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: 8267244
• 负责人: Laura DeBusk
• 金额: $ 2.3万
• 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 2012-04-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267244
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Address; Affect; BCL6 gene; Binding Sites; Biological; Biological Assay; Biology; Cell Cycle; Cell Proliferation; Cells; Chromosomal translocation; Chromosomes, Human, Pair 8; Colorectal Cancer; DNA Binding Domain; DNA Damage; DNA Double Strand Break; DNA biosynthesis; DNA-Binding Proteins; Defect; Development; Embryo; Epithelial Cells; Erythroid; Family; Family member; Fibroblasts; Gene Family; Genes; Genome Stability; HDAC3 gene; Histones; Human; In Vitro; Intestines; Knockout Mice; Large Intestine Carcinoma; Malignant Neoplasms; Mediating; Mesenchymal; Mitosis; Mus; Mutation; Myelogenous; Oncogenes; Physiological; Play; Point Mutation; RUNX1 gene; Recruitment Activity; Role; Stem cells; TAL1 gene; TCF7L2 gene; Tissues; Work; ZNF145 gene; defined contribution; experience; genome sequencing; in vivo; leukemia; member; mouse model; progenitor; protein protein interaction; public health relevance; recombinase; t(8; 21)(q22; q22); 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）：MTG 8是转录辅助抑制因子MTG家族的成员，由于其在白血病中的频繁易位而首次被鉴定。它与其他共阻遏物如Bcl 6和组蛋白脱乙酰酶（HDAC）如HDAC 3相关。mtg 8基因敲除小鼠显示中肠缺失，这归因于间充质细胞缺陷。因此，在初步工作中，分离了无Mtg 8的鼠胚胎成纤维细胞（MEF），并发现其显示出显著的细胞增殖缺陷。细胞周期分析确定了G2/M期延迟，这可以追溯到与DNA复制相关的双链DNA断裂。MTG 8已通过人结直肠癌（CRC）肿瘤的全基因组测序以及表明MTG 8突变与CRC的发展相关的研究被鉴定为候选癌症基因。三个突变，R386 W、R395 W和A471 V是癌症驱动突变，并且所有三个突变都在蛋白质：蛋白质相互作用的区域中发现，最显著的是在Bcl 6和HDAC 3的结合位点附近，已知Bcl 6和HDAC 3两者都影响基因组稳定性。我假设MTG 8相互作用是基因组稳定性所必需的，并且MTG 8的CRC相关突变影响其与转录调节因子和/或基因组稳定性的关联。为了解决这一假设，提出了以下具体目标：具体目标1。表征MTG 8在基因组稳定性中的作用。定义MTG 8对DNA损伤控制的贡献。 目标1B。确定CRC相关MTG 8突变的体外效应。具体目标2。确定CRC相关MTG 8突变在体内的生物学作用。在特定目标1中，将分析野生型Mtg 8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。在特定目标2中，将开发含有人CRC中发现的点突变的小鼠品系。然后将对这些小鼠系进行MTG 8在基因组稳定性中的生理作用以及CRC中发现的突变如何影响其功能的表征。 公共卫生相关性：该项目名为“MTG 8在基因组稳定性和结直肠癌发展中的作用”，旨在研究MTG 8突变对结直肠癌（CRC）的影响。该项目的信息将有助于进一步解释CRC的生物学，更重要的是，描述CRC相关治疗的新靶点。