ESTROGEN-MEDIATED CELL CYCLE ARREST VIA P53 AND P21

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，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经历的排卵次数高度相关，因此卵巢功能本身可能使OSE处于转化的风险中。 我们开发了一种培养系统来研究卵巢因素-最显著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类灵长类OSE细胞的影响。 在自然月经周期中，雌激素水平在局部卵巢环境中达到微摩尔浓度的峰值。 我们证明，这些浓度诱导人卵巢癌细胞和正常人和恒河猴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是未知的。 因此，我们提出了一组实验，以确定这些蛋白质在介导雌激素依赖性周期阻滞中的作用，通过测定p53激活，抑制p53功能，并用野生型ER，p53和/或显性阴性p53抑制正常或缺陷细胞。 雌激素受体的这种新功能可能对理解基于雌激素的癌症治疗成功和失败的机制很重要。

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.