Targeting BRM as novel model of prostate hyperplasia

将 BRM 作为前列腺增生的新模型

• 批准号: 7273875
• 负责人: KAREN E KNUDSEN
• 金额: $ 15.83万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2007-12-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273875
• 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 SWI/SNF 亚基的丢失与分化受损、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被招募至 DNA，并利用 ATP 水解的力量来改变染色质结构和基因转录。每个 SWI/SNF 复合物由中央 ATP 酶（BRG1 的 BRM）和大约 8-10 个相关蛋白（对于 BRG1 相关因子，被视为 BAF）的组合组装组成，这为 SWI/SNF 作用提供了特异性。动物模型表明，BRM 通常在分化细胞中表达，而 BRG1 优先在未分化细胞类型中表达。因此，前列腺管腔上皮细胞表达 BRM 但不表达 BRG1。尽管尚未研究 BRM 基因座的改变，但已知含有 BRM (9p22-24) 的区域在人类前列腺癌中丢失。此外，9号染色体的单体性已被频繁观察到。我们之前已经证明，BRM 相关的 SWI/SNF 复合物调节与前列腺癌进展和发展相关的关键转录因子。首先，我们证明 BRM 是雄激素受体 (AR) 刺激靶基因转录的能力所必需的。其次，我们和其他人证明视网膜母细胞瘤肿瘤抑制蛋白 (RB) 需要 SWI/SNF 来阻止细胞周期进展。鉴于 AR 和 RB 在控制雄激素依赖性增殖和分化中的重要作用，我们探讨了体内 BRM 损失对前列腺细胞增殖的影响。使用 Brm -/- 小鼠，我们证明 BRM 功能的消除会导致早期显着的增生，并具有潜在的侵袭性和对雄激素的超敏性。我们还提供数据证明 BRM 表达在前列腺癌中降低。这些数据支持这样的假设：BRM 在前列腺中具有重要的生长抑制功能。鉴于前列腺增生和癌症模型的缺乏，这一探索性 R21 提案旨在：1）表征在 Brm -/- 小鼠中观察到的增生性病变，2）利用组织重组直接确定 BRM 损失对前列腺上皮细胞的影响。所描述的研究将建立该模型在前列腺癌分析中的实用性，并揭示前列腺中 BRM 损失的生物学后果。