GONAD-SPECIFIC TRANSCRIPTION FACTORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。受调节的基因表达途径的破坏导致细胞增殖控制的丧失是人类癌细胞的一个标志。因此，在多细胞生物中，不同的信号通路已经进化到精心协调多种细胞类型的及时增殖。在哺乳动物卵巢中，卵泡颗粒细胞包围并滋养发育中的卵母细胞。TAF4b是多蛋白TFIID复合物的性腺特异性组分，TFIID复合物是一种通用的RNA聚合酶II转录因子。TAF4b缺失小鼠的产生揭示了TAF4b在及时调节正常颗粒细胞增殖所需的基因表达中的特定作用。基于这些数据，我们假设TAF4b在卵巢中的过度表达会导致基因表达模式异常，导致颗粒细胞过度增殖。为了验证这一假设，我们建议观察TAF4b过表达对培养小鼠颗粒细胞基因表达和增殖的影响。我们还将通过生产在卵巢中表达外源性TAF4b蛋白的转基因小鼠来测试体内过表达TAF4b的影响。我们将利用卵巢组织学结合转基因卵巢的增殖试验来检验TAF4b过表达是否导致卵巢颗粒性肿瘤的形成。总之，这些研究将比较体外和体内taf4b依赖的表达模式，并将得出正常细胞增殖所需的基因表达的基本机制。更重要的是，这些研究将是了解TAF4b水平升高是否与女性卵巢癌相关的第一步。卵巢癌是美国女性癌症死亡的第五大原因。大约5%到10%的卵巢癌患者患有卵巢颗粒源性肿瘤。通过对TAF4b调控的颗粒细胞的基本生长控制的研究，可能会发现在颗粒源性卵巢癌中失调的重要遗传途径。为这些研究而产生的转基因小鼠也可能产生颗粒瘤形成的新小鼠模型。这样的动物模型可能最终产生诊断或治疗这种毁灭性疾病的有用工具。

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. Disruption of regulated gene expression pathways leading to the loss of cell proliferation control is a hallmark of human cancer cells. Accordingly, diverse signaling pathways have evolved to carefully orchestrate the timely proliferation of multiple cell types in multi-cellular organisms. In the mammalian ovary, somatic folli-cle granulosa cells surround and nurture the developing oocyte during normal oognesis. TAF4b is a gonadal-specific component of the multi-protein TFIID complex that is a general RNA polymerase II transcription fac-tor. The production of TAF4b-null mice has uncovered a specific role for TAF4b in the timely regulation of gene expression required for normal granulosa cell proliferation. Based on these data, we hypothesize that over-expression of TAF4b in the ovary will cause aberrant gene expression patterns that lead to over-proliferation of granulosa cells. To test this hypothesis, we propose to look at the effects of over-expression of TAF4b on gene expression and proliferation in cultured mouse granulosa cells. We also will test the effects of over-expressing TAF4b in vivo by producing transgenic mice that express exogenous TAF4b protein in the ovary. Ovarian histology combined with proliferation assays of transgenic ovaries will be used to examine whether TAF4b over-expression leads to granulosa tumor formation in the ovary. Together, these studies will compare TAF4b-dependent expression patterns in vitro and in vivo and will yield fundamental mechanism of gene expression required for normal cellular proliferation. More importantly, these studies will be the first steps towards the understanding whether elevated TAF4b levels may be associated with ovarian cancer in women. Ovarian cancer is the fifth leading cause of cancer deaths among women in the United States. Ap-proximately five to ten percent of these ovarian cancer patients suffer from granulosa-derived tumors of the ovary. The study of fundamental growth control of granulosa cells regulated by TAF4b may yield important genetic pathways that are dysregualated in granulosa-derived ovarian cancer. The transgenic mice produced for these studies may also yield new mouse models of granulosa tumor formation. Such animal models may ultimately yield useful tools in the diagnostic or therapeutic treatment of this devastating disease.