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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 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经历的排卵数量高度相关，因此卵巢功能本身可能使OSE面临转变的风险。 我们开发了一种培养系统，以研究卵巢因子的影响 - 最著名的类固醇和蛋白质激素对人类和非人类的灵长类动物OSE细胞在体外生长。 在自然的月经周期中，雌激素水平在当地卵巢环境中的微摩尔浓度下达到峰值。 我们证明，这些浓度会诱导人卵巢癌细胞以及正常的人类和恒河类细胞中的细胞周期停滞。 当前的数据表明，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，但是这些相互作用的性质尚不清楚。 因此，我们提出了一组实验，以定义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，并用野生型ER，p53和/或主动p53转染正常或缺陷的细胞。 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衰竭的机制可能很重要。