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The Role of pRB and Co-repressors in Transcriptional Regulation

pRB 和辅阻遏物在转录调控中的作用

基本信息

批准号：
8761281
负责人：
Brian D Dynlacht
金额：
$ 3.39万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-11-29 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8761281
关键词：
Ablation Animal Model Apoptosis Binding Biochemical Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cells Chromatin Chromatin Remodeling Factor Complex Coupled DNA E2F transcription factors Enzymes Exhibits Family Funding G1 Phase Gene Expression Gene Expression Regulation Gene Mutation Gene Targeting Genes Genetic Transcription Growth Health Histone Deacetylase In Vitro Individual Knockout Mice Lead Light Maintenance Mammalian Cell Muscle Muscle Cells Muscle Fibers Normal Cell Nucleosomes Phase Transition Phenotype Physiological Play Population Positioning Attribute Proliferating Protein Isoforms Proteins RNA Interference Recruitment Activity Regulation Repression Repressor Proteins Retinoblastoma Retinoblastoma Protein Role Specificity Transcriptional Regulation Tumor Suppressor Proteins base cdc Genes cell growth chromatin modification chromatin remodeling gene repression genome-wide histone methyltransferase histone modification in vivo p107 protein prevent promoter tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cellular differentiation is tightly coordinated with, and dependent upon, permanent cell cycle exit. The tumor suppressor pRB prevents tumorigenesis by virtue of its ability to suppress proliferation. It is clear that the pRB tumor family, which is comprised of pRB and the related proteins, p107 and p130 (also known as pocket proteins), is recruited to promoters through the E2F transcription factor. Once recruited, pocket proteins coordinate changes in gene expression with cell cycle progression and cell cycle exit, during transient growth arrest (quiescence) and permanent growth arrest that occurs upon cellular differentiation. Pocket proteins play a role in recruiting a cadre of co-repressors, such as Sin3-HDAC and histone methyltransferases, that modify chromatin and silence gene expression. Yet the mechanisms underlying the pRB-dependent changes in gene expression are not well understood. It is important to unravel these mechanisms, since they are likely to shed light on transcriptional controls associated with normal cell growth and tumor suppressive mechanisms. It is also unclear what transcriptional controls distinguish cells progressing through the M/G1 phase transition from those observed in cells re-emerging from growth arrest (the G0/G1 phase transition) and how differences in factor recruitment and chromatin modifications dictate transient growth arrest versus permanent cell cycle exit. We have found that pRB and the Sin3 co-repressor play a role in both settings. In this proposal, we seek to build upon results of the previous funding period and explore answers to these fundamental issues in the following Aims: (1) We will examine the role of E2F, pocket proteins, and Sin3 isoforms in factor recruitment, chromatin modification, and nucleosome remodeling during permanent cell cycle exit in muscle cells. (2) We will determine whether Sin3A and Sin3B isoforms can specifically regulate target gene transcription and purify endogenous complexes. (3) We will investigate the phenotype of Sin3 conditional knock-outs and attempt to unravel a role for Sin3 isoforms in maintaining cell cycle arrest in an animal model.

描述（由申请人提供）：细胞分化与永久性细胞周期退出紧密协调，并依赖于永久性细胞周期退出。肿瘤抑制因子pRB通过其抑制增殖的能力来防止肿瘤发生。很明显，由pRB和相关蛋白p107和p130（也称为口袋蛋白）组成的pRB肿瘤家族通过E2 F转录因子募集到启动子。一旦被招募，口袋蛋白在细胞分化后发生的短暂生长停滞（静止）和永久生长停滞期间协调基因表达的变化与细胞周期进展和细胞周期退出。口袋蛋白在招募一批共阻遏物中发挥作用，如Sin 3-HDAC和组蛋白甲基转移酶，它们修饰染色质并沉默基因表达。然而，pRB依赖的基因表达变化的机制还没有得到很好的理解。重要的是要解开这些机制，因为它们可能揭示与正常细胞生长和肿瘤抑制机制相关的转录控制。目前还不清楚是什么转录控制区分细胞进展通过M/G1期转变从那些观察到的细胞重新出现从生长停滞（G 0/G1期转变），以及如何在因子募集和染色质修饰的差异决定短暂的生长停滞与永久的细胞周期退出。我们已经发现，pRB和Sin 3共阻遏物在这两种情况下发挥作用。在这项提案中，我们寻求建立在前一个资助期的结果基础上，并在以下目标中探索这些基本问题的答案：（1）我们将研究E2 F，口袋蛋白和Sin 3亚型在肌细胞永久细胞周期退出过程中的因子募集，染色质修饰和核小体重塑中的作用。(2)我们将确定Sin 3A和Sin 3B亚型是否可以特异性地调节靶基因的转录和纯化内源性复合物。(3)我们将研究Sin 3条件性基因敲除的表型，并试图在动物模型中阐明Sin 3亚型在维持细胞周期停滞中的作用。