Tumor suppressor roles of E2F7 & E2F8 in hepatocellular carcinoma

E2F7 的肿瘤抑制作用

基本信息

批准号：
9457804
负责人：
GUSTAVO Walter LEONE
金额：
$ 27.12万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9457804
关键词：
Affinity Chromatography Aging Alleles Alpha Cell Amino Acid Sequence Animals Apoptosis Asses Binding Biochemical Biochemical Genetics Biophysics Carcinogens Cell Cycle Cell Cycle Regulation Cell Differentiation process Complex Cyclin A DNA DNA Binding DNA Binding Domain Data Development Dimerization E2F1 gene Evolution Family Family member Gene Expression Gene Family Gene Targeting Generations Genes Genetic Genetic Transcription Genome Goals Hepatocyte Human Individual Knock-in Knock-in Mouse Knockout Mice Laboratories Liver Macromolecular Complexes Mediating Modeling Mus N-terminal Pathway interactions Physiological Physiology Play Ploidies Positioning Attribute Primary carcinoma of the liver cells Protein Isoforms Protein Sequence Analysis Proteins Publishing Reagent Recruitment Activity Reporter Repression Research Role Series Structure Testing Transcription Repressor/Corepressor Transcriptional Regulation Tumor Suppression Tumor Suppressor Proteins Work arm base clinically relevant cyclin A2 defined contribution dimer falls gene repression genetic profiling in vivo member mouse model mutant novel programs promoter protein complex protein expression public health relevance tool transcription factor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The E2F family of transcription factors are encoded by eight distinct genes that based on structure-function studies and amino acid sequence analysis, fall into two main subclasses, activator E2Fs (E2F1-3) and repressor E2Fs composed of canonical repressors (E2F4-6) and atypical repressors (E2F7-8). Unlike other E2F family members, E2F7 and E2F8 bind DNA independent of dimerization with DP1/DP2 proteins and lack amino acid sequences typically used to interact with Rb-related proteins, and thus these atypical E2Fs may function outside the canonical CDK-Rb-E2F pathway. With the recent development of key genetic tools to conditionally disrupt or express E2f7 and E2f8 in mice, knocking mice that conditionally express endogenous wild type and mutant forms of E2F8 protein and knockin mice containing altered promoters of two key E2F-responsive target genes (Cdc6 and Cyclin A2) we expect to make significant strides towards a mechanistic understanding of how this important arm of the E2F family contribute to the control of transcription, cell cycle, and tumor suppression in vivo. Key preliminary data shows that E2F8 plays a critical role in endocycles and tumor suppression in the mouse liver and that its activity appears to be mediated by physical interactions with E2F7 and associated macro-molecular complexes to regulate gene expression outside the influence of the Cdk-Rb pathway. The overarching hypothesis of this proposal is that E2F8 functions as a transcriptional repressor to control cell cycles, genome ploidy levels and acts as a tumor suppressor in HCC. Three specific aims utilizing genetic, biochemical, and global profiling approaches will directly test this hypothesis. The long-term goal of these studies is to understand how the "atypical (E2F8) arm" contributes to the overall E2F transcriptional program in controlling cell cycles and tumor suppression.

描述（由申请人提供）：转录因子 E2F 家族由八个不同的基因编码，基于结构功能研究和氨基酸序列分析，这些基因分为两个主要亚类：激活子 E2F (E2F1-3) 和阻遏子 E2F，其组成为典型阻遏蛋白 (E2F4-6) 和非典型阻遏蛋白 (E2F7-8)。与其他 E2F 家族成员不同，E2F7 和 E2F8 与 DP1/DP2 蛋白二聚化无关地结合 DNA，并且缺乏通常用于与 Rb 相关蛋白相互作用的氨基酸序列，因此这些非典型 E2F 可能在经典 CDK-Rb-E2F 途径之外发挥作用。随着最近开发出在小鼠中条件性破坏或表达 E2f7 和 E2f8 的关键遗传工具，条件性表达内源野生型和突变型 E2F8 蛋白的敲除小鼠以及含有两个关键 E2F 响应靶基因（Cdc6 和Cyclin A2）我们期望在机制理解 E2F 家族的这一重要分支如何有助于转录控制、细胞周期和肿瘤抑制方面取得重大进展体内。关键的初步数据表明，E2F8 在小鼠肝脏的内循环和肿瘤抑制中发挥着关键作用，其活性似乎是通过与 E2F7 和相关大分子复合物的物理相互作用介导的，以在 Cdk-Rb 的影响之外调节基因表达途径。该提议的总体假设是 E2F8 作为转录抑制因子来控制细胞周期、基因组倍性水平，并在 HCC 中充当肿瘤抑制因子。利用遗传、生化和全局分析方法的三个具体目标将直接检验这一假设。这些研究的长期目标是了解“非典型（E2F8）臂”如何在控制细胞周期和肿瘤抑制方面对整体 E2F 转录程序做出贡献。