The role of MTG8 in genomic stability and colorectal cancer development

MTG8 在基因组稳定性和结直肠癌发展中的作用

• 批准号: 7913644
• 负责人: Laura DeBusk
• 金额: $ 5.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-11-16 至 2013-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913644
• 关键词: Address; Affect; Binding Sites; Biological; Biology; CBFA2T1 gene; Carcinoma; Cell Cycle; Cell Proliferation; Cells; Colorectal Cancer; DNA Damage; DNA Double Strand Break; DNA biosynthesis; Defect; Development; Embryo; Family; Fibroblasts; Genome Stability; HDAC3 gene; Histones; Human; In Vitro; Knockout Mice; Large Intestine Carcinoma; Malignant Neoplasms; Mesenchymal; Mitosis; Mus; Mutation; Oncogenes; Physiological; Point Mutation; Role; Work; defined contribution; genome sequencing; in vivo; leukemia; member; protein protein interaction; public health relevance; tumor

DESCRIPTION (provided by applicant): MTG8 is a member of the MTG family of transcriptional co-repressors, first identified due to their frequent translocations in leukemia. It associates with other co-repressors, such as Bcl6, and histone deaceytlases (HDACs), such as HDAC3. Mtg8-null mice show a deletion of the mid-gut, which was attributed to a mesenchymal cell defect. Therefore, in preliminary work, isolated Mtg8-null murine embryonic fibroblasts (MEFs) were isolated and found to show a dramatic cell proliferation defect. Cell cycle analysis identified a G2/M phase delay, which could be traced to double strand DNA breaks that were associated with DNA replication. MTG8 has been identified as a candidate cancer gene by whole genome sequencing of human colorectal carcinomas (CRC) tumors as well as a study indicating that MTG8 mutations are associated with the development of CRC. Three mutations, R386W, R395W and A471V are cancer driver mutations and all three mutations are found in regions of protein:protein interactions, most notably near the binding sites of Bcl6 and HDAC3 both of which are known to affect genomic stability. I hypothesize that MTG8 interaction is required for genomic stability and that CRC- associated mutations of MTG8 affects its association with transcriptional regulators and/or genomic stability. In order to address this hypothesis, the following specific aims are proposed: Specific Aim 1. Characterize the role of MTG8 in genomic stability Aim 1A. Define the contribution of MTG8 to DNA damage control. Aim 1B. Define the effects of CRC-related MTG8 mutations in vitro. Specific Aim 2. Determine the biological role of CRC-related MTG8 mutations in vivo. In Specific Aim 1, the role of wild type Mtg8 and CRC- associated mutations on genomic stability will be analyzed as well as the effect of the CRC-related mutations on protein: protein interactions. In Specific Aim 2, mouse lines will be developed that contain the point mutations found in human CRCs. These mouse lines will then be characterized for the physiological role of MTG8 in genomic stability as well as how the mutations found in CRCs affect its functions. PUBLIC HEALTH RELEVANCE: The project entitled "The role of MTG8 in genomic stability and colorectal cancer development" addresses the effect of MTG8 mutations on colorectal cancer (CRC). Information from this project will help to further explain the biology of CRC and, more importantly, describe new targets for CRC-related therapies.

描述(由申请人提供)：MTG8是MTG转录共抑制因子家族的成员，最初被发现是因为它们在白血病中频繁易位。它与其他共抑制物，如Bcl6，以及组蛋白脱乙酰基酶(HDAC)，如HDAC3结合。Mtg8基因缺失的小鼠表现出中肠的缺失，这归因于间充质细胞缺陷。因此，在前期工作中，分离的Mtg8缺失的小鼠胚胎成纤维细胞(MEF)被分离出来，并发现其具有显著的细胞增殖缺陷。细胞周期分析发现细胞出现G2/M期延迟，这可以追溯到与DNA复制相关的双链DNA断裂。MTG8已被人类结直肠癌(CRC)全基因组测序确定为候选癌基因，并有研究表明MTG8突变与结直肠癌的发生发展有关。三个突变，R386W，R395W和A471V是致癌突变，所有这三个突变都在蛋白质区域发现：蛋白质相互作用，最显著的是在Bcl6和HDAC3的结合位点附近，这两个已知都会影响基因组稳定性。我假设MTG8相互作用是基因组稳定性所必需的，并且MTG8的CRC相关突变会影响其与转录调控因子和/或基因组稳定性的关联。为了解决这一假设，提出了以下特定目标：特定目标1.表征MTG8在基因组稳定目标1A中的作用。确定MTG8对DNA损伤控制的贡献。目标1B。确定结直肠癌相关的MTG8突变在体外的影响。具体目的2.确定结直肠癌相关MTG8突变在体内的生物学作用。在具体目标1中，将分析野生型Mtg8和CRC相关突变对基因组稳定性的作用以及CRC相关突变对蛋白质：蛋白质相互作用的影响。在特定的目标2中，将开发包含在人类CRC中发现的点突变的小鼠品系。然后将对这些小鼠品系进行鉴定，以确定MTG8在基因组稳定性中的生理作用，以及在CRC中发现的突变如何影响其功能。 公共卫生相关性：题为“MTG8在基因组稳定和结直肠癌发展中的作用”的项目解决了MTG8突变对结直肠癌(CRC)的影响。来自该项目的信息将有助于进一步解释结直肠癌的生物学，更重要的是，描述结直肠癌相关治疗的新靶点。