This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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