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MOLECULAR ANALYSIS OF TRANSCRIPTIONAL REPRESSION BY TGIF

TGIF 转录抑制的分子分析

基本信息

批准号：
8066237
负责人：
David Wotton
金额：
$ 10.11万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066237
关键词：
Affect Antidiabetic Drugs Biochemical Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Proliferation Cells Cholecalciferol Complex Defect Development Developmental Process Embryo Embryonic Development Epithelial Esophageal Neoplasms Event Failure Family Fibroblasts Forebrain Development Gene Expression Gene Targeting Genes Genetic Transcription Goals Growth Guanine Hereditary Disease Holoprosencephaly Homeostasis Human Human Genetics In Vitro Knockout Mice Ligands Lymphoid Cell Malignant Neoplasms Mammalian Cell Mediating Mediator of activation protein Mesoderm Molecular Analysis Mutation Normal Cell Nuclear Receptors PPAR gamma Pathway interactions RXR Recruitment Activity Regulatory Element Regulatory Pathway Repression Resistance Response Elements Retinoic Acid Receptor Retinoic Acid Response Element Retinoid Receptor Retinoid X Receptor alpha Retinoids Role Signal Pathway Signal Transduction Smad Proteins Smad protein Small Interfering RNA Testing Thiazolidinediones Thymine Thyroid Hormones Transforming Growth Factor beta Tretinoin Ubiquitination cell growth regulation cell type chromatin immunoprecipitation craniofacial gene repression inhibitor/antagonist loss of function mutation mSin3 response tumor progression tumorigenesis ubiquitin ligase

项目摘要

The cellular responses activated by TGF beta family signaling underlie many developmental and proliferative events, including mesoderm induction, dorsalization and antiproliferative responses in mammalian cells. TGIF is a transcriptional represser which recruits a complex of general corepressors, including mSin3 and CtBP. TGIF interacts with TGF beta activated Smads and in response to TGF beta signaling represses expression of genes which are activated by TGF beta. Additionally, TGIF recruits a ubiquitin ligase (TiuH), resulting in ubiquitination and degradation of Smad2,the critical mediator of TGF beta signaling. Together, these functions of TGIF act to set the maximal transcriptional response of a cell to TGF beta. TGIF also inhibits gene expression via a specific retinoid X receptor (RXR)dependent retinoic acid response element. However, the mechanism of this repression and the range of genes affected remain to be determined. Mutations in the human TGIF gene result in holoprosencephaly, a severe defect of craniofacial development, in which the primary defect is a failure of ventral forebrain development. Both TGF beta and retinoic acid signaling are known to regulate forebrain development, and both pathways are implicated in HPE. It is not known whether TGIF mutations cause HPE by disrupting TGF beta signals or retinoid signaling. We will test the hypothesis that TGIF is an RXR alpha specific corepressor that inhibits RXR alpha dependent gene expression in the absence of ligand. RXR alpha is a partner for several nuclear receptors in addition to retinoic acid receptors, such that a specific inhibitor of RXRfunction will regulate many nuclear receptor pathways. We will determine which RXR alpha dependent nuclear receptor responses are repressed by TGIF and the role of corepressor recruitment and nuclear receptor ubiquitination in this repression. We will determine whether TGIF and Tiull preferentially target RXR-PPARgamma complexes via a specific interaction of Tiull with PPAR gamma. Finally, we will test whether TGIF regulates cell cycle progression by blocking TGF beta mediated growth inhibition, or by other TGF beta independent means. In many cell types, including epithelial and lymphoid cells, TGF beta signaling arrests the cell cycle, and mutations which result in loss of TGF beta responses contribute to human cancer. TGIF is amplified in esophageal tumors, which are more resistant to TGF beta mediated growth inhibition, suggesting a role for TGIF in tumorigenesis.

由TGF β家族信号传导激活的细胞反应是许多发育和增殖的基础。这些事件包括哺乳动物细胞中的中胚层诱导、背化和抗增殖反应。 TGIF是一种转录抑制因子，它募集一种包括mSin 3和 CtBP。TGIF与TGF β激活的Smads相互作用，并响应TGF β信号转导抑制表达由TGF β激活的基因。此外，TGIF募集泛素连接酶（TiuH），导致TGF β信号传导的关键介质Smad 2的泛素化和降解。我们一起努力， TGIF的这些功能用于设定细胞对TGF β的最大转录应答。TGIF也通过特异性类维生素A X受体（RXR）依赖性视黄酸反应元件抑制基因表达。然而，这种抑制的机制和受影响的基因范围仍有待确定。人类TGIF基因突变导致前脑无裂畸形，这是一种严重的颅面发育缺陷，其中主要缺陷是腹侧前脑发育失败。TGF β和维甲酸已知信号传导调节前脑发育，并且这两种途径都涉及HPE。不已知TGIF突变是否通过破坏TGF β信号或类维生素A信号导致HPE。我们将测试假设TGIF是RXR α特异性辅阻遏物，抑制RXR α依赖性基因，在不存在配体的情况下表达。RXR α是几种核受体的伴侣，视黄酸受体，这样RXR功能的特异性抑制剂将调节许多核受体途径。我们将确定哪些RXR α依赖性核受体反应被抑制， TGIF以及辅阻遏物募集和核受体泛素化在这种阻遏中的作用。我们将确定TGIF和Tiull是否通过特异性靶向靶向RXR-PPARgamma复合物， TiII与PPAR γ相互作用。最后，我们将测试TGIF是否调节细胞周期进程，阻断TGF β介导的生长抑制，或通过其它TGF β非依赖性手段。在许多细胞类型中，包括上皮细胞和淋巴细胞，TGF β信号阻滞细胞周期， TGF β反应的丧失导致人类癌症。TGIF在食管肿瘤中扩增，对TGF β介导的生长抑制更有抗性，表明TGIF在肿瘤发生中的作用。