ESTROGEN-MEDIATED CELL CYCLE ARREST VIA P53 AND P21

通过 P53 和 P21 雌激素介导的细胞周期停滞

• 批准号: 7715991
• 负责人: Jay W Wright
• 金额: $ 2.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715991
• 关键词: Biological Assay; Biology; CDKN1A gene; Cell Cycle Arrest; Cells; Computer Retrieval of Information on Scientific Projects Database; Data; Dominant-Negative Mutation; Environment; Epithelium; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Failure; Funding; Grant; Hormones; Human; In Vitro; Incidence; Institution; Macaca mulatta; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Menstrual cycle; Nature; Numbers; Ovarian; Ovulation; Proteins; Rate; Reproduction; Research; Research Personnel; Resources; Risk; Role; Source; Steroids; Surface; System; TP53 gene; Therapeutic; United States National Institutes of Health; Woman; base; cancer cell; experience; nonhuman primate; novel; oncoprotein p21; research study; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ovarian surface epithelium (OSE) is the primary source of ovarian cancers in women, yet little is known about its normal biology or the basis of its high rate of transformation. Because the incidence of ovarian cancer correlates highly with the number of ovulations a woman experiences, it is possible that ovarian function itself places the OSE at risk for transformation. We developed a culture system to study the effects of ovarian factors - most notably steroid and protein hormones associated with reproduction - on human and nonhuman primate OSE cells grown in vitro. During the natural menstrual cycle, estrogen levels peak at micromolar concentrations in the local ovarian environment. We demonstrated that these concentrations induce cell cycle arrest in human ovarian cancer cells and normal human and rhesus OSE cells. Current data suggest this arrest is mediated by functional interactions between the estrogen receptor alpha (ER), p53 and p21, but the nature of these interactions is unknown. We therefore proposed a set of experiments to define the roles of these proteins in mediating estrogen-dependent cycle arrest, by assaying p53 activation, inhibiting p53 function, and transfecting normal or deficient cells with wild type ER, p53, and/or dominant negative p53. This novel function of the estrogen receptor may be important in understanding the mechanisms of hormone-based cancer therapeutic success and failure.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 卵巢表面上皮（OSE）是女性卵巢癌的主要来源，但对其正常生物学或其高转化率的基础知之甚少。 由于卵巢癌的发病率与女性的排卵次数高度相关，因此卵巢功能本身可能使 OSE 面临转化风险。 我们开发了一种培养系统来研究卵巢因素（最显着的是与生殖相关的类固醇和蛋白质激素）对体外生长的人类和非人灵长类 OSE 细胞的影响。 在自然月经周期中，局部卵巢环境中雌激素水平达到微摩尔浓度的峰值。 我们证明这些浓度可诱导人卵巢癌细胞以及正常人和恒河猴 OSE 细胞的细胞周期停滞。 目前的数据表明，这种停滞是由雌激素受体 α (ER)、p53 和 p21 之间的功能相互作用介导的，但这些相互作用的性质尚不清楚。 因此，我们提出了一系列实验来确定这些蛋白质在介导雌激素依赖性周期停滞中的作用，通过测定p53激活、抑制p53功能以及用野生型ER、p53和/或显性失活p53转染正常或缺陷细胞。 雌激素受体的这种新功能对于理解基于激素的癌症治疗成功和失败的机制可能很重要。