Targeting BRM as novel model of prostate hyperplasia

将 BRM 作为前列腺增生的新模型

• 批准号: 7564246
• 负责人: KAREN E KNUDSEN
• 金额: $ 1.43万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564246
• 关键词: 9p22; ATP Hydrolysis; ATP phosphohydrolase; Ablation; Age; Aging; Androgen Receptor; Androgen Therapy; Androgens; Animal Model; Animals; Biological; Biological Models; Biological Response Modifiers; Castration; Cell Cycle Progression; Cell Nucleus; Cell Proliferation; Cells; Chromatin Remodeling Factor; Chromatin Structure; Chromosomes, Human, Pair 9; Clinical; Collaborations; Complex; DNA; Data; Development; Epithelial Cells; Epithelium; Fostering; Frequencies; Genetic Transcription; Growth; Heterozygote; Hyperplasia; Hypersensitivity; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Molecular; Monosomy; Mus; Nucleosomes; Phenotype; Physical condensation; Prostate; Prostatic; Prostatic Epithelium; Prostatic hypertrophy; Proteins; Recruitment Activity; Role; SMARCA4 gene; Signal Transduction; Specificity; Structure; Time; Tissue Recombination; Tumor Suppressor Proteins; Undifferentiated; Week; brahma; cell type; combinatorial; design; implantation; in vivo; neoplastic; novel; response; retinoblastoma tumor suppressor; transcription factor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Loss of specific SWI/SNF subunits is associated with compromised differentiation, aberrant proliferation and tumorigenesis. SWI/SNF chromatin remodeling complexes are recruited to DNA by selected sequence-specific transcription factors, and use the power of ATP hydrolysis to alter chromatin structure and gene transcription. Each SWI/SNF complex is composed of a combinatorial assembly of a central ATPase (either BRM of BRG1), and approximately 8-10 associated proteins (deemed BAFs, for BRG1 associated factors), which lend specificity to SWI/SNF action. Animal models have revealed that BRM is typically expressed in differentiated cells, whereas BRG1 is preferentially expressed in undifferentiated cell types. Accordingly, prostatic luminal epithelial cells express BRM but not BRG1. Although alterations of the BRM locus have not been studied, the region containing BRM (9p22-24) is known to be lost in human prostate cancer. Moreover, monosomy of chromosome 9 has been observed with high frequency. We have previously demonstrated that BRM-associated SWI/SNF complexes regulate critical transcription factors associated with prostate cancer progression and development. First, we demonstrated that BRM is required for the ability of the androgen receptor (AR) to stimulate target gene transcription. Second, we and others demonstrated that the retinoblastoma tumor suppressor protein (RB) requires SWI/SNF to halt cell cycle progression. Given the important roles of AR and RB in governing androgen dependent proliferation and differentiation, we probed the impact of BRM loss in vivo on cellular proliferation in the prostate. Using Brm -/- mice we demonstrate that ablation of BRM function results in early, significant hyperplasia with potential invasion and hypersensitivity to androgen. We also present data to demonstrate that BRM expression is reduced in prostate cancer. These data support the hypothesis that BRM serves an important growth suppressive function in the prostate. Given the paucity of models for prostatic hyperplasia and cancer, this exploratory R21 proposal is designed to: 1) characterize the hyperplastic lesions observed in Brm -/- mice and 2) directly establish the impact of BRM loss on prostatic epithelial cells using tissue recombination. The studies described will establish the utility of this model for analysis of prostate cancer, and reveal the biological consequence of BRM loss in the prostate.

描述（由申请人提供）：特定的SWI/SNF亚基的丢失与分化，异常增殖和肿瘤发生有关。 SWI/SNF染色质重塑复合物通过选定的序列特异性转录因子募集到DNA，并利用ATP水解的能力来改变染色质结构和基因转录。每个SWI/SNF复合物均由中央ATPase（BRG1的BRM）和大约8-10个相关蛋白（对于BRG1相关因素）的组合组合组成，这对SWI/SNF动作具有特异性。动物模型表明，BRM通常在分化细胞中表达，而BRG1在未分化的细胞类型中优先表达。因此，前列腺腔上皮细胞表达BRM，但不能表达BRG1。尽管尚未研究BRM基因座的改变，但已知包含BRM的区域（9P22-24）在人类前列腺癌中丧失。此外，已经观察到了9号染色体的单肌。我们先前已经证明，与BRM相关的SWI/SNF复合物调节与前列腺癌的进展和发育相关的关键转录因子。首先，我们证明了雄激素受体（AR）刺激靶基因转录的能力是必需的。其次，我们和其他人表明，视网膜细胞瘤肿瘤抑制蛋白（RB）需要SWI/SNF停止细胞周期的进展。鉴于AR和RB在治理雄激素依赖性增殖和分化中的重要作用，我们探测了BRM在体内对前列腺细胞增殖的影响。使用BRM - / - 小鼠，我们证明了BRM功能的消融会导致早期的显着增生，并具有潜在的侵袭和对雄激素的过敏性。我们还提供了数据，以证明前列腺癌中BRM表达降低。这些数据支持BRM在前列腺中具有重要的生长抑制功能的假设。鉴于前列腺增生和癌症模型的匮乏，该探索性R21提案的设计为：1）表征在BRM - / - 小鼠中观察到的增生性病变，以及2）直接建立BRM损失对前列腺上皮细胞的影响。描述的研究将建立该模型用于分析前列腺癌的实用性，并揭示前列腺中BRM丧失的生物学后果。