Tumor suppressor roles of E2F7 & E2F8 in hepatocellular carcinoma

E2F7 的肿瘤抑制作用

• 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
• 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

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）：E2F家族的转录因子由8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，激活剂E2F（E2F1 - 3）和由典型阻遏物（E2F4 - 6）和非典型阻遏物（E2F7 - 8）组成的阻遏物E2F。与其他E2F家族成员不同，E2F7和E2F8不依赖于与DP1/DP2蛋白的二聚化而结合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途径之外起作用。随着最近在小鼠中有条件地破坏或表达E2f7和E2f8的关键遗传工具的发展，有条件表达内源性野生型和突变型E2F8蛋白的敲入小鼠和含有两个关键E2F应答靶基因的改变的启动子的敲入小鼠（Cdc6和Cyclin A2）我们希望在从机理上理解E2F家族的这一重要分支如何有助于控制转录、细胞周期和体内肿瘤抑制。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起着关键作用，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，以调节Cdk-Rb途径影响之外的基因表达。该提议的首要假设是E2F8作为转录抑制因子发挥作用以控制细胞周期、基因组倍性水平，并且在HCC中作为肿瘤抑制因子。三个具体的目标，利用遗传，生物化学和全球概况的方法将直接测试这一假设。这些研究的长期目标是了解“非典型（E2F8）臂”如何有助于控制细胞周期和肿瘤抑制的整体E2F转录程序。