; Colon Carcinoma; DNA; Development; Down-Regulation; Ensure; Equilibrium; Frequencies; Funding; G1 Phase; G2 Phase; Genetic Materials; Human; Knockout Mice; Lead; MLH1 gene; Maintenance; Malignant Neoplasms; Metaphase; Microsatellite Instability; Mismatch Repair; Mitosis; Mitotic; Mitotic Checkpoint; Molecular; Mus; Mutation; PLK1 gene; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Prophase; Proteins; Regulation; Role; S Phase; Stress; Testing; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; Work; base; cancer type; functional hypothalamic amenorrhea; human STK6 protein; human disease; in vivo; insight; mouse model; overexpression; premature; prevent; research study; tumor; tumor initiation; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The genetic material DNA is packaged and organized into chromosomes in cells. Abnormal numbers of chromosomes or changes in chromosomal structures or organizations will cause human diseases including cancers. Many mitotic checkpoint pathways are evolved in the cell to maintain chromosomal stability. Studies in the last decade have highlighted the importance of spindle assembly checkpoint in the maintenance of chromosomal stability. While spindle checkpoint clearly plays a critical role in this process, mutations or dysregulations of spindle checkpoint components are not frequently observed in cancers, suggesting that tumor-associated instability could result from other deficiencies. One of these deficiencies is likely to be Chfr downregulation, which has been repeatedly observed in many types of cancers. Checkpoint protein with FHA and RING domains (Chfr) is involved in early mitotic checkpoint. It comprises of a RING domain and functions as an E3 ubiquitin ligase. During the last funding period, we have established Chfr knockout mice and demonstrated directly that Chfr acts as tumor suppressor. In addition, we showed that the major function of Chfr is to regulate the stability of several key mitotic proteins including Aurora A and PLK1. Our current working hypothesis is that Chfr normally acts throughout G1, S and G2 phases, but is specifically downregulated in mitosis. The function of Chfr is to prevent premature accumulation of many key mitotic regulators before the entry of mitosis. In the absence of Chfr and probably due to untimely upregulation of these Chfr substrates, cells would undergo abnormal mitotic transitions, which result in low frequency of chromosomal instability and thus promote tumorigenesis. Therefore, the identification of Chfr substrates and the understanding of Chfr downregulation in mitosis will reveal how Chfr normally act to prevent tumor initiation in vivo. We recently identified a potential mitotic kinase TOPK as a Chfr substrate. In addition, we demonstrated that Chfr deficiency greatly promoted tumorigenesis in MLH1-deficient mice, suggesting that chromosomal instability caused by Chfr deficiency may synergize with microsatellite instability caused by mismatch repair deficiency to facilitate tumorigenesis. Based on these preliminary studies, we propose to: (1) Study the functional interaction between Chfr and TOPK in mitosis; (2) Explore whether balanced regulation of TOPK expression is critical for the maintenance of chromosomal stability and tumor suppression; (3) Determine whether chromosomal instability caused by Chfr downregulation cooperates with mismatch repair deficiency in tumor initiation. PUBLIC HEALTH RELEVANCE: Chfr (Checkpoint with FHA and RING domains) is frequently downregulated in human cancers and specific deletion of Chfr in mice promotes tumorigenesis, suggesting that Chfr functions as a tumor suppressor. As E3 ubiquitin ligase, Chfr regulates the stability of several key mitotic regulators and thus assures proper mitotic transitions. Further study the regulation and function of Chfr will reveal mechanistically how Chfr deficiency in humans contributes to cancer development.

描述（由申请人提供）：遗传物质DNA被包装并组织成细胞中的染色体。染色体数目的异常或染色体结构或组织的改变会引起包括癌症在内的人类疾病。细胞中进化出许多有丝分裂检查点途径来维持染色体的稳定性。近十年来的研究强调了纺锤体组装检查点在维持染色体稳定性中的重要性。虽然纺锤体检查点在这一过程中明显起着关键作用，但纺锤体检查点成分的突变或失调在癌症中并不常见，这表明肿瘤相关的不稳定性可能是由其他缺陷引起的。其中一个缺陷可能是Chfr下调，这在许多类型的癌症中都被反复观察到。具有FHA和RING结构域的检查点蛋白（Chfr）参与早期有丝分裂检查点。它由一个环结构域组成，功能为E3泛素连接酶。在上一个资助期内，我们建立了Chfr基因敲除小鼠，并直接证明了Chfr作为肿瘤抑制因子的作用。此外，我们发现Chfr的主要功能是调节包括Aurora A和PLK1在内的几种关键有丝分裂蛋白的稳定性。我们目前的工作假设是Chfr通常在G1， S和G2期起作用，但在有丝分裂中特异性下调。Chfr的功能是防止许多关键的有丝分裂调节因子在有丝分裂开始前过早积累。在缺乏Chfr的情况下，可能由于这些Chfr底物的过早上调，细胞会发生异常的有丝分裂转变，导致染色体不稳定的频率降低，从而促进肿瘤的发生。因此，鉴定Chfr底物和了解Chfr在有丝分裂中的下调将揭示Chfr在体内如何正常阻止肿瘤的发生。我们最近发现了一个潜在的有丝分裂激酶TOPK作为Chfr底物。此外，我们证明Chfr缺乏极大地促进了mlh1缺陷小鼠的肿瘤发生，这表明Chfr缺乏引起的染色体不稳定可能与错配修复缺陷引起的微卫星不稳定协同促进肿瘤发生。基于这些初步研究，我们建议：(1)研究Chfr和TOPK在有丝分裂中的功能相互作用；(2)探讨TOPK是否均衡调节