ESTROGEN-MEDIATED CELL CYCLE ARREST VIA P53 AND P21

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 卵巢表面上皮(OSE)是女性卵巢癌的主要来源，但人们对其正常生物学和高转移率的基础知之甚少。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会使OSE处于转化的风险中。我们开发了一个培养系统来研究卵巢因子--尤其是与生殖有关的类固醇和蛋白质激素--对体外培养的人和非人灵长类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。我们证明了这些浓度在人卵巢癌细胞以及正常人和恒河猴卵巢癌细胞中诱导细胞周期停滞。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所介导的，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，通过检测P53的激活，抑制P53的功能，以及将野生型ER、P53和/或显性阴性P53导入正常或缺陷细胞，来确定这些蛋白在介导雌激素依赖的周期停滞中的作用。雌激素受体的这一新功能可能对理解基于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.