Function of Myeloid Translocation Gene Related-1

髓样易位基因相关1的功能

基本信息

批准号：
7600372
负责人：
SCOTT W HIEBERT
金额：
$ 32.92万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7600372
关键词：
Acute Myelocytic Leukemia Alleles Apoptosis Breast Breast Cancer Cell CBFA2T1 gene Cancer cell line Cell Lineage Cell Nucleus Cells Chemicals Chromosomal translocation Co-Immunoprecipitations DNA Binding Data Development Diet Endocrine Family Family member Gene Family Gene Targeting Genes Genetic Genetic Transcription Germ Lines Growth Hematopoietic Neoplasms Homologous Gene In Vitro Intestines Knockout Mice Malignant Neoplasms Mediating Microinjections Mus Mutagenesis Myelogenous Myeloproliferative disease Oncogenes Phenotype Protein Family Recruitment Activity Regulator Genes Regulatory Pathway Role Signal Transduction Small Intestines Stem cells TCF7L2 gene Testing Tumor Suppressor Proteins Xenopus adenoma base beta catenin c-myc Genes defined contribution gene repression in vivo inhibitor/antagonist leukemia loss of function malignant breast neoplasm protein function research study response self-renewal transcription factor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The chromosomal translocations that are closely associated with cancer, most frequently hematopoietic malignancies, disrupt master regulatory genes. Myeloid Translocation Gene Related-1 (MTGR1) is a transcriptional co-repressor that is closely related to 2 genes that are frequently disrupted by chromosomal translocations in acute myeloid leukemia, ETO (MTG8) and MTG16. In addition, LOH of MTG16 is found in up to 40% of the most common form of breast cancer and re-expression of MTG16 impairs the growth of breast cancer cell lines. Thus, the MTG family of co-repressors may function as tumor suppressors. To begin to understand the regulatory pathways that depend on this family of co-repressors, we deleted Mtgr1 from the germ line of mice. These mice are mostly normal, although they are uniformly smaller than their wild-type littermates. However, within their small intestines they have lost the majority of the cell lineage that produces Paneth, goblet, and endocrine cells. Based on this phenotype, we took a candidate approach to test whether DNA binding transcription factors that are required for the normal function of stem cells in the small intestine might recruit Mtgr1. We found that Mtgr1 associates with Tcf4, but not Math1 or Hes1. TCF4 is a DNA binding factor that mediates Wnt signaling in the small intestine. Deletion of Tcf4 in mice causes depletion of the small intestinal stem cell compartment, indicating that Tcf4 is required for stem cell self renewal. TCF4 associates with co-repressors to repress transcription, but in response to Wnt signaling beta-catenin enters the nucleus and dislodges these co-repressors to activate transcription of target genes such as c-Myc. In co-immunoprecipitation experiments Mtgr1 associated with Tcf4, but co-expression of beta-catenin impaired this association, suggesting that Mtgr1 is a negative regulator of Wnt signaling. In addition, we found that the Tcf4-regulated genes c-Myc and Id2 were expressed at higher levels in Mtgr1-null mice, consistent with a role for Mtgr1 as a co-repressor that is recruited by Tcf4. Given that the oncogenes c-Myc and Id2 are over expressed in the small intestines of Mtgr1-null mice and the association of loss of function of MTG family members in leukemia and breast cancer, we hypothesize that MTG family proteins act as tumor suppressors or genetic modifiers of tumor suppressors by negatively regulating Wnt signaling. We will directly test the role of the MTG family in tumorigenesis using a combination of in vitro and in vivo studies.

描述（由申请人提供）：与癌症（最常见的是造血系统恶性肿瘤）密切相关的染色体易位会破坏主调控基因。髓样易位基因相关 1 (MTGR1) 是一种转录辅阻遏物，与急性髓系白血病中经常被染色体易位破坏的 2 个基因 ETO (MTG8) 和 MTG16 密切相关。此外，在高达 40% 的最常见乳腺癌中发现了 MTG16 的 LOH，并且 MTG16 的重新表达会损害乳腺癌细胞系的生长。因此，MTG 共抑制因子家族可能起到肿瘤抑制因子的作用。为了开始了解依赖于该共抑制因子家族的调控途径，我们从小鼠种系中删除了 Mtgr1。这些小鼠大多是正常的，尽管它们都比野生型同窝小鼠小。然而，在它们的小肠内，它们失去了产生潘氏细胞、杯状细胞和内分泌细胞的大部分细胞谱系。基于这种表型，我们采用了一种候选方法来测试小肠干细胞正常功能所需的 DNA 结合转录因子是否可能招募 Mtgr1。我们发现 Mtgr1 与 Tcf4 关联，但与 Math1 或 Hes1 不关联。 TCF4 是一种 DNA 结合因子，介导小肠中的 Wnt 信号传导。小鼠中 Tcf4 的缺失会导致小肠干细胞室的耗竭，表明 Tcf4 是干细胞自我更新所必需的。 TCF4 与共阻遏物结合以抑制转录，但响应 Wnt 信号转导，β-连环蛋白进入细胞核并去除这些共阻遏物以激活靶基因（如 c-Myc）的转录。在免疫共沉淀实验中，Mtgr1 与 Tcf4 相关，但 β-catenin 的共表达破坏了这种关联，表明 Mtgr1 是 Wnt 信号传导的负调节因子。此外，我们发现 Tcf4 调节基因 c-Myc 和 Id2 在 Mtgr1 缺失小鼠中表达水平较高，这与 Mtgr1 作为 Tcf4 招募的共阻遏物的作用一致。鉴于癌基因 c-Myc 和 Id2 在 Mtgr1 缺失小鼠的小肠中过度表达，并且 MTG 家族成员功能丧失与白血病和乳腺癌有关，我们假设 MTG 家族蛋白充当肿瘤抑制因子或遗传基因。通过负向调节 Wnt 信号传导来调节肿瘤抑制因子。我们将结合体外和体内研究直接测试 MTG 家族在肿瘤发生中的作用。