PELP1, a Novel Regulator of Estrogen Receptor

PELP1，一种新型雌激素受体调节剂

• 批准号: 6933178
• 负责人: Ratna K Vadlamudi
• 金额: $ 9.8万
• 依托单位: LSU HEALTH SCIENCES 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 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933178
• 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）：乳腺癌是女性中主要的癌症类型。甾体激素17 β -雌二醇（E2）在控制基因表达方面发挥重要作用，参与多种生物过程，包括发育、体内平衡和乳腺肿瘤进展。雌激素的生物学效应是通过与雌激素受体（ER）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药物有反应的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/或抗雌激素在特定细胞或肿瘤中的相关作用取决于调节内质网活性的不同共激活因子或共抑制因子的浓度。尽管有了这些进展，我们对共激活因子（作为内质网的关键调节因子）和内质网信号传导之间的直接因果关系及其对乳腺癌病理生物学的影响的理解仍然很少。本研究旨在利用新的体外和体内乳腺上皮模型系统，确定一种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，我克隆了一个新的ER α调节蛋白脯氨酸谷氨酸和亮氨酸富蛋白（PELP1），它在乳腺中大量表达。PELP1是一种新基因，因为它与现有的共激活因子没有同源性，它的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，与相邻的正常乳腺组织相比，PELP1可能在人乳腺肿瘤中过表达。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，并通过超刺激内质网途径导致恶性进展。本提案的总体目标是：(1)通过结构域分析和创建显性负突变体来表征介导PELP1调控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的分子作用机制；(3)利用在诱导启动子下表达PELP1的细胞系，研究PELP1过表达对细胞生长速率、细胞周期进程的影响，表征PELP1在细胞增殖中的作用；(4)表征PELP1在肿瘤发生中的作用。这些研究将使我们了解新克隆的PELP1的功能及其在内质网信号传导中的作用，并为广泛认可的雌激素和抗雌激素差异反应提供分子解释。这一建议是新颖的，因为PELP1中存在独特的结构基元，具有不同的细胞功能，并且它在乳腺肿瘤中上调。