权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The tumor suppressive role of PBRM1, the bromodomain-containing subunit of the PBAF chromatin remodeling complex

PBRM1（PBAF 染色质重塑复合物的含溴结构域亚基）的肿瘤抑制作用

基本信息

批准号：
9311552
负责人：
Emily Carla Dykhuizen
金额：
$ 34.94万
依托单位：
PURDUE UNIVERSITY
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：
2017-05-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311552
关键词：
Adult Affinity Animal Model Belief Binding Binding Sites Biological Assay Biology Bromodomain Cell Adhesion Cell Adhesion Molecules Cell Line Cell Polarity Cells Cellular Assay Cellular Morphology Cessation of life Chromatin Chromatin Remodeling Factor Chromatin Structure Clear Cell Clinic Code Complex Conventional (Clear Cell) Renal Cell Carcinoma Data Disease Disease-Free Survival Enzymes Epigenetic Process Epithelial Epithelial Cells Event Fostering Gene Activation Gene Expression Regulation Genes Genetic Transcription Genomic Segment Genomics Goals Health Histone Acetylation Histones Human Investigation Kidney Lysine Maintenance Malignant Neoplasms Massive Parallel Sequencing Mediating Mesenchymal Minor Missense Mutation Mission Modeling Molecular Mutate Mutation Nucleosomes Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Protein Binding Domain Proteins Public Health Recruitment Activity Regulation Renal Cell Carcinoma Renal carcinoma Research Resistance Role SMARCA4 gene Sampling Signal Transduction Site Survival Rate Testing Therapeutic Therapeutic Intervention Therapeutic Uses Transcriptional Activation Transcriptional Regulation Treatment Efficacy Tumor Suppression Tumor Suppressor Proteins Work base chemotherapy chromatin remodeling genome-wide improved improved outcome in vivo inhibitor/antagonist innovation knock-down mutational status new therapeutic target polybromo response targeted treatment three dimensional cell culture transcription factor transcriptome sequencing translational impact tumor tumorigenesis

项目摘要

Project Summary Metastatic clear cell renal cell carcinoma (ccRCC) has low disease-free survival and limited therapeutic options. The only treatments for ccRCC have been elucidated as a result of mechanistic understanding of tumor suppression by VHL (von Hippel-Lindau), the most commonly mutated gene in ccRCC. After VHL, the second most commonly mutated gene in ccRCC patients is Polybromo-1 (PBRM1), a subunit of the SWI/SNF (or BAF for BRG1/BRM associated factors) chromatin remodeling complex, subunits of which are mutated in 20% of human cancers. PBRM1 is characterized by six sequential bromodomains proposed to bind acetylated lysines and is a subunit in a minor BAF subcomplex called PBAF (for Polybromo-1 BAF). The overall goal of this proposal is to determine the mechanism of PBRM1-mediated chromatin targeting of the PBAF complex and how that relates to downstream transcriptional regulation of genes important for tumor suppression in ccRCC. Based on our preliminary data, we hypothesize that several of the six bromodomains of PBRM1 are required for multivalent targeting of the PBAF complex to multiple histone acetylation sites located at genomic regions important for the regulation of genes involved in cell adhesion and epithelial maintenance. In the proposed study we plan to 1) Use cellular assays and animal models to confirm and characterize PBRM1 as a tumor suppressor involved in the regulation of cell adhesion, 2) Define how PBRM1 status predicts therapeutic efficacy of established and proposed ccRCC drugs, 3) Identify genomic binding sites for PBRM1 in ccRCC and the transcriptional regulation by PBAF-mediated chromatin remodeling, and 4) Define the histone acetylation marks responsible for specific recruitment of PBRM1 and PBAF. The proposed study will greatly increase our understanding of the mechanisms involved in renal tumorigenesis and expand our understanding of the tumor suppressive mechanisms of BAF-mediated chromatin remodeling. It is our belief that this study will provide direct evidence of novel therapeutic targets for treating renal cancer.

项目概要转移性透明细胞肾细胞癌（ccRCC）的无病生存率较低且治疗选择有限。由于对肿瘤机制的了解，ccRCC 的唯一治疗方法已被阐明 VHL (von Hippel-Lindau) 抑制，这是 ccRCC 中最常见的突变基因。继VHL之后，第二个 ccRCC 患者中最常见的突变基因是 Polybromo-1 (PBRM1)，它是 SWI/SNF（或 BAF）的一个亚基对于 BRG1/BRM 相关因子）染色质重塑复合体，其中 20% 的亚基发生突变人类癌症。 PBRM1 的特征是六个连续的溴结构域，拟结合乙酰化赖氨酸是称为 PBAF（Polybromo-1 BAF）的次要 BAF 子复合体中的一个亚基。本次活动的总体目标提案的目的是确定 PBRM1 介导的染色质靶向 PBAF 复合物的机制，以及这与 ccRCC 肿瘤抑制重要基因的下游转录调控有何关系。根据我们的初步数据，我们假设 PBRM1 的六个溴结构域中的几个是必需的用于将 PBAF 复合物多价靶向位于基因组区域的多个组蛋白乙酰化位点对于参与细胞粘附和上皮维持的基因的调节很重要。在提议的我们计划进行的研究 1) 使用细胞测定和动物模型来确认和表征 PBRM1 作为肿瘤参与细胞粘附调节的抑制因子，2) 定义 PBRM1 状态如何预测治疗已建立和拟议的 ccRCC 药物的功效，3) 识别 ccRCC 中 PBRM1 的基因组结合位点，以及 PBAF 介导的染色质重塑的转录调控，以及 4) 定义组蛋白乙酰化负责具体招募 PBRM1 和 PBAF 的标记。拟议的研究将大大提高我们的了解肾肿瘤发生的机制并扩大我们对肿瘤的了解 BAF 介导的染色质重塑的抑制机制。我们相信这项研究将提供治疗肾癌新治疗靶点的直接证据。