Function of Myeloid Translocation Gene Related-1

髓样易位基因相关1的功能

• 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
• 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

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）：与癌症密切相关的染色体易位，最常见的造血恶性肿瘤，破坏主调节基因。髓样转运基因相关1（MTGR1）是一种转录共抑制剂，与2个基因密切相关，这些基因经常受到急性髓样白血病，ETO（MTG8）和MTG16中染色体易位的破坏。此外，在多达40％的乳腺癌形式的40％中发现了MTG16的LOH，MTG16的重新表达会损害乳腺癌细胞系的生长。因此，共抑制剂的MTG家族可能充当肿瘤抑制因子。为了开始理解取决于该共抑制剂家族的调节途径，我们从小鼠的生殖线中删除了MTGR1。这些小鼠大多是正常的，尽管它们比野生型同窝窝小。但是，在其小肠中，他们失去了产生潘妮，杯状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中干细胞正常功能所需的DNA结合转录因子是否可能募集MTGR1。我们发现MTGR1与TCF4相关，而不是Math1或Hes1。 TCF4是介导小肠中Wnt信号传导的DNA结合因子。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与共抑制剂相连以抑制转录，但响应Wnt信号β-catenin进入细胞核，并将这些共抑制剂驱散以激活靶基因（例如C-MYC）的转录。在与TCF4相关的共免疫沉淀实验中，但是β-catenin的共表达损害了这种关联，这表明MTGR1是WNT信号传导的负调节剂。此外，我们发现在MTGR1-NULL小鼠中，TCF4调节的基因C-MYC和ID2在较高水平上表达，这与MTGR1作为TCF4募集的共抑制剂的作用一致。鉴于Oncogenes C-MYC和ID2在MTGR1-NULL小鼠的小肠道中过度表达，并且MTG家族成员在白血病和乳腺癌中的功能丧失缔合，我们假设MTG家族蛋白通过负调控Wnt信号来假设肿瘤抑制剂或肿瘤抑制剂的肿瘤抑制剂。我们将使用体外和体内研究的组合直接测试MTG家族在肿瘤发生中的作用。