GONAD-SPECIFIC TRANSCRIPTION FACTORS

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。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 受调控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标志。 因此，不同的信号传导途径已经发展到仔细地协调多细胞生物体中多种细胞类型的及时增殖。 在哺乳动物的卵巢中，体细胞卵泡颗粒细胞在正常的卵子发生过程中包围并滋养发育中的卵母细胞。 TAF 4 b是多蛋白TFIID复合物的性腺特异性组分，其是一种通用RNA聚合酶II转录因子。 TAF 4 b基因敲除小鼠的产生揭示了TAF 4 b在正常颗粒细胞增殖所需的基因表达的及时调节中的特定作用。 基于这些数据，我们假设卵巢中TAF 4 b的过度表达将导致异常的基因表达模式，导致颗粒细胞过度增殖。 为了验证这一假设，我们建议在培养的小鼠颗粒细胞中观察TAF 4 b过表达对基因表达和增殖的影响。 我们还将通过产生在卵巢中表达外源TAF 4 b蛋白的转基因小鼠来测试体内过表达TAF 4 b的影响。 卵巢组织学结合转基因卵巢的增殖测定将用于检查TAF 4 b过表达是否导致卵巢中的颗粒层肿瘤形成。 总之，这些研究将在体外和体内比较TAF 4 b依赖性表达模式，并将产生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TAF 4 b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。 这些卵巢癌患者中大约有5%到10%患有卵巢颗粒细胞源性肿瘤。 对TAF 4 b调节的颗粒细胞基本生长控制的研究可能会产生颗粒细胞源性卵巢癌中失调的重要遗传途径。 这些研究产生的转基因小鼠也可能产生新的颗粒层肿瘤形成的小鼠模型。 这种动物模型可能最终产生有用的工具，在诊断或治疗这种毁灭性疾病的治疗。

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.