PELP1, a Novel Regulator of Estrogen Receptor

PELP1，一种新型雌激素受体调节剂

• 批准号: 7209920
• 负责人: Ratna K Vadlamudi
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209920
• 关键词: athymic mouse; biological signal transduction; breast neoplasms; cell cycle; cell line; cell proliferation; chromatin; estrogen receptors; gene deletion mutation; gene induction /repression; genetic promoter element; histones; hormone regulation /control mechanism; hormone related neoplasm /cancer; human tissue; immunoprecipitation; mammary epithelium; mutant; neoplasm /cancer genetics; neoplastic growth; protein binding; protein structure function; site directed mutagenesis; transcription factor

DESCRIPTION (provided by applicant): Breast cancer is the leading type of cancer among women. Steroid hormone 17 beta-estradiol (E2) plays an important role in controlling the expression of genes involved in a wide variety of biological processes, including development, homeostasis and breast tumor progression. The biological effects of estrogen are mediated by its binding to estrogen receptor (ER). Approximately 70% of breast cancer cells express ER. Many ER-positive tumors that initially responded to antiestrogens later acquire resistance and exhibit mixed/agonist responses. Recent evidence suggests that the relevant action of estrogen and or antiestrogens in a given cell or tumor depends on the concentration of different coactivators or corepressors that modulate ER activity. In spite of these developments, our understanding of direct cause- and effect relationship between coactivators (as a critical regulators of ER) and ER signaling, and its impact on the pathobiology of breast cancer remains poorly understood. This proposal is intended to establish the role of a newly discovered coactivator (PELP1, see below) in the molecular progression of breast cancer using novel in vitro and in vivo mammary epithelial model systems. Recently, I cloned a novel ER alpha regulatory protein, Proline Glutamic acid and Leucine rich Protein (PELP1), that is abundantly expressed in the mammary gland. PELP1 is novel as it has no homology with existing coactivators, its expression is developmentally regulated in the mammary gland and upregulated ERalpha-driven transcription. In addition, PELP1 interacts with the retinoblastoma protein and promotes its hyperphosphorylation. Furthermore, PELP1 may be over expressed in human breast tumors compared to adjacent paired normal mammary gland tissues. My working hypothesis is that upregulation of PELP1 expression and functions may confer a growth advantage to breast epithelial cells and result in malignant progression by hyperstimulating ER pathway. The overall goals of this proposal are to (1) characterize the molecular events that mediate PELP1 regulation of ER pathways by domain analysis and by creating dominant negative mutants; (2) characterize the molecular mechanism of action of PELP1 by studying the nuclear function of PELP1 including, intrinsic/associated enzymatic activities, chromatin modification, and correlation with coactivation function; (3) characterize the role of PELP1 in cell proliferation by using cell lines expressing PELP1 under an inducible promoter, and studying the role of overexpression on the growth-rate, cell cycle progression and (4) characterize the role of PELP1 in tumorigenesis. The proposed studies will allow us to understand the functions of newly cloned PELP1, its role in ER signaling and provide a molecular explanation for the widely recognized differential responses of estrogen and antiestrogens. This proposal is novel because of the presence of unique structural motifs with diverse cellular functions in PELP1 and the fact that it is upregulated in breast tumors.

描述（由申请人提供）：乳腺癌是女性中最主要的癌症类型。类固醇激素 17 β-雌二醇 (E2) 在控制涉及多种生物过程（包括发育、体内平衡和乳腺肿瘤进展）的基因表达方面发挥着重要作用。雌激素的生物学效应是通过其与雌激素受体（ER）的结合介导的。大约 70% 的乳腺癌细胞表达 ER。许多最初对抗雌激素有反应的 ER 阳性肿瘤后来获得耐药性并表现出混合/激动剂反应。最近的证据表明，雌激素和/或抗雌激素在给定细胞或肿瘤中的相关作用取决于调节 ER 活性的不同共激活剂或辅阻抑剂的浓度。尽管取得了这些进展，我们对共激活因子（作为 ER 的关键调节因子）和 ER 信号传导之间的直接因果关系及其对乳腺癌病理学影响的了解仍然知之甚少。该提案旨在利用新型体外和体内乳腺上皮模型系统确定新发现的共激活因子（PELP1，见下文）在乳腺癌分子进展中的作用。 最近，我克隆了一种新型 ER α 调节蛋白，即富含脯氨酸、谷氨酸和亮氨酸的蛋白 (PELP1)，它在乳腺中大量表达。 PELP1 是新颖的，因为它与现有的共激活因子没有同源性，其表达在乳腺中受到发育调节并上调 ERα 驱动的转录。此外，PELP1 与视网膜母细胞瘤蛋白相互作用并促进其过度磷酸化。此外，与相邻的配对正常乳腺组织相比，PELP1 在人类乳腺肿瘤中可能过度表达。我的工作假设是 PELP1 表达和功能的上调可能赋予乳腺上皮细胞生长优势，并通过过度刺激 ER 通路导致恶性进展。 该提案的总体目标是（1）通过结构域分析和创建显性失活突变体来表征介导 PELP1 调节 ER 通路的分子事件； (2) 通过研究 PELP1 的核功能，包括内在/相关酶活性、染色质修饰以及与共激活功能的相关性，表征 PELP1 作用的分子机制； (3) 通过使用在诱导型启动子下表达 PELP1 的细胞系来表征 PELP1 在细胞增殖中的作用，并研究过表达对生长速率、细胞周期进程的作用；(4) 表征 PELP1 在肿瘤发生中的作用。拟议的研究将使我们能够了解新克隆的 PELP1 的功能及其在 ER 信号传导中的作用，并为广泛认可的雌激素和抗雌激素的差异反应提供分子解释。这一提议是新颖的，因为 PELP1 中存在具有多种细胞功能的独特结构基序，并且它在乳腺肿瘤中表达上调。